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Advances in Therapeutics and Diagnostics

Bisphosphonates

Julie T. Lin, MD, and Joseph M. Lane, MD

Bone resorption and formation are normally linked and therefore maintain bone strength. When the metabolic linkage is altered, bone structural and material proper- ties decline. Postmenopausal and glucocorticoid- induced osteoporosis, Paget’s disease of bone, and fibrous dysplasia are some of the conditions in which there is high-turnover bone resorption, leading to bone with impaired structure susceptible to fracture. Low bone mineral density (BMD) occurs when the rate of resorption exceeds that of formation. High-turnover states ensue with disproportionately increased osteo- clastic activity, resulting in increased resorption. Bisphosphonates interfere with osteoclast activity and thus decrease the rate of bone resorption. Similarly, metastatic disease of bone, especially the lytic phase, appears to be mediated by both osteoclastic resorption and other mechanisms. The use of bisphosphonates has dramatically changed the clinical course of some patients with cancer by decreasing the morbidity of skeletal involvement.

Structure and Mechanism of Action

Bisphosphonates are pyrophosphate analogues in which the oxygen in P–O–P has been replaced by a car- bon, resulting in a metabolically stable P–C–P structure resistant to enzymatic destruction. Bisphosphonates have two side chains: R1 affects binding affinity to bone; R2 affects antiresorptive capacity and, possibly, side-effect profile. Bisphosphonates vary in potency based on these specific side chains (Fig. 1). Etidronate is a non–nitrogen-containing bisphosphonate with a simple alkyl side chain, whereas pamidronate and alendronate contain basic aminoalkyl groups. Risedronate and zolendronate contain heteroaromatic rings with nitrogen- containing side chains. Tiludronate is a sulfur-containing bisphosphonate. First-generation bisphosphonates, such as etidronate and clodronate, inhibit bone formation and bone resorp- tion equally. With each successive generation, there has been increased potency, with more selectivity for inhibi- tion of resorption and less inhibition of bone formation. Second-generation bisphosphonates include pamid- ronate and alendronate; the third generation includes the highly potent risedronate and zolendronate.

Bisphosphonates have a particular affinity for areas of increased bone turnover, such as in metastatic bony lesions and Paget’s disease. They primarily work by inhibiting osteoclast function using two main mecha- nisms. First, bisphosphonates have a high affinity for hydroxyapatite of bone, binding to it irreversibly and therefore inhibiting osteoclast-resorbing surface. Second, absorbed bisphosphonates inhibit osteoclast function by interfering with their critical biologic path- ways. Short-chain bisphosphonates such as clodronate inhibit the Krebs cycle; long-chain bisphosphonates such as alendronate inhibit the fatty chain pathway and the ability to form biologic membranes. Bis- phosphonates also exhibit apoptotic effects on osteo- clasts.

Pharmacokinetics

Oral bisphosphonates have a very low bioavailability and poor gastrointestinal absorption rates (from <0.7% for alendronate and risedronate to 6% for etidronate and tiludronate). Oral absorption can be diminished even further in the presence of mineral water, other liq- uids, or food in the stomach. Absorbed bisphosphonate remains mainly in the skeleton for prolonged periods (half-lives of 1.5 to 10 years), whereas nonincorporated bisphosphonate is excreted in the urine within two passes through the kidney.

Dr. Lin is Fellow, Rehabilitation Medicine and Metabolic Bone Disease, Hospital for Special Surgery, New York, NY. Dr. Lane is Chief, Metabolic Bone Disease Service, and Medical Director, Osteoporosis Prevention Center, Hospital for Special Surgery, New York.

One or more of the authors or the departments with which they are affili- ated has received something of value from a commercial or other party related directly or indirectly to the subject of this article.

Reprint requests: Dr. Lane, 535 East 70th Street, New York, NY 10021.

Copyright 2003 by the American Academy of Orthopaedic Surgeons.

J Am Acad Orthop Surg 2003;11:1-4

Bisphosphonates

H PO 3 H 2 CH 2 PO 3 H 2 OH Etidronate
H
PO 3 H 2
CH 2
PO 3 H 2
OH
Etidronate
H N PO 3 H 2 (CH 2 ) 2 PO 3 H 2 OH H
H
N
PO 3 H 2
(CH 2 ) 2
PO 3 H 2
OH
H
Pamidronate
H N H PO 3 H 2 (CH 2 ) 3 OH PO 3 H 2
H
N
H
PO 3 H 2
(CH 2 ) 3 OH
PO 3 H 2
Alendronate
PO 3 H 2 CH 2 OH N
PO 3 H 2
CH 2
OH
N

PO 3 H 2

Risedronate
Risedronate
PO 3 H 2 OH PO 3 H 2 CH 2 N N
PO 3 H 2
OH
PO 3 H 2
CH 2
N
N
Zolendronate
Zolendronate

Figure 1

Structural formulas of five bisphosphonates.

 

Indications for Use

Indications for bisphosphonates include such conditions as postmenopausal and glucocorticoid-induced osteo- porosis, Paget’s disease, osteolytic and osteoblastic bone metastases, and other orthopaedic problems, such as fibrous dysplasia, heterotopic ossification, and myositis ossificans. Off-label uses are supported by results of controlled clinical trials. Many bisphosphonates have been shown to be effica- cious in the management of postmenopausal and gluco- corticoid-induced osteoporosis. Currently, however, only oral alendronate and risedronate are approved for both the prevention and treatment of osteoporosis. Oral bisphosphonates reduce the risk of hip fracture by as much as 50%. Because of the incidence of gastrointesti- nal symptoms with oral bisphosphonates, treatment with intravenous pamidronate and zolendronate may be indicated for patients unable to tolerate even weekly dosages of oral alendronate and risedronate. Alendronate has been proved to be effective in post- menopausal osteoporosis. In 2,027 women with preexist- ing vertebral fractures, alendronate 5 mg daily for 24 months, then increased to 10 mg, resulted in fewer radio- graphic vertebral fractures in the treatment group. 1 Risk of clinical fracture was 13.6% in the alendronate group versus 18.2% in the placebo group. There was an average increase in lumbar spine BMD of about 5% after 1 year, then 1.5% per year for the next 2 years. At the end of 3 years, there was an increase in BMD of about 6% in the femoral neck and about 7% in the trochanter. In the Fracture Intervention Trial, 2 3,658 osteoporotic women with either vertebral fracture or osteoporosis at the femoral neck were treated with alendronate for 3 to 4 years. There was decreased risk of fracture in the treated women, with relative risks of 0.47 for hip fracture , 0.52 for radiographic vertebral fracture, 0.55 for clinical vertebral fracture, and 0.70 for all clinical fractures. Alendronate has marked efficacy for men and for individuals on steroids. A single weekly dose is as clinically effective as daily dosage but with lower incidences of dyspepsia, esophagitis, and gastroesophageal reflux disease (GERD). Risedronate also is effective in increasing BMD and reducing fracture risk. An oral daily dose of risedronate

(5 mg) resulted in BMD increases after 6 months of ther- apy, and at 24 months, lumbar spine BMD increased from baseline by 4%, with increases of 1.3% and 2.7% in the femoral neck and femoral trochanter, respectively. 3 In 2,458 postmenopausal women, those receiving oral risedronate 5 mg daily increased BMD by 3% to 4% in the femoral neck, femoral trochanter, and lumbar spine at 3 years. 4 Risk of new vertebral and nonvertebral frac- tures also decreased. A single weekly oral dose of 35 mg is as effective as a daily dosage. Risedronate dimin- ishes the hip fracture rate by 50%. Parenteral pamidronate also has been successfully used in the treatment of osteoporotic postmenopausal women intolerant to oral bisphosphonates. In 36 patients, five courses of cyclical intravenous pamid- ronate was effective in reducing bone turnover. 5 Thirteen patients who received 30 mg of pamidronate intravenously over 3 months had an increased BMD of 6.2% in the lumbar spine and 4.7% in the hip. 6 To date, no fracture rate data have been reported for pamid- ronate. Parenteral zolendronate administered at annual inter- vals produced effects on bone turnover and BMD com- parable to those seen with oral bisphosphonates in the treatment of postmenopausal osteoporosis. In one trial, increases in the treatment group were 4.3% to 5.1% high- er for the spine than in the placebo group (P < 0.001), with suppressed biochemical markers of bone formation. 7 No fracture prevention data for zolen- dronate are currently available. Etidronate, alendronate, risedronate, and tiludronate are all efficacious in the management of Paget’s disease. A 400-mg daily dose of etidronate for 6 months, a 40-mg daily course of oral alendronate for 6 months, a 30-mg daily dose of risedronate for 2 months, or a 400-mg daily dose of tiludronate for 3 months controls Paget’s disease. 8 In addition, several intravenous infusions of pamidronate are effective. Bisphosphonates can affect patients with bony metastatic disease in a number of ways. They control hypercalcemia, reduce bone pain, delay skeletally related events (SREs), reduce the number of pathologic frac- tures, and, in some cases, prolong survival. Initially, oral clodronate and, subsequently, intravenous pamidronate

Julie T. Lin, MD, and Joseph M. Lane, MD

have been shown to reduce the number of vertebral frac- tures in patients with myeloma. 9 In a pooled group of 1,962 women with advanced breast cancer, administra- tion of pamidronate 90 mg reduced the rate of SREs by a mean of 30%. 10 All studies showed a delay in the median time to SREs. Zolendronate has been shown to be as effective as pamidronate and should be combined with either chemotherapy or hormonal therapy in women with metastatic bone disease. Zolendronate 4 mg in a 15-minute infusion has been utilized in hormone refrac- tory prostate cancer metastatic to bone. Results showed a statistically significant advantage over placebo in delaying the first SRE (P = 0.011), a reduced proportion of patients having SREs (P = 0.021), and decreased overall skeletal morbidity (P = 0.006). 11 Zolendronate is the first bisphosphonate shown to be effective in both lytic and blastic metastatic disease. Pamidronate decreases fractures in osteogenesis imperfecta, controls Paget’s disease, and reverses the bone changes of fibrous dysplasia. Alendronate has been used off-label for fibrous dysplasia. 12 Further- more, oral and intravenous etidronate may be helpful in treating fibrous dysplasia. Bisphosphonates work by inhibiting the bone mineralization of ectopic bone matrix that can occur in acute episodes.

Drug Interactions and Adverse Effects

Bisphosphonates generally should not be taken with antacids that contain aluminum or magnesium, bottled water containing minerals, or calcium supplements because these agents decrease bisphosphonate absorp- tion. In addition, food renders bisphosphonates ineffec- tive; a 2-hour interval between meals and the adminis- tration of a dose is recommended. Aminoglycosides taken with bisphosphonates may cause severe hypocal- cemia. Adverse effects from oral bisphosphonates include gastrointestinal complications such as gastritis or esophagitis, abdominal pain, nausea, vomiting, diarrhea, and constipation. To minimize gastrointestinal inflam- mation and ulcer, patients should remain upright (sitting or standing) for at least 30 minutes after taking the med- ication. In patients with a questionable history of GERD, incremental dosage increases are advisable. For exam- ple, one dose (alendronate 70 mg) can be given the first month, then every 2 weeks, then weekly while monitor- ing for evidence of intolerance. Tolerance is generally improved with once-weekly rather than daily dosing. Electrolyte disturbances such as hypocalcemia and hypophosphatemia may occur. Renal impairment may result, and bisphosphonates should be used sparingly in patients with renal insufficiency. Etidronate impairs

mineralization of newly formed bone and may result in osteomalacia and fracture if taken in large doses. Less common reported side effects include hallucinations, taste disorders, pseudomembranous colitis, iritis, arthralgia, pericarditis, hepatotoxicity, and scleritis. Overdosage of bisphosphonates may result in hypocal- cemia. Intravenous pamidronate and zolendronate may cause bone pain, fever, and malaise. Bone pain may be more likely to occur when intravenous infusions of these bisphosphonates are taken without calcium. Influenza- like symptoms may be particularly associated with intra- venous bisphosphonates but may be managed with diphenhydramine and acetaminophen before infusion. Furthermore, adverse side effects may be minimized with increased infusion time and volume. Bisphosphonates are contraindicated in patients with hypocalcemia or severe renal impairment (creatinine clearance <30 mL/min) and in those who cannot remain upright for at least 30 minutes. In addition, bisphospho- nates should generally be avoided in those with sympto- matic GERD, gastrointestinal bleeding, Crohn’s disease, or malabsorption syndromes; in women of childbearing age; and in patients who have been receiving bisphos- phonate therapy for 7 years. Studies have shown that alendronate used for 7 years in postmenopausal osteo- porosis was well tolerated and effective. While no stud- ies link bisphosphonates to birth defects in humans, ani- mal studies have linked bisphosphonates with fetal abnormalities. The effect of bisphosphonates in delaying fracture healing has been raised. 13 Peter et al 14 showed no delay in fracture repair and mechanical restoration but did show retardation of callus remodeling.

Dosage and Cost

Bisphosphonates are available for both oral and intra- venous administration. Dosages and costs are dependent on the condition being treated and length of therapy (Table 1).

Summary

Bisphosphonates are powerful antiresorptive agents appropriate for use in patients with many metabolic bone disease states. They are effective in enhancing bone density in patients with structurally flawed bone and in minimizing morbidity and mortality by prevent- ing fractures. Furthermore, they appear to be cost effi- cient and safe for short-term use in humans. While oral bisphosphonates may increase the risk for gastrointesti- nal complications such as esophagitis, adhering to the

Bisphosphonates

 

Table 1 Dosages of Bisphosphonates and Costs* in Selected Conditions

 

Condition

Etidronate

Alendronate

Risedronate

Pamidronate

Zolendronate

Tiludronate

Osteoporosis

400 mg/d

10 mg/d or

5 mg/d

30 mg q 3 mo

4 mg/yr

N/A

treatment

× 14 d q 3 mo

70 mg/wk

or 35 mg/wk

($1,155.00)

($988.99)

(cost/yr)

($432.88)

($919.08 § )

($871.08 § )

Osteoporosis

N/A

35 mg/wk

N/A

N/A

N/A

prevention

Paget’s disease

400 mg/d

40 mg/d

30 mg/d

90 mg ($866.25),

N/A

400 mg/d

(treatment course)

× 6 mo

× 6 mo

× 2 mo

then 30 mg

× 3 mo

 

($1,391.88)

($1,181.94)

($1,047.98)

q 3 mo ($288.75)

($1,185.97)

 

Bone metastases

N/A

N/A

90 mg q 4 wk

4 mg q 3-4 wk

N/A

Hypercalcemia

7.5 mg/kg/

15 mg

N/A

90 mg PRN

Single 4-mg

N/A

of malignancy

d × 3 d

doses PRN

Fibrous dysplasia

N/A

70 mg/wk ll

N/A

60-90 mg q 2 mo ll

N/A

N/A

* Costs at a large chain discount suburban pharmacy in Stamford, CT, December 2002. Does not include dispensing fee. For postmenopausal women, men, and glucocorticoid-induced. Off-label use in the United States § Once-weekly dose ll Until N-telopeptide plateaus N/A = not applicable

 
 

specific instructions as well as switching to a once-week- ly dose may minimize the risk. Intravenous bisphospho- nates are appropriate in patients with Paget’s disease and metastatic osteolytic bone metastases and are being

used off-label in osteoporotic patients unable to tolerate oral bisphosphonates. Bisphosphonates are the agent of choice for the treatment of osteoporosis and Paget’s dis- ease.

References

  • 1. Black DM, Cummings SR, Karpf DB, et al: Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 1996;348:1535-1541.

  • 2. Black DM, Thompson DE, Bauer DC, et al: Fracture risk reduc- tion with alendronate in women with osteoporosis: The Fracture Intervention Trial. J Clin Endocrinol Metab 2000;85:4118-4124.

  • 3. Fogelman I, Ribot C, Smith R, Ethgen D, Sod E, Reginster J-Y: Risedronate reverses bone loss in postmenopausal women with low bone mass: Results from a multinational, double-blind, placebo-controlled trial. J Clin Endocrinol Metab 2000;85:1895-
    1900.

  • 4. Harris ST, Watts NB, Genant HK, et al: Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: A randomized controlled trial. JAMA 1999;282:1344-1352.

  • 5. Peretz A, Body JJ, Dumon JC, et al: Cyclical pamidronate infu- sions in postmenopausal osteoporosis. Maturitas 1996;25:69-75.

  • 6. Guttmann G, Van Linthoudt D: Efficacy of intravenous pamidronate in osteoporosis, mineralometric evaluation [French]. Schweiz Rundsch Med Prax 1999;88:2057-2060.

  • 7. Reid IR, Brown JP, Burckhardt P, et al: Intravenous zoledronic

acid in postmenopausal women with low bone mineral density. N Engl J Med 2002;346:653-661.

  • 8. Fraser WD, Stamp TC, Creek RA, Sawyer JP, Picot C: A double- blind, multicentre, placebo-controlled study of tiludronate in Paget’s disease of bone. Postgrad Med J 1997;73:496-502.

  • 9. Berenson JR, Hillner BE, Kyle RA, et al: American Society of Clinical Oncology clinical practice guidelines: The role of bisphos- phonates in multiple myeloma. J Clin Oncol 2002;20:3719-3736.

  • 10. Pavlakis N, Stockler M: Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2002;1:CD003474.

  • 11. Lipton A, Small E, Saad F, et al: The new bisphosphonate, Zometa (zoledronic acid), decreases skeletal complications in both osteolytic and osteoblastic lesions: A comparison to pamidronate. Cancer Invest 2002;20(suppl 2):45-54.

  • 12. Lane JM, Khan SN, O’Connor WJ, et al: Bisphosphonate therapy in fibrous dysplasia. Clin Orthop 2001;382:6-12.

  • 13. Fleisch H: Can bisphosphonates be given to patients with fractures? J Bone Miner Res 2001;16:437-440.

  • 14. Peter CP, Cook WO, Nunamaker DM, Provost MT, Seedor JG, Rodan GA: Effect of alendronate on fracture healing and bone remodeling in dogs. J Orthop Res 1996;14:74-79.

“10” As the Journal of the American Academy of Orthopaedic Surgeons enters its second decade of

“10”

As the Journal of the American Academy of Orthopaedic Surgeons enters its second decade of publication with volume 11, issue 1, I would like to spend a moment reflecting on the achievements of the last decade and the potential for progress during the next. JAAOS grew out of the foresight of the Board of Directors of the Academy, who saw a need for another means of provid- ing educational material to orthopaedic surgeons and those interested in the care of musculoskeletal condi- tions. The developments in orthopaedic surgery as well as the breadth and volume of written material had expanded exponentially. This made it very difficult to be able to read all of the new material on any given topic, let alone in the entire field of orthopaedic surgery. The authors of articles in JAAOS were therefore directed to evaluate the primary source material available on a topic and construct a review that selected the most cred- ible material and emphasized the important concepts. With appropriate selection of the breadth of the topic, this approach allowed the readers, within a succinct 10- page review, to update their knowledge, understand the limitations of the primary source material, and, if de- sired, pursue a point of interest in an article from the list of references. Since the initial issue of JAAOS in 1993, both the field of musculoskeletal care and the way we learn about new developments have continued to evolve rapidly. The editorial board has reacted to changes in both areas to continue to make JAAOS relevant for the readership. New formats have made the Journal more accessible to all of its readers, no matter their preference. In 1997, the CD-ROM version was developed and has been updated annually so that readers can have all of the material available on any computer. The advent of the JAAOS website allowed immediate access to even the most cur- rent issue. It now provides enhanced search capabilities and abstracts of the articles in seven languages. The PDA version is being introduced this year at the Annual Meeting of the American Academy of Orthopaedic Surgeons in New Orleans. Subscribers will be able to download single articles or entire issues of JAAOS to view on their handheld devices. The approach to the editorial content also has changed, with new types of review articles that cover the expanding realm of information on musculoskeletal conditions. Perspectives on Modern Orthopaedics deals with innovations in treatment or diagnosis about which the material defining the effectiveness is often prelimi- nary or incomplete, and thus not suitable for a full-

length submission. The series of articles developed in conjunction with the Orthopaedic Research Society gives a glimpse of possibilities for the future, defining how the research advances of today may translate into improved treatment tomorrow. Advances in Thera- peutics and Diagnostics provides the clinician with a brief summary of how certain pharmaceuticals or diag- nostic modalities are useful specifically in the evalua- tion or treatment of musculoskeletal problems. “10” is also a digital representation of data: zeroes and ones. The newest section added to JAAOS, which appears in this issue, is Web and Wireless Review. The initial topic is websites that deal with software for the electronic medical office. In each subsequent issue, this section will review a specific type of website, a utility for your computer or PDA, an online textbook, or other applications relevant to the orthopaedic surgeon. Web addresses for each site discussed will be included, and direct links will be available in the article on the JAAOS website at www.jaaos.org. For those who are comfort- able with these applications, we hope the columns by our knowledgeable reviewers will help you assess the quality of a site and its applicability. For those who are less facile, perhaps both the reviews and the easy acces- sibility will introduce you to new options for enhancing your knowledge and practice. We know from our most recent reader survey that use of the JAAOS website has increased markedly in the last 2 years, and we will con- tinue to add features to enhance its value. Finally, we would like to thank so many of you for participating in our latest reader survey. We appreciate both your input as well as the high regard you have for the Journal of the American Academy of Orthopaedic Surgeons as a critical element in your continuing educa- tion. None of this would have been possible without the dedicated staff in the Journal office in Chicago during the last 10 years. Each individual has contributed something unique to the development of JAAOS. The quality of the editorial content is a direct reflection of the efforts of my predecessor, John Frymoyer, MD, the talented associate editors, the many dedicated reviewers, and certainly those of you who have given of your time to write the articles that are the core of the success of JAAOS. You all truly rate a “10,” and with your continued support, the next decade of JAAOS will be similarly successful.

Alan M. Levine, MD Editor-in-Chief

Rheumatoid Arthritis of the Shoulder Andrew L. Chen, MD, MS, Thomas N. Joseph, MD, and Joseph

Rheumatoid Arthritis of the Shoulder

Andrew L. Chen, MD, MS, Thomas N. Joseph, MD, and Joseph D. Zuckerman, MD

Abstract

Rheumatoid arthritis affecting the shoulder region is a progressive disorder that results in pain, loss of range of motion, and functional disability. The inflammatory response, which is of unknown etiology, results in synovitis, pannus formation, and articular destruction. Even when patient history and physical examination suggest rheumatoid involvement of the shoulder, labora- tory assessment and radiographic evaluation often are necessary to establish the diagnosis. Nonsurgical management is the primary treatment, including pharmacologic and physical therapy regimens for patients with mild symp- toms and functional disability. Surgical intervention is indicated in patients with significant pain and functional limitation when nonsurgical treatment fails to provide relief. The procedure selected depends on careful assessment of the degree of articular cartilage injury and compromise of the periarticular soft tissues.

J Am Acad Orthop Surg 2003;11:12-24

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder of unclear etiology characterized by an erosive, symmetrical polyarthritis that may lead to progressive disabil- ity. The estimated prevalence is 1% worldwide, with a female-to-male ratio of 3:1 that diminishes with age. The prevalence increases starting in the third decade of life; RA affects more than 5% of the population older than 70 years. Approximately 91% of patients with long-standing RA (>5 years’ duration) develop shoulder symptoms. 1,2 Rheumatoid disease causes a microvascular injury and mild syn- ovial cell proliferation, with perivas- cular lymphocytosis. The continued inflammation results in the forma- tion of an erosive, hyperplastic syn- ovium (pannus) as well as joint swelling (Fig. 1). Immune complex deposition and complement activa- tion on the articular surfaces pro- duce degradation of proteoglycans

and collagen. The release of inflam- matory cytokines results in contin- ued cartilage damage, bone erosion, and soft-tissue degradation, often involving the insertion of the rotator cuff. In addition, through poorly understood mechanisms, chondro- cytes themselves may play a role in articular destruction through possi- ble participation in proteolytic digestion of cartilage matrix. 3,4

Clinical Course

The initial presentation of RA is highly variable; however, more than 90% of patients report generalized symptoms of fatigue, musculoskele- tal pain, variable fever, and weight loss. 1,2 Some may present with joint pain alone, which may be monoar- ticular or polyarticular without sys- temic findings. Early involvement typically affects the small joints of the hand and foot. The knee, ankle,

wrist, and elbow usually are in- volved later. Particularly in the early phases of the disease, the clini- cal course may be characterized by quiescence during periods of remis- sion. Rheumatoid involvement of the shoulder may present with an in- sidious onset of pain, swelling, and progressive loss of motion, reflect- ing both articular and periarticular involvement. Patients often are unaware of the early loss of motion, perhaps because of their ability to compensate with motion at adjacent joints or with the contralateral ex- tremity. As motion loss progresses, the patient may find it difficult to reach previously accessible objects on high shelves or to perform activi- ties behind the back, such as fasten- ing a brassiere or obtaining objects from a back pocket. RA may affect all of the synovial joints of the shoulder region—the glenohumeral, acromioclavicular, and sternoclavic-

Dr. Chen is Chief Resident, Department of Orthopaedic Surgery, New York University– Hospital for Joint Diseases, New York, NY. Dr. Joseph is Chief Resident, Department of Orthopaedic Surgery, New York University– Hospital for Joint Diseases. Dr. Zuckerman is Professor and Chairman, Department of Ortho- paedic Surgery, New York University–Hospital for Joint Diseases.

Reprint requests: Dr. Zuckerman, 301 East 17th Street, New York, NY 10003.

Copyright 2003 by the American Academy of Orthopaedic Surgeons.

Andrew L. Chen, MD, MS, et al

ab c Figure 1 Low-power photomicrograph of pannus (a) eroding through articular cartilage
ab
c
Figure 1
Low-power photomicrograph of pannus (a) eroding through articular cartilage

(b), with invasion and destruction of subchondral bone (c) (hematoxylin-eosin, original

magnification ×100).

ular joints. The scapulothoracic articulation (not a true synovial joint) may become secondarily affected as the involvement of adja- cent joints progresses. Rheumatoid involvement of the shoulder often is associated with soft-tissue patholo- gy. Seventy-five percent of patients with RA of the shoulder eventually have rotator cuff compromise, with 20% to 35% developing full-thick- ness tears. 5

Evaluation

Physical Examination

Subcutaneous rheumatoid nod- ules may be present over the elbow, forearm, Achilles tendon, or other joints. Rales on inspiration or rubs with chest excursion may indicate pleuritis, pleural effusion, or pericar- dial effusion. Generalized swelling and warmth of the affected joint, with a variably sized effusion, are com- mon findings. Range of motion may be diminished because of swelling

and pain secondary to synovitis and capsular distension. The patient with shoulder in- volvement typically holds the extremity at the side in a protective position. Initially, active motion may be limited by pain while pas- sive motion is unaffected. As the process progresses, both active and passive motion become limited, leading to fixed contractures in all three important planes of motion— forward elevation, external rotation, and internal rotation. Muscle atro- phy occurs as a result of rotator cuff involvement as well as disuse (Fig. 2). With progressive articular and osseous glenohumeral disease, painful crepitus will be evident. The glenohumeral joint is symp- tomatic without associated acromio- clavicular or sternoclavicular in- volvement in two thirds of cases. 1 Painful cross-chest adduction is nonspecific and can indicate either glenohumeral or acromioclavicular disease. Tenderness to palpation of the acromioclavicular or sternocla-

vicular joints suggests involvement, as do warmth and swelling. Subacromial or subdeltoid bursi- tis may occur in the absence of sig- nificant articular destruction and causes local pain and swelling. Bursitis may limit motion but will not cause fixed contractures, as seen with joint involvement.

Laboratory Evaluation

Patients without a history of RA should have a complete work-up for inflammatory or autoimmune etiolo- gies (Table 1). Further testing, including HLA typing or serum pro- tein characterization, generally is unnecessary during the initial stages of evaluation but may be done once the diagnosis of RA has been sug- gested. Sterile aspiration of the gleno- humeral joint may help differentiate RA of the shoulder from other eti- ologies. This is especially important in a patient with an inflamed,

Andrew L. Chen, MD, MS, et al ab c Figure 1 Low-power photomicrograph of pannus (a)

Figure 2 Atrophy of the shoulder girdle musculature, as well as subdeltoid/sub- acromial swelling, are evident in this patient with advanced rheumatoid disease of the shoulder.

Rheumatoid Arthritis of the Shoulder

Table 1 Laboratory Profile of a Patient With Rheumatoid Arthritis

Test

Result

Complete blood cell count

Normocytic, normochromic anemia without leukocytosis

Erythrocyte sedimentation rate

Elevated

Serum immunoglobulins, immune

Elevated

complexes, cryoglobulins Antinuclear antibody titer

Variable

Anti-DNA, anti-ENA (nonhistone nuclear antigens) antibodies

Negative

Serum complement

Negative

Rheumatoid factor

Positive in 75% of patients

ENA = extractable nuclear antigen

warm, tender shoulder in whom septic arthritis must be ruled out, particularly in the presence of a fever (Table 2).

Radiographic Evaluation

The earliest radiographic sign of rheumatoid involvement of the glenohumeral articulation is re- gional osteopenia of the humeral head or glenoid (Fig. 3, A). With disease progression, marginal ero-

sions and cysts become apparent at the inferior margin of the humeral head, with subsequent involvement of the glenoid (Fig. 3, B). Humeral head erosions may be evident ini- tially at the articular margins, at sites of soft-tissue insertion where inflammation is greatest (Fig. 3, C). These erosions may progress to involve large portions of the head, eventually resulting in areas of bone loss or even flattening of the head.

Glenoid erosions can be central or peripheral. Superior migration of the humeral head may occur as a result of involvement of the rotator cuff, with eventual pseudoarticula- tion between the humeral head and the acromion process and erosion of the undersurface of the acromion extending into the acromioclavicu- lar joint 1,6,7 (Fig. 3, D). Although less commonly encountered, extensive destructive arthritis, or arthritis mutilans, can occur. Sclerosis is un- common and usually reflects a later stage after the inflammatory com- ponent has subsided and secondary degenerative arthritis develops. Acromioclavicular involvement is a continuum, from subchondral osteopenia to marginal erosions to extensive osteolysis. Magnetic resonance imaging (MRI) is useful for demonstrating osseous, articular, and soft-tissue changes. Joint effusion, synovial inflammation, pannus formation, and capsular distension can be iden- tified. The extent of rotator cuff involvement may be determined, ranging from inflammation to atten- uation to extensive, full-thickness compromise. MRI is especially use- ful for the evaluation of shoulder

Table 2 Comparison of Synovial Fluid Aspirates

Synovial Fluid

Characteristic

Rheumatoid Arthritis

Osteoarthritis

Septic Arthritis

Volume Color Viscosity Mucin clotting White blood cells

Increased Clear to turbid, yellow-green Low Fair to poor 15,000-20,000/mL, with

Slightly increased Clear, yellow High Normal 0-2,000/mL, with

Increased Turbid to grossly purulent Low Variable >100,000/mL, with

Glucose

60% to 70% neutrophils <25% serum glucose level

<25% neutrophils Equivalent to serum glucose level

>75% neutrophils <50% serum glucose level

Protein

Normal to increased

Normal

Increased

Other

Variable cholesterol crystals, low complement

Gram stain may reveal pathogens

Andrew L. Chen, MD, MS, et al

A B
A
B
Andrew L. Chen, MD, MS, et al A B C D Figure 3 A, Anteroposterior radiograph

C

Andrew L. Chen, MD, MS, et al A B C D Figure 3 A, Anteroposterior radiograph

D

Figure 3 A, Anteroposterior radiograph showing early changes of rheumatoid disease. Osteopenia, with minimal articular degenerative changes, and superior migration of the humeral head consistent with rotator cuff compromise are present. B, Intermediate changes of symmetric glenohumeral joint space loss and early cyst formation. C, As the disease progresses, more extensive erosions are evident about the humeral head and gle- noid; progressive glenoid bone loss results in medialization of the humeral head. The superior migration of the humeral head indicates progressive rotator cuff deterioration. D, Extensive articular destruction, or arthritis mutilans, reflects end-stage changes with extensive erosions and bone loss.

weakness and pain not fully ex- plained by bony changes seen on plain radiography. 8 Computed tomography (CT) may be indicated when preopera- tive analysis of humeral head defects and glenoid articular ero- sions is necessary. Albertsen et al 9 reported agreement between preop- erative CT results and intraopera- tive findings, concluding that CT could characterize osseous defects and bone loss more accurately than can standard radiography (Fig. 4). This is particularly important in evaluating glenoid erosion to deter- mine whether implantation of a gle- noid component is possible.

Differential Diagnosis

Although RA is the most com- mon inflammatory arthritis to affect the shoulder, its variable, nonspecific presentation may re- quire that other conditions be excluded before the diagnosis can be established. Glenohumeral aspi- ration is often helpful (Table 2). Patients with septic arthritis often have high fever and local findings of erythema and swelling. Rotator cuff arthroplasty may be associated with anterosuperior instability and superior humeral migration, often with secondary erosive changes on the inferior aspect of the acromion and the acromioclavicular joint.

Crystalline arthropathies of the shoulder can have presentations similar to that of RA. An insidious onset of mild shoulder discomfort with low-grade inflammation accompanied by blood-tinged syn- ovial fluid replete with debris, hydroxyapatite crystals, and few inflammatory cells (mostly mono- cytes) is indicative of Milwaukee shoulder (calcium hydroxyapatite crystalline arthropathy). Positive staining of crystals with alizarin red S confirms the diagnosis. Both gout (sodium urate crystal deposition) and pseudogout (calcium pyrophos- phate dihydrate crystal deposition) may have articular cartilage calcifi- cations but may be differentiated on synovial fluid examination; calcium pyrophosphate dihydrate deposition has positively birefringent rhom- boid-shaped crystals, while gout has negatively birefringent needle- shaped crystals. 5,10,11 Osteoarthritis is the most com- mon form of glenohumeral arthritis, affecting up to 80% to 85% of women older than 70 years. 12 Osteoarthritis may be secondary to trauma or frac- ture, developmental dysplasia, or old sepsis, or may be a manifestation of “burned out” inflammatory arthri- tis. Its characteristic radiographic presentation shows asymmetric joint space narrowing, subchondral scle- rosis, and osteophytes about the glen- oid and humeral head (Fig. 5).

Classification

The Laine classification of RA of the glenohumeral articulation has three stages based on clinical and radio- graphic findings. 13 In stage I, slight limitation of shoulder motion is pres- ent, with mild to moderate pain and tenderness to palpation. Crepi- tation may be appreciated on range of motion. Radiographs show only generalized osteopenia. Stage II is characterized by moderate limita- tion of shoulder motion, moderate

Rheumatoid Arthritis of the Shoulder

Rheumatoid Arthritis of the Shoulder A B C Figure 4 Axial CT views of the shoulder.

A

Rheumatoid Arthritis of the Shoulder A B C Figure 4 Axial CT views of the shoulder.

B

Rheumatoid Arthritis of the Shoulder A B C Figure 4 Axial CT views of the shoulder.

C

Figure 4 Axial CT views of the shoulder. A, Early involvement, with joint space narrowing (arrows) but maintenance of glenoid mor- phology. B, Later-stage changes showing significant glenoid bone loss and erosion (arrows) into the glenoid neck. C, Advanced changes, with extensive erosion (arrows) of the glenoid and humeral head.

to severe pain, and crepitus. Radio- graphic findings include osteopenia, erosive bony changes, and joint space narrowing. In stage III, severe functional deficits are present; range of motion is painful and limits activ- ities of daily living. Radiographs show advanced erosive changes of the humeral head and glenoid. 13 Neer 14 classified RA of the shoulder into three categories based on clini- cal and radiographic findings; his dry, wet, and resorptive stages are approximately equivalent to those of Laine et al. 13

Nonsurgical Management

Nonsurgical management of the rheumatoid shoulder is indicated for mild to moderate (stage I) dis- ease, when synovial inflammation is the primary manifestation before significant bony changes occur. The emphasis is on optimal use of med- ications (Fig. 6).

Intra-articular Corticosteroid Injection

Intra-articular injection of corti- costeroids for RA of the shoulder has been described for the treat- ment of acute and subacute inflam- matory synovitis. Although the intra-articular administration of

corticosteroids often may result in dramatic symptomatic relief, it should be considered as only a temporizing measure for patients who have not responded to oral medications. Multiple injections can have a deleterious effect on connective tissue structures, in- cluding the articular cartilage and the rotator cuff tendons, and there- fore should be avoided. 1,15 Most physicians suggest limiting injec- tions to three and to consider re- peat injections only when signifi- cant improvement has resulted from the previous injection.

Physical Therapy

Maintenance and/or improve- ment of shoulder motion may be enhanced by physical therapy con- sisting of passive and active-assisted range-of-motion exercises. During periods of active synovitis, motion should be maintained with assisted and passive motion exercises focus- ing on forward elevation, external rotation, and internal rotation be- hind the back. As the synovitis and inflammation improve, stretching can be initiated to improve the over- all range of motion. Isometric exer- cises for the deltoid muscle and rotator cuff can effectively maintain muscle tone and strength during periods of exacerbation. With reso-

lution of the acute episode, therapy can progress to include more rigor- ous strengthening and stretching to regain full range of motion. Ideally, exercises should be performed five times a day in 10-minute sessions rather than in one or two long ses- sions.

Rheumatoid Arthritis of the Shoulder A B C Figure 4 Axial CT views of the shoulder.

Figure 5 Anteroposterior radiograph of an osteoarthritic glenohumeral joint shows subchondral sclerosis, cyst formation, humeral head flattening, and osteophyte formation. This classic appearance is readily distinguishable from the radiographic changes typical of RA (Figure 3).

Andrew L. Chen, MD, MS, et al

Signs and symptoms Pain Erythema Swelling Loss of range of motion
Signs and symptoms
Pain
Erythema
Swelling
Loss of range of motion
Moderate-Severe Mild Minimal or no radiographic changes Mild to severe radiographic changes Failure/ Nonsurgical treatment Surgical
Moderate-Severe
Mild
Minimal or no
radiographic changes
Mild to severe
radiographic changes
Failure/
Nonsurgical treatment
Surgical
progression
Activity modification
Medications
NSAIDs
Disease-modifying drugs
Antimetabolics
Oral corticosteroids
Physical therapy
Intra-articular corticosteroid injection
treatment
Mild to moderate
radiographic changes
Severe
radiographic
Cartilage-preserving
changes
Synovectomy
Débridement
Cartilage-sacrificing
Prosthetic replacement
Symptomatic
Hemiarthroplasty
Total shoulder arthroplasty
improvement
Primary humeral head involvement
Irreparable rotator cuff tear
Inadequate glenoid bone stock for
total shoulder arthroplasty
Humeral and glenoid involvement
Rotator cuff intact or reparable
Adequate glenoid bone stock
Observation
Observation
  • Rehabilitation

Figure 6

Algorithm for treatment of RA of the shoulder.

Surgical Management

Surgical management of the rheu- matoid shoulder is indicated when medications and physical therapy are no longer effective in relieving pain and maintaining function. Selection of procedure is based on a careful assessment of the degree of involvement of the articular car- tilage, subchondral bone, and peri- articular soft tissues. Cartilage-pre- serving procedures are indicated when some articular cartilage re- mains intact and the goal is to pre- vent or slow disease progression by

methods such as synovectomy. Cartilage-sacrificing procedures (eg, hemiarthroplasty, total shoulder arthroplasty, and arthrodesis) are indicated when articular cartilage loss is extensive and beyond preser- vation.

Basic Principles

Staging of Procedures

The polyarticular nature of RA often necessitates multiple surgical

procedures.

Most authors agree

that the most disabling articulation should be addressed first; 16-19 how-

ever, staging also depends on the

nature of the procedures (eg, arthro- scopic or open). Given equal symp- tomatology, opinions vary regard-

ing prioritization of upper versus

lower extremity. When shoulder

surgery is done first, lower extremi-

ty procedures should be delayed at

least 3 months to avoid weight bear-

ing on the recovering shoulder. This period may be extended to

more than 6 months to allow heal-

ing of additional soft-tissue proce-

dures such as rotator cuff repair.

When the lower extremity is ad-

dressed first, shoulder surgery

should be delayed until assistive

ambulatory devices are no longer necessary.

When multiple upper extremity

procedures are necessary, the most symptomatic joint should be ad-

dressed first. In general, prioritiza-

tion should be given to the proce-

dure that results in the greatest func-

tional improvement. Neer et al 17

maintained that hand or wrist involvement should be addressed before ipsilateral elbow or shoulder

disease because functional limita- tions of the hand or wrist may pre- clude rehabilitation of the elbow or

shoulder due to a lack of incentive to

use the involved upper extremity. Friedman and Ewald 18 stated that the elbow should be addressed first; giving priority to surgical management of the elbow yields greater subjective and objective functional improvement of the up- per limb and allows for a longer interval between arthroplasties. Gill et al 19 reported that arthroplas- ty of both the shoulder and elbow for end-stage RA may be done successfully independent of the sequence of joint replacements. With multiple upper extremity in- volvement, technical considerations such as humeral component stem length in shoulder or elbow arthro- plasty also must be taken into ac- count in anticipation of future pro- cedures.

Rheumatoid Arthritis of the Shoulder

Timing

The timing of surgical manage- ment should be dictated by the degree of symptoms and the clini- cal presentation. Early surgical in- tervention with synovectomy or bursectomy may be indicated for patients with only a diminished range of motion or a decreased subacromial space. Surgical inter- vention also may be based on the degree of bone loss rather than just pain and disability because further disease progression could preclude later reconstructive surgery.

Systemic Considerations

The systemic nature of RA re- quires careful multidisciplinary assessment before surgery. The cer- vical spine must be evaluated for stability before endotracheal intuba- tion. Subtle myelopathy secondary to cord compression from C1-C2 instability may be mistaken for dif- fuse joint involvement resulting in weakness. Of particular concern are the possible need for perioperative corticosteroids, the increased risk of infection because of immunosup- pression, and perioperative anemia.

Cartilage-Preserving Procedures

Bursectomy and/or synovectomy is indicated for patients with primar- ily active synovitis without evidence of extensive articular destruction. Although joint débridement may provide symptomatic relief in pa- tients with soft-tissue swelling and evidence of inflammation, it seldom results in a significant increase in range of motion. 20 Synovectomy also may be done in patients with rapidly progressing synovitis in an effort to slow disease progression. However, the results of synovecto- my generally depend on the degree of articular cartilage involvement; the best results are obtained in patients with early (stage I) disease. 1 Synovectomy may be either open or arthroscopic, with successful return to pain-free motion in up to 80% of

patients. 21 Arthroscopic gleno- humeral synovectomy and subacro- mial bursectomy appear to allow early return to function. Acromio- plasty or coracoacromial ligament release is generally not done in patients with RA because doing so could compromise the coracoacro- mial arch and may lead to antero- superior instability, particularly in patients with rotator cuff dys- func tion.

Cartilage-Sacrificing Procedures

When either nonsurgical man- agement or cartilage-preserving procedures fail to provide adequate relief, prosthetic replacement is indicated for patients with unremit- ting or progressive pain and func- tional limitation. Approximately 20% to 35% of patients who require prosthetic replacement have con- comitant rotator cuff tears; these may be addressed at the time of arthroplasty, necessitating a modifi- cation of the postoperative course. Rozing and Brand 22 examined the results of rotator cuff repair at the time of shoulder arthroplasty for RA and concluded that concomitant cuff repair significantly (P = 0.002) improved postoperative clinical shoulder scores compared with patients in whom tears were not repaired. The modular humeral compo- nents are available in a range of stem sizes and humeral heads. The varying stem sizes enable secure fix- ation both with and without cement. Cement fixation is more often used in rheumatoid patients because of the poor bone quality and proximal bone loss. Humeral heads are avail- able in varying neck lengths and diameters, allowing improved soft- tissue balancing that enhances the stability of the implant. Asymmetric humeral heads are used to modify offset as well as to change the orien- tation of the component. These modifications are designed to im- prove soft-tissue balancing and the

stability of the articulation. Famili- arity with the components of the system allows the surgeon to opti- mize fixation, making a stable, func- tional articulation more likely. A range of shoulder implant sys- tems is available. Most use an all- polyethylene glenoid component; metal-backed components are no longer common. The glenoid com- ponent is designed for cement fixa- tion, with a keel or multiple pegs for insertion into the glenoid.

Hemiarthroplasty

Indications for proximal humeral replacement (shoulder hemiarthro- plasty) include extensive humeral head involvement with minimal or no involvement of the glenoid artic- ular surface (uncommon in the rheumatoid shoulder); extensive humeral head and glenoid involve- ment with associated osteopenia and/or bone loss, such that secure fixation of the glenoid component is unattainable; and extensive articular cartilage deterioration in the pres- ence of a massive, irreparable rotator cuff tear. In younger patients (<65 years) who wish to maintain an active lifestyle, concerns about gle- noid component loosening have led some to avoid the use of glenoid components. However, long-term pain relief is less reliable than with glenoid resurfacing, and continued degeneration of the glenoid can result in progressive symptoms. 23,24 The procedure is done with the patient in a beach-chair position, using an anterior deltopectoral approach. During the exposure, soft tissues are handled carefully as they may often be attenuated. The subscapularis tendon and under- lying capsule are divided 1 cm medial to the insertion on the lesser tuberosity. There may be significant contracture of the anterior soft tissues requiring mobilization of the subscapularis tendon and the underlying capsule. This is general- ly done by releasing the adhesions

of the subscapularis at the base of the coracoid and along the anterior glenoid neck. This should allow significant lateral excursion of the subscapularis tendon and muscle, which will enhance postoperative external rotation. In general, a cir- cumferential capsular release around the glenoid margin, freeing the inferior and posterior capsules, will mobilize the rotator cuff, enhancing both intraoperative expo- sure and postoperative mobility. After resection of the humeral head, the glenoid is carefully in- spected to evaluate the integrity of the articular cartilage and the pres- ence and degree of bone loss. Rarely is the articular cartilage of the gle- noid sufficiently intact to obviate the need for resurfacing, particularly when significant humeral head changes are present. Therefore, iso- lateral humeral destruction is not the common indication for hemiarthro- plasty in rheumatoid patients. More often, there is extensive glenoid bone loss, or the remaining bone is of insufficient quality to allow secure fixation of the glenoid com- ponent. When there is significant asymmetric glenoid wear, reaming of the glenoid should be considered to restore the concavity and thereby enhance the stability of the prosthet- ic glenoid articulation. The rotator cuff also should be carefully in- spected: irreparable defects of the supraspinatus, infraspinatus, or teres minor tendons also preclude insertion of a glenoid component. The proximal humeral osteotomy is performed to place the component in 25° to 40° of retroversion. Se- quential reaming of the humeral shaft determines the appropriate component size. The decision to place a cemented or cementless humeral component generally is made intraoperatively. Cementless implantation is acceptable in most cases. However, in patients with ex- tensive rheumatoid involvement of the proximal humerus with large

Andrew L. Chen, MD, MS, et al

cyst formation, cementing often is necessary to achieve rotational and axial stability. A modular implant is preferable because it provides an opportunity to adjust the soft-tissue balancing and enhance stability. Repair of the subscapularis tendon is critical. When the closure is com- plete, the amount of external rota- tion possible without undue tension on the subscapularis repair should be documented to guide the postop- erative rehabilitation program. Hemiarthroplasty results in reli- able pain relief and improvement of function and range of motion, al- though the outcome is not as pre- dictable in patients with RA as in patients with osteoarthritis. 25 This is thought to be the result of poor bone stock and compromised soft tissues. Koorevaar et al 26 examined the out- comes of 19 cases of shoulder hemi- arthroplasty for RA at a mean of 8 years; 64% of patients reported little or no pain, and no patient com- plained of severe pain. Recurrence of symptoms and functional debili- tation because of progressive gle- noid degeneration may necessitate glenoid resurfacing, primarily in patients in whom the indication for hemiarthroplasty was a reasonably intact glenoid surface.

Total Shoulder Arthroplasty

Total shoulder arthroplasty is in- dicated for patients with debilitating pain and end-stage RA of the shoul- der with extensive humeral head and glenoid articular cartilage loss, yet with sufficient bone stock and soft-tissue integrity to achieve a sta- ble articulation. The initial exposure and preparation are the same as for the patient undergoing hemiarthro- plasty. Exposure of the glenoid is obtained by subscapularis mobiliza- tion and capsular releases. With the glenoid exposed, the anterior gle- noid neck is palpated to identify the direction for preparation of the gle- noid component fixation. The glenoid is prepared using a combi-

nation of drills, reamers, and burrs. The reaming should provide an exacting congruency with the back surface of the glenoid component. Proper alignment of the reamer will correct asymmetric glenoid wear and allow restoration of more anatomic component orientation. Proper glenoid preparation is con- firmed by insertion of a trial compo- nent. A dry field is obtained for optimal bone-cement interface, and the glenoid component is then cemented in place. The humeral head component is then inserted, as described. Appropriate soft-tissue balancing, which is essential for a stable articulation, is achieved by a combination of selective soft-tissue releases and insertion of appropri- ately sized prosthetic components (Fig. 7). Rotator cuff tears should be re- paired at the time of total shoulder arthroplasty. The repair sequence varies, but generally the extent of the rotator cuff tear is identified with the initial exposure. The edges of the tear are tagged with sutures, and the rotator cuff is mobilized so that it can be advanced laterally to its insertion. After insertion of the gle- noid component but before insertion of the humeral component, sutures are passed through drill holes in the greater tuberosity that will later be used for the tendon-to-bone repair. These sutures are left in place while the humeral component is inserted. When the components are in place and the humeral head is reduced, the rotator cuff repair is completed using the previously placed tendon- to-bone sutures. Any additional tendon-to-tendon sutures can be placed, as well. Performing the final portion of the rotator cuff repair after implantation of the compo- nents eliminates the stress on the repair that would occur if significant manipulation of the shoulder were necessary. Occasionally, additional surgical releases and rotator cuff mobilization are necessary to allow

Rheumatoid Arthritis of the Shoulder

for secure repair to the greater tuberosity. The coracoacromial liga- ment usually is not released during hemiarthroplasty or total shoulder arthroplasty. When rotator cuff repair is necessary, the undersurface of the acromion should be inspect- ed careful ly, but acromioplasty is rarely necessary. The goal is to maintain the integrity of the coraco- acromial arch because of its contri- bution to glenohumeral stability in these significantly compromised shoulders. Several investigators have report- ed that total shoulder arthroplasty for end-stage RA results in short- and long-term pain relief, satisfac- tory increases in range of motion, and markedly improved functional status. 27-29 Because of soft-tissue compromise and the inflammatory nature of the disease, the results of total shoulder arthroplasty in pa- tients with RA have not been shown to be as satisfactory or reliable as those in patients with osteoarthri- tis. 25 Despite concerns about proxi- mal humeral migration and glenoid radiolucent lines, long-term results have shown that the degree of pain relief, range of motion, abduction force, and functional status do not diminish significantly over time. 30

Postoperative Rehabilitation

The postoperative rehabilitation regimen must be tailored to the spe- cific needs of each patient. Design of the regimen is based on the sur- geon’s intraoperative assessment of the quality of the soft tissues, com- ponent stability, and any associated repairs. Patients should be coun- seled that maximum benefit after prosthetic shoulder replacement may not be realized until 6 months to 1 year after surgery. Rehabilitation begins on the first postoperative day, with active range of motion for the ipsilateral hand, wrist, and elbow, and passive and active-assisted range of motion for the shoulder. Initially, this includes

Rheumatoid Arthritis of the Shoulder for secure repair to the greater tuberosity. The coracoacromial liga- ment
Rheumatoid Arthritis of the Shoulder for secure repair to the greater tuberosity. The coracoacromial liga- ment
A B *
A
B
*

C

* D
*
D
Rheumatoid Arthritis of the Shoulder for secure repair to the greater tuberosity. The coracoacromial liga- ment

E

Rheumatoid Arthritis of the Shoulder for secure repair to the greater tuberosity. The coracoacromial liga- ment

F

Figure 7 Anteroposterior (A) and axillary (B) radiographs of the left shoulder in a 69- year-old woman with seropositive RA and debilitating pain for 1 year. T1-weighted coro- nal (C) and axial (D) magnetic resonance images of the same patient showing attenuation of the rotator cuff tendon (black arrow) but without a full-thickness tear. The humeral head erosions (asterisk) are extensive and well delineated. Glenoid bony architecture (white arrow) indicates that there is probably sufficient bone stock for placement of a gle- noid component. Anteroposterior (E) and axillary (F) radiographs immediately after total shoulder arthroplasty.

supine passive forward elevation and external rotation exercises with the arm at the side. The degree of external rotation allowed during the

initial 6 postoperative weeks is determined by the intraoperative repair of the subscapularis tendon; in general, 30° to 40° of external rota-

tion may be tolerated without plac- ing undue tension on the repair. At approximately 4 to 6 weeks, a more active shoulder range of motion is initiated along with internal rotation behind the back. Isometric strength- ening exercises are started 4 weeks after surgery, and resistive strength- ening exercises usually are initiated 10 to 12 weeks postoperatively when active range of motion has pro- gressed.

Andrew L. Chen, MD, MS, et al

Complications

Adverse events have been report- ed in up to 11.0% of total shoulder arthroplasties and up to 15.7% of shoulder hemiarthroplasties 31 (Table 3). Cofield et al 31 categorized com- plications of shoulder arthroplasty into four groups: (1) coexisting in- juries to the shoulder at the time of surgery, such as rotator cuff tear or chronic dislocation; (2) problems with the healing process after sur-

gery, such as failure of subscapularis tendon healing resulting in anterior shoulder instability or weakness in internal rotation, or overexuberant postoperative fibrosis causing joint stiffness; (3) complications related to the general health of the patient, such as infection secondary to chronic immunosuppression; and (4) com- plications associated with joint arthroplasty, such as periprosthetic fracture or component loosening.

Table 3 Complications After Total Shoulder Arthroplasty and Shoulder Hemiarthroplasty

Total Shoulder Arthroplasty *

Shoulder Hemiarthroplasty

Complication

No.

%

Complication

No.

%

Rotator cuff tear

23

1.9

Instability

14

2.8

Instability

18

1.5

Glenoid arthritis

12

2.4

Glenoid loosening

15

1.3

Tuberosity nonunion

9

1.8

Intraoperative fracture

15

1.3

Rotator cuff tear

9

1.8

Component malposition

7

0.6

Nerve injury

8

1.6

Nerve injury

7

0.6

Infection

5

1.0

Infection

5

0.4

Intraoperative fracture

3

0.6

Humeral loosening

4

0.3

Humeral loosening

3

0.6

Postoperative fracture

4

0.3

Wound problem

2

0.4

Wound problem

4

0.3

Tuberosity malposition

2

0.4

Wire breakage

3

0.3

Hematoma

2

0.4

Impingement

3

0.3

Perioperative death

2

0.4

Tuberosity nonunion

3

0.3

Postoperative fracture

1

0.2

Chronic pain, unexplained

3

0.3

Heterotopic ossification

1

0.2

Reflex dystrophy

2

0.2

Impingement

1

0.2

Hematoma

2

0.2

Reflex dystrophy

1

0.2

Component dissociation

2

0.2

Acromioclavicular pain

1

0.2

Extruded cement

2

0.2

Chronic pain, unexplained

1

0.2

Heterotopic ossification

1

0.1

Stiffness

1

0.2

Stiffness

1

0.1

Total

78

15.7

Spacer dislocation

1

0.1

Intraoperative death

1

0.1

Pulmonary embolism

1

0.1

Total

127

11.0

* 1,183 shoulders in 22 series treated between 1980 and 1999. 498 shoulders in 20 series treated between 1980 and 1999. Percentages given for complications are rounded. (Adapted with permission from Cofield RH, Chang W, Sperling JW: Complications of shoulder arthroplasty, in Iannotti JP, Williams GR [eds]: Disorders of the Shoulder: Diagnosis and Management. Philadelphia, PA: Lippincott Williams & Wilkins, 1999, pp 571-593.)

Rheumatoid Arthritis of the Shoulder

Significant instability after shoul- der arthroplasty usually is recogniz- able by physical examination and radiography and can be related to improper soft-tissue balancing, rota- tor cuff disruption, component mal- position, improper component sizing, or component loosening. Other fac- tors associated with instability after prosthetic replacement of the shoul- der include older age, chronic preop- erative shoulder dislocation, and aberrant glenoid anatomy resulting from glenoid bone deficiency or asymmetric wear. Soft-tissue balanc- ing intraoperatively should allow for up to 50% translation both anteriorly and posteriorly. Superior subluxation of the glenohumeral component is not necessarily indicative of rotator cuff disruption; inferior subluxation in the immediate postoperative period usually represents deltoid atony but can indicate inadequate soft-tissue tensioning, which may require sec- ondary surgical corrections. Axillary nerve neurapraxia is the most common injury. The musculo- cutaneous nerve may also be injured during exposure or overzealous retraction of the conjoined tendon. Radial nerve palsy also has been described secondary to cement extrusion from the canal distally, especially with revision arthroplasty or inadvertent humeral cortical pen- etration. If this finding is noted on postoperative radiographs, explo- ration is indicated. Continuity of the nerve should be confirmed and all cement removed. In most other cases of nerve injury, an initial peri- od of observation is indicated because most nerve injuries repre- sent neurapraxia. If neurologic improvement does not occur within 4 weeks, electromyography should be done to document the degree of neurologic injury and assess the potential for recovery. Exploration may be indicated for nerve palsies that do not improve by 12 weeks. Periprosthetic fractures may occur intraoperatively or postoperatively.

Intraoperative fractures can occur during humeral shaft preparation or insertion of the humeral component; postoperative fractures usually are a result of trauma. Fractures entirely distal to the humeral component may be treated nonsurgically with a fracture brace. Fractures proximal to the tip of the stem can be treated by cerclage wiring, plate fixation com- bined with cerclage wires, or, for intraoperative fractures, insertion of a long-stem component combined with cerclage wiring. The risk of infection after pros- thetic replacement is increased in the presence of diabetes mellitus, RA, lupus erythematosus, remote sites of infection, prior shoulder surgery, or use of immunosuppressive medica- tions. Little has been published that specifically addresses the treatment of infected shoulder arthroplasty. For acute or subacute infection (<3 months after prosthetic replace- ment), open irrigation and débride- ment, followed by 6 to 8 weeks of intravenous antibiotics, is usually adequate. For delayed infection, component removal and insertion of antibiotic-impregnated cement is necessary. Staged reimplantation may be undertaken after the suc- cessful eradication of infection, as documented by normalization of the white blood cell count, sedimenta- tion rate, C-reactive protein level, and intraoperative frozen section. Prosthetic loosening almost always involves the glenoid compo- nent and is best minimized by careful glenoid preparation with preservation of bone stock, meticu- lous cement technique, and close attention to soft-tissue balancing. Massive, unreconstructable rotator cuff tears are a relative contraindica- tion to glenoid replacement. These tears underscore the importance of the rotator cuff in maintaining joint position and preventing excessive, eccentric glenoid loading that can increase the risk of early loosening. Clinically significant glenoid loosen-

ing is uncommon compared with radiographic findings suggestive of loosening. Accordingly, it is im- portant to exclude other causes of shoulder pain, such as occult infec- tion or rotator cuff tear. If glenoid revision is done, removal of the loose component may reveal a large cen- tral glenoid defect that may not be structurally amenable to component reinsertion, even after bone grafting. In such cases, impaction grafting may be done with contouring of the remaining glenoid bone to a slight concavity for pseudocongruence with the humeral head component.

Arthrodesis

Although arthrodesis of the gleno- humeral joint has been described for end-stage RA, 32 advances in pros- thetic replacement and surgical tech- nique have largely supplanted arthrodesis as the predominant pri- mary treatment of the end-stage rheumatoid shoulder. Arthrodesis of the rheumatoid shoulder should be undertaken only for selected indi- cations. These indications include failed total shoulder arthroplasty or end-stage involvement with a recent history of joint sepsis. In these situa- tions, patients may benefit from glenohumeral fusion in 30° of abduc- tion, 30° of forward flexion, and 30° of internal rotation to allow for hand- to-mouth and hygiene activities. Arthrodesis can be done using a vari- ety of techniques, including screw fixation or plate-and-screw fixation. Although plate-and-screw fixation offers the potential avoidance of post- operative spica immobilization, the bone quality in rheumatoid patients may limit the security of the fixation, and additional external (spica) immo- bilization still will be needed postop- eratively. The utility of shoulder arthrodesis must be evaluated in the context of ipsilateral and contralateral upper extremity involvement.

Acromioclavicular Involvement

Rheumatoid involvement of the

acromioclavicular joint is common, affecting up to 63% of rheumatoid patients with painful shoulders. 33 It is often adequately addressed nonsurgically with medications and corticosteroid injection. How- ever, persistent or progressively debilitating pain secondary to extensive, symptomatic erosions may necessitate distal clavicular resection with synovectomy, typi- cally with successful results. 7 Petersson 33 reported acromioclavic- ular joint resection and subacromi- al bursectomy to be an effective procedure at follow-up of 18 to 62 months. Either open or arthroscop- ic resection of the distal clavicle may be done. In the setting of RA, however, resection rarely is per- formed as an isolated procedure; more often, it is done at the time of prosthetic replacement.

Andrew L. Chen, MD, MS, et al

Sternoclavicular Involvement

The reported incidence of rheu- matoid involvement of the sterno- clavicular joint ranges from 1% to 41%. 34 Symptomatology typically is overshadowed by glenohumeral involvement and usually responds to nonsurgical intervention and intra-articular injections. Recalci- trant symptoms lasting more than 6 to 12 months may be addressed with sternoclavicular joint débride- ment and medial clavicle resec- tion. 34 Care must be taken to pre- serve the stabilizing ligaments to avoid complications associated with sternoclavicular instability.

Summary

Care of the patient with RA of the shoulder requires a multidisciplin-

ary approach involving the primary care provider, rheumatologist, orthopaedic surgeon, and physi- cal/occupational therapists. Early rheumatoid involvement of the shoulder with minimal articular de- struction and functional limitations may be managed nonsurgically with medications and physical ther- apy. Advanced rheumatoid disease of the shoulder with significant pain and articular destruction may neces- sitate surgical intervention, ranging from synovectomy to total shoulder arthroplasty. Although the results of prosthetic shoulder replacement for end-stage RA are not compara- ble to those achieved for osteo- arthritis, symptomatic improvement often is dramatic, with satisfactory relief of pain, improved range of motion, and increased functional ability.

References

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  • 2. Petersson CJ: Painful shoulders in patients with rheumatoid arthritis: Prevalence, clinical and radiological fea- tures. Scand J Rheumatol 1986;15:275-279.

  • 3. Lipsky PE: Rheumatoid arthritis, in Wilson JD, Braunwald E, Isselbacher KJ, et al (eds): Harrison’s Principles of Internal Medicine , ed 12. New York, NY: McGraw-Hill, 1991, pp 1437-1442.

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ing of the shoulder in patients with rheumatoid arthritis. Ann Rheum Dis

1990;49:7-11.

9. Albertsen M, Egund N, Jonsson E,

Lidgren L: Assessment at CT of the rheumatoid shoulder with surgical cor- relation. Acta Radiol 1994;35:164-168.

  • 10. Ellman MH, Brown NL, Curran JJ: Shoulder arthritis: Distinguishing among the many causes of inflamma- tion. Postgrad Med 1983;73:158-167.

  • 11. Weiss TE, Gum OB, Biundo JJ Jr: Rheumatic diseases: 1. Differential diag- nosis. Postgrad Med 1976;60:141-150.

  • 12. Brandt KD, Kovalov-St. John K: Osteoarthritis, in Wilson JD, Braunwald E, Isselbacher KJ, et al (eds): Harrison’s Principles of Internal Medicine , ed 12. New York, NY: McGraw-Hill, 1991, pp 1475-1479.

  • 13. Laine VAI, Vainio KJ, Pekanmäki K: Shoulder affections in rheumatoid arthri- tis. Ann Rheum Dis 1954;13:157-160.

  • 14. Neer CS: The rheumatoid shoulder, in Crubbs RL, Mitchell NS (eds): The Sur- gical Management of Rheumatoid Arthritis. Philadelphia, PA: JB Lippincott, 1971, pp 117-127.

  • 15. Rozental TD, Sculco TP: Intra-articular corticosteroids: An updated overview. Am J Orthop 2000;29:18-23.

  • 16. Neer CS II: Reconstructive surgery and rehabilitation of the shoulder, in Kelley WN, Harris ED Jr, Ruddy S, Sledge CB (eds): Textbook of Rheumatology, ed 2. Philadelphia, PA: WB Saunders, 1985, vol 2, pp 1855-1870.

  • 17. Neer CS II, Watson KC, Stanton FJ: Recent experience in total shoulder replacement. J Bone Joint Surg Am 1982;64:319-337.

  • 18. Friedman RJ, Ewald FC: Arthroplasty of the ipsilateral shoulder and elbow in patients who have rheumatoid arthritis. J Bone Joint Surg Am 1987;69:661-666.

  • 19. Gill DR, Cofield RH, Morrey BF: Ipsilateral total shoulder and elbow arthroplasties in patients who have rheumatoid arthritis. J Bone Joint Surg Am 1999;81:1128-1137.

  • 20. Hess EV: Rheumatoid arthritis: Treat- ment, in Schumacher HR Jr, Klippel JH, Robinson DR (eds): Primer on the Rheumatic Diseases, ed 9. Atlanta, GA: Arthritis Foundation, 1988, pp 93-96.

  • 21. Petersson CJ: Shoulder surgery in rheumatoid arthritis. Acta Orthop Scand 1986;57:222-226.

  • 22. Rozing PM, Brand R: Rotator cuff re- pair during shoulder arthroplasty in rheumatoid arthritis. J Arthroplasty 1998;13:311-319.

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  • 23. Cofield RH, Frankle MA, Zuckerman JD: Humeral head replacement for glenohumeral arthritis. Semin Arthro- plasty 1995;6:214-221.

  • 24. Boyd AD Jr, Thomas WH, Scott RD, Sledge CB, Thornhill TS: Total shoul- der arthroplasty versus hemiarthro- plasty: Indications for glenoid resur- facing. J Arthroplasty 1990;5:329-336.

  • 25. McCoy SR, Warren RF, Bade HA III, Ranawat CS, Inglis AE: Total shoulder arthroplasty in rheumatoid arthritis. J Arthroplasty 1989;4:105-113.

  • 26. Koorevaar RC, Merkies ND, de Waal Malefijt MC, Teeuwen M, van den Hoogen FH: Shoulder hemiarthro- plasty in rheumatoid arthritis: 19 cases reexamined after 1-17 years. Acta Orthop Scand 1997;68:243-245.

  • 27. Sojbjerg JO, Frich LH, Johannsen HV,

Sneppen O: Late results of total shoul- der replacement in patients with rheumatoid arthritis. Clin Orthop

1999;366:39-45.

  • 28. Stewart MP, Kelly IG: Total shoulder replacement in rheumatoid disease: 7- to 13-year follow-up of 37 joints. J Bone Joint Surg Br 1997;79:68-72.

  • 29. Friedman RJ, Thornhill TS, Thomas WH, Sledge CB: Non-constrained total shoulder replacement in patients who have rheumatoid arthritis and class-IV function. J Bone Joint Surg Am 1989;71:494-498.

  • 30. Sneppen O, Fruensgaard S, Johannsen HV, Olsen BS, Sojbjerg JO, Andersen NH: Total shoulder replacement in rheumatoid arthritis: Proximal migra- tion and loosening. J Shoulder Elbow Surg 1996;5:47-52.

  • 31. Cofield RH, Chang W, Sperling JW: Complications of shoulder arthroplasty, in Iannotti JP, Williams GR (eds): Disorders of the Shoulder: Diagnosis and Management . Philadelphia, PA: Lip- pincott Williams & Wilkins, 1999, pp 571-593.

  • 32. Rybka V, Raunio P, Vainio K: Arthrodesis of the shoulder in rheumatoid arthri- tis: A review of forty-one cases. J Bone Joint Surg Br 1979;61:155-158.

  • 33. Petersson CJ: The acromioclavicular joint in rheumatoid arthritis. Clin Orthop 1987;223:86-93.

  • 34. Wirth MA, Rockwood CA Jr: Chronic conditions of the acromioclavicular and sternoclavicular joints, in Chapman MW, Madison M (eds): Operative Orthopaedics, ed 2. Philadelphia, PA: JB Lippincott, 1993, vol 2, pp 1673-1693.

Malignant Bone Tumors: Limb Sparing Versus Amputation Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD

Malignant Bone Tumors:

Limb Sparing Versus Amputation

Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD

Abstract

Amputation, once the mainstay of treatment of malignant bone tumors, now is used selectively and infrequently. Most patients are candidates for limb- sparing procedures because of effective chemotherapeutic agents and regi- mens, improved imaging modalities, and advances in reconstructive surgery. Patient age as well as tumor location and extent of disease help define the most appropriate surgical alternatives. Options for skeletal re- construction include modular endoprostheses, osteoarticular or bulk allo- grafts, allograft-prosthetic composites, vascularized bone grafts, arthrodesis, expandable prostheses, rotationplasty, and limb-lengthening techniques. Two key factors must be considered: survival rates should be no worse than those associated with amputation, and the reconstructed limb must provide satisfactory function. Functional outcome studies comparing limb-sparing procedures and amputation have inherent limitations, including the inability to randomize treatment and the subjective nature of important outcome measures.

J Am Acad Orthop Surg 2003;11:25-37

Primary malignant bone tumors are rare lesions, with fewer than 3,000 new cases per year in the United States. Before the 1970s, manage- ment routinely consisted of trans- bone amputations or disarticula- tions, with dismal survival rates (10% to 20%). With the develop- ment of more effective chemothera- peutic agents and treatment proto- cols in the 1970s and 1980s, survival rates improved, which allowed the focus of management to shift to limb preservation. 1 Computed tomography and magnetic reso- nance imaging (MRI) allow the pre- cise visualization of the anatomic location of a tumor and its relation to surrounding structures. Preop- erative planning has been advanced through the use of these modalities, fostering better patient selection for

specific treatment strategies and lowering the morbidity rates of biopsy and subsequent resection. 2,3 Currently, 80% to 85% of patients with primary malignant bone tumors involving the extremities (eg, osteosarcoma, Ewing’s sarco- ma, and chondrosarcoma) can be treated safely with wide resection and limb preservation. Multi- modality therapy has increased long-term survival rates of patients with chemotherapy-sensitive tumors to 60% to 70%. 1,4 There are a num- ber of options for skeletal recon- struction after bone tumor resection, and it is important to compare the clinical and especially functional outcomes based on type of recon- struction, location of the tumor, and limb-sparing versus ablative sur- gery.

Limb-Sparing Surgery Principles and Guidelines

There are four basic principles or goals of limb-sparing procedures:

(1) Local recurrence should be no greater and survival no worse than with amputation. (2) The proce- dure, or treatment of its complica- tions, should not delay adjuvant therapy. (3) Reconstruction should be enduring and not associated with a large number of local complica- tions requiring secondary proce- dures and frequent hospitalizations. (4) Function of the limb should approach that obtained by amputa- tion, although body image, patient preference, and lifestyle may influ- ence the decision. 5 Before consideration of limb preservation, the patient needs to be appropriately staged and assessed through a multidisciplinary ap- proach. Some elements of the dis- ease may warrant concern, includ-

Dr. DiCaprio is Resident, Department of Orthopaedics and Rehabilitation, Yale Univer- sity School of Medicine, New Haven, CT. Dr. Friedlaender is Wayne O. Southwick Professor and Chair, Department of Orthopaedics and Rehabilitation, Yale University School of Medicine.

Reprint requests: Dr. DiCaprio, PO Box 208071, New Haven, CT 06520-8071.

Copyright 2003 by the American Academy of Orthopaedic Surgeons.

Malignant Bone Tumors: Limb Sparing Versus Amputation

ing relative contraindications to such procedures (Table 1). Multi- drug neoadjuvant chemotherapy, popularized first for patients with osteosarcoma by Rosen in the late 1970s, is usually initiated as appro- priate after histologic diagnosis and staging. Chemotherapy helps con- trol systemic disease by attacking micrometastases, dramatically increasing overall survival rates. 1 Neoadjuvant therapy also “steril- izes” the reactive zone around the tumor by destroying microscopic disease at the periphery of the pri- mary lesion, thus facilitating resec- tion. Additionally, in some patients with a relative contraindication to limb salvage, such as a pathologic fracture in the upper extremity, the use of chemotherapy with a favor- able response may allow limb sal- vage to be considered. However, not all malignant bone tumors (and especially chondrosarcomas) have a viable and effective chemotherapy regimen. When appropriate, after 8 to 12 weeks of preoperative neoadjuvant chemotherapy, wide tumor resec- tion is performed to establish local tumor control. Achieving tumor- free resection margins is of para- mount importance and remains the primary goal in surgical oncology. Most resections are performed through an extensile longitudinal incision, permitting access to the major neurovascular bundle, with complete removal of all biopsy tracts. By definition, a wide resec- tion will include a cuff of normal tis- sue surrounding the resected speci- men. Skeletal defects are large, averaging 15 to 20 cm, reflecting the size of these tumors and the need for negative margins. After recon- struction, muscle transfers may be necessary to provide adequate motor function. Finally, adequate, healthy soft-tissue coverage is essential to prevent early wound complications and subsequent infection. Coverage may require complex local flaps or

Table 1 Relative Contraindications to Limb-Sparing Procedures

Major neurovascular structures encased by tumor when vascular bypass is not feasible Pathologic fracture with hematoma violating compartment boundary Inappropriately performed biopsy or biopsy-site complications Severe infection in the surgical field Immature skeletal age with predicted leg-length discrepancy >8 cm Extensive muscle or soft-tissue involvement Poor response to preoperative chemotherapy

even free tissue grafts. When in- dicated on the basis of histologic diagnosis, adjuvant chemotherapy consisting of multiple agents for synergistic activity is continued for 6 to 12 months after wide tumor resection. After negative tumor margins are obtained, there is often a large skele- tal defect requiring reconstruction. Several options are available. 6 Pa- tient age, tumor location, and extent of disease narrow the list of appro- priate surgical alternatives.

Modular Endoprostheses

Indications and Advantages

Currently available metallic pros- thetic systems offer a lightweight, strong, inert means for skeletal reconstruction. Modularity of pros- thetic design allows intraoperative flexibility based on the final amount of tissue resected. A rigorous reha- bilitation program can be initiated immediately after implantation (usually done with bone cement), allowing early joint range of motion and weight bearing. Prosthetic reconstruction carries a lower risk of deep infection than do allografts, and nonunion is not a concern because there are no osteosynthesis sites. Endoprosthetic use also avoids the risk of disease transmis- sion and immune responses that

exists with allograft reconstruction. Longevity, complications, and func- tional outcome vary by anatomic site, type of prosthesis, and fixation technique.

Complications and Clinical Results

Early complications associated with the extensive nature of most musculoskeletal oncology proce- dures include wound necrosis/ dehiscence, infection, thromboem- bolic disease, neurapraxia, and joint instability. Meticulous surgical tech- nique and attention to soft-tissue handling and reconstruction can significantly decrease the frequency of these complications. Late compli- cations include aseptic loosening, infection, joint or prosthetic insta- bility, fatigue fracture of the pros- thesis, and wear or dissociation of modular components. Late infec- tion remains the most serious prob- lem because most prosthesis-related complications can be successfully treated with revision surgery. Con- cerns include the suboptimal attach- ment of soft tissues to the metallic components. In an attempt to determine pros- thesis and extremity survivorship, Horowitz et al 7 reviewed their expe- rience with 93 prosthetic reconstruc- tions over 8 years: 16 proximal femur, 61 distal femur, and 16 proxi- mal tibia. Minimum follow-up was

Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD

24 months (mean, 80 months). Prosthesis survival at 5 years was 88%, 59%, and 54% for proximal femur, distal femur, and proximal tibia reconstructions, respectively. The overall event-free prosthesis survival was 63% at 5 years and 36% at 10 years. Aseptic loosening was cause for failure in approximately 20% at 5 years and 30% at 10 years. Limb survival for the entire group was 87% at 5 years and 81% at 10 years. Patients with lesions of the proximal tibia had the longest sur- vival rate, with 93% alive at 10 years. (Histologies included 11 osteosarco- mas, 4 malignant fibrous histiocy- tomas, and 1 chondrosarcoma.) The group as a whole had a survival rate of 72% at 10 years and was com- posed of a variety of histologies, including 65 osteosarcomas, 13 chondrosarcomas, 10 malignant fibrous histiocytomas, 3 Ewing’s sar- comas, and 2 liposarcomas. Aseptic loosening is the primary long-term concern with this method of reconstruction for tumors around the knee. Whereas allografts success- fully stabilize after 3 to 5 years, pros- theses begin to exhibit their inherent biomechanical limitations after 10 years. For the current rotating-hinge knee design, reported follow-up is limited to approximately 10 years. Malawer and Chou 8 in 1995 showed an 83% survival of prostheses at 5 years and 67% at 10 years. Of 52 patients who survived and were available at 3-year follow-up, only 10 were available at the 10-year follow- up. They had a revision rate of 15%, infection rate of 13%, amputation rate of 11%, and local recurrence rate of 6%. Overall, 44% of patients had at least one complication. These sur- vivorship data are limited because of the small number of patients but may represent an improvement from the simple-hinge, custom-made prosthe- ses, for which 5-year survival of 80% drops to 53% at 20 years. 7,9-11 Of 1,001 patients treated with cemented, custom-made endopros-

theses, aseptic loosening was the principal mode of failure among the 210 requiring revision. 10 Seventy- four revisions (35.2% of those re- vised) were done for aseptic loosen- ing. At 10 years, the rates of aseptic loosening were 6.2%, 32.6%, and 42% for the proximal femur, distal femur, and proximal tibia, respec- tively. The poorest prognosis for prosthesis survival without aseptic loosening was in young patients (<20 years) with distal femoral pros- thetic reconstruction in whom a high percentage of femur had been re- placed. Experience to date indicates that acetabular loosening rates have been extremely high, simple-hinge prostheses have a higher loosening rate than do rotating-hinge designs, and cemented fixation provides the lowest rate of loosening. 9 Most loose prostheses can be revised to improve functioning. Infection rates range from 0% to 13%. 8,9,11 Proximal tibial reconstruc- tions carry the highest risk of infec- tion, as do other regions where soft- tissue coverage is tenuous. Infection is the most serious complication as- sociated with limb-sparing proce- dures and is the most common reason for amputation after attempted re- construction. Rates have decreased, however, with the more common use of rotational or free flaps now readily available through microsurgical tech- niques. Joint instability is a major concern in reconstructions about the hip and shoulder. Dislocation rates for the hip range from 10% to 15%. 7-9,12,13 Reconstruction of the abductor mechanism and the use of bipolar components have improved stability and function. 11 Fatigue fracture of intramedul- lary stems has become extremely uncommon with the increase in stem diameters, improvements in design, and current metallurgy used during fabrication. 11 Dissociation also is rare with modern prostheses; most join with Morse tapers.

Regional Considerations

Prosthesis survival for proximal femoral replacements is generally reported as 77% to 100% at 10 years, falling to 57% at 20 years. 9,11-13 Poor abductor muscle function remains a common reason for decreased func- tional grades. Zehr et al 12 reviewed their experience with 33 patients after proximal femoral resection and reconstruction with an allograft- prosthetic composite (16 patients) or a megaprosthesis (17 patients). The primary mode of failure for compos- ites was infection, and for megapros- theses, instability. The 10-year prosthetic survival rate was 76% for the composite group and 58% for the megaprosthetic group. Instability occurred in 0% and 28% of the com- posite and megaprosthetic cohorts, respectively; infection rates were 17% and 6%, respectively. Both groups functioned well, with 87% and 80% functional scores for the respective cohorts. Allograft-pros- thetic composites have been shown to have a survival advantage over megaprostheses used for proximal femoral reconstructions. 12,14 Overall survival of a simple- hinge distal femoral knee replace- ment prosthesis at 5, 10, and 20 years is 80%, 65%, and 53%, respec- tively. 9,10 Functional evaluation reveals 69% to 93% good to excel- lent results with less than 10 years of follow-up. 7-11,15 Prosthetic sur- vival analysis shows that a higher percentage of femoral bone resected distally is related to a higher risk of prosthetic failure. 15 The extent of soft-tissue resection is another im- portant factor. The most common cause of failure for distal femoral prostheses is aseptic loosening. As length of follow-up increases, the rate of prosthetic survival diminishes. Better long-term results are antici- pated since simple-hinge designs have given way to modular rotating- hinge systems (Fig. 1). Proximal tibial prosthetic replace- ment survivorship has been poor

Malignant Bone Tumors: Limb Sparing Versus Amputation

Malignant Bone Tumors: Limb Sparing Versus Amputation A B C D Figure 1 A 16-year-old boy

A

Malignant Bone Tumors: Limb Sparing Versus Amputation A B C D Figure 1 A 16-year-old boy

B

Malignant Bone Tumors: Limb Sparing Versus Amputation A B C D Figure 1 A 16-year-old boy

C

Malignant Bone Tumors: Limb Sparing Versus Amputation A B C D Figure 1 A 16-year-old boy

D

Figure 1 A 16-year-old boy presented with knee pain of 7 months’ duration and a history of bilateral retinoblastoma in infancy. A, Anteroposterior radiograph of the knee shows an aggressive, eccentric, osteoblastic distal femoral metaphyseal lesion with extensive periosteal reaction (Codman’s triangle, arrow). Coronal (B) and sagittal (C) T2-weighted MRI scans demonstrate the heterogeneous lesion, periosteal reaction (white arrow), and soft-tissue extension (black arrow). Open biopsy confirmed the diagnosis of high-grade osteosarcoma. Treatment included preoperative chemotherapy, wide tumor resection, skeletal reconstruction, and postoperative chemotherapy. D, Anteroposterior radiograph after distal femoral reconstruction with a modular rotating-hinge knee prosthesis.

because of tenuous soft-tissue cover- age and unreliable extensor mecha- nism reconstruction. Survival rates vary from 45% to 74% at 5 years and 45% to 50% at 10 years. 9 Malawer and Chou 8 found proximal tibial replacements to have the highest complication and revision rate and worst Musculoskeletal Tumor Society (MSTS) functional scores (Table 2) for any region reconstruct- ed. Wound problems and subse- quent infections have decreased with the routine use of flaps but remain frequent problems for recon- structions in this anatomic site. Grimer et al 17 reported an initial infection rate of 36% that was re- duced to 12% by the use of a medial gastrocnemius flap. Local recur- rence was observed in 12.6% of patients and was associated with poor response to chemotherapy and close margins of excision. They also found that 70% of patients at 10 years required further surgical pro- cedures and reported a 25% risk of amputation at 10 years. 17 Many designs and techniques are available for proximal humeral

replacements. The technique of Malawer and Chou, 8 including implantation of a large-segment prosthesis stabilized by static recon- struction with Dacron tape and dynamic reconstruction by muscle transfers, has yielded the best re- ported results of any site of pros- thetic replacement, with an average MSTS functional score of 86.7% (26/30) and no cases of instability. However, there is a wide range of

results reported for this site, with in- stability the primary reason for poor functional outcome. 7,9,11 O’Connor et al 18 reported on 11 patients who underwent proximal humeral pros- thetic reconstruction. Two demon- strated evidence of stress shielding, six had signs of instability, one had a deep infection, and two had ce- ramic prosthesis loosening or frac- ture. Four of the 11 patients went on to secondary arthrodesis. Those

Table 2 Musculoskeletal Tumor Society Functional Evaluation 16

Lower Extremity Data *

Upper Extremity Data *

Pain Function Emotional acceptance Use of supports Walking ability Gait

Pain Function Emotional acceptance Hand positioning Manual dexterity Lifting ability

* Within each category, each of the six factors is graded 0 to 5. The higher the number, the greater the improvement in outcome. The sum total for the six categories can equal a Maximum Extremity Score of 30 points (5 × 6). Outcome is reported as a per- centage of the Maximum Extremity Score.

Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD

not converted to arthrodesis were satisfied regarding pain, emotional acceptance, and manual dexterity and were dissatisfied regarding function, positioning of the hand, and lifting ability.

Osteoarticular or Bulk Allografts

Indications and Advantages

Frozen allografts have been used longer than any other tumor recon- struction option. Allografts are favored by some for their potential for longevity because they function as a biologic reconstruction. Incor- poration of the allograft by the host is a slow and incomplete process. Osteoarticular allografts permit the uninvolved portion of the joint to be preserved; this approach allows the strongest means of soft-tissue or periarticular ligament reconstruc- tion (Fig. 2). Although associated with more early complications than are endoprostheses, allograft recon- structions stabilize after 3 to 5 years and therefore do better in long-term follow-up studies. Mankin et al 19 found that, after 3 years, approxi- mately 75% of grafts are retained by patients and remain successful for more than 20 years. Seventy per- cent to 80% of patients obtain a good or excellent functional result after allograft reconstruction, although this varies with type of graft, anatomic site, and stage of disease. 19 The unpredictable early outcomes with allografts and the frequent need for multiple proce- dures to obtain a successful end result have led many orthopaedic oncologists to favor modern endo- prostheses. With their potential for long-term stability, however, allo- grafts play a key role in younger patients (<20 years), in whom an enduring reconstruction can limit the additional revisions seen with long-term follow-up of patients with endoprosthetic constructs.

Complications and Clinical Results

Allografts used for tumor recon- struction have a high rate of early complications. Cumulative compli- cation rates approach 50% in some series, with most patients requiring additional surgery. 19 Infection, frac- ture, joint instability, and nonunion have vexed allograft reconstruction for 30 years. 19-26 Immunologic com- plications 27 and risk of disease trans- mission 28 are of lesser concern but do exist. With osteoarticular allo- grafts, osteoarthritis becomes mani- fest at 5 to 10 years in 15% of pa- tients and is best treated with a resurfacing arthroplasty. 19 Tumor recurrence, infection, and fracture are the most devastating complica- tions and account for more than 85% of allograft failures. 19 Most of the clinical outcome studies pertaining to the use of massive allografts come from the Orthopaedic Oncology Unit at Massachusetts General Hospital, with a series of more than 1,100 allograft reconstructions. 19-24 Lord et al 20 reported on the inci- dence, nature, and treatment of infections in bone allografts. A ret- rospective review of 283 patients with more than 2 years of follow-up revealed an infection rate of 11.7% (33/283). Gram-positive organisms, particularly Staphylococcus epider- midis, were the most common patho- gens. Risk factors reflected those of a population treated by wide resec- tion of soft tissue and bone, chemo- therapy, and radiation therapy. Wound complications are the most common problem and were associ- ated with early infection; additional surgical intervention is the most common risk factor for late infection. Eighty-two percent of infected cases (27/33) were considered failures and required amputation or removal of the allograft to control infection. Salvage is sometimes possible, but it requires an aggressive approach involving resection of the infected allograft, implantation of a spacer or

external fixation, intravenous antibi- otics, oral antibiotics for extended periods, and reimplantation of a new allograft or conversion to a metallic endoprosthesis. In a retrospective review of 274 allograft recipients after limb-spar- ing tumor resections with a mini- mum follow-up of 4 years, Berrey et al 21 reported a fracture incidence of 16% (43/274). There were no major distinguishing or predictive features in the allograft group between patients who had a fracture of the

A B
A
B

Figure 2 A 17-year-old boy presented with knee pain of 2 months’ duration. Radiographs, MRI, and biopsy confirmed osteosarcoma. A, Initial postoperative anteroposterior radiograph demonstrates distal femoral reconstruction with an osteoarticular allograft stabilized with two orthogonal dynamic compression plates. The patient underwent a bone-graft proce- dure 1 year later to treat an allograft-to- host bone nonunion. B, Anteroposterior radiograph 2 years after reconstruction demonstrates solid union of the osteosyn- thesis site.

Malignant Bone Tumors: Limb Sparing Versus Amputation

allograft and those who did not. There was a trend toward a higher incidence of nonunion in patients with fractures, but it was not statisti- cally significant. The mean time to fracture was 28.6 months after the index surgery, with more than 70% of fractures occurring within 3 years. The results in this population after treatment approached those of pa- tients who had never had a fracture. The mean time to union was 7.4 months (range, 4 to 14 months), with all but four fractures treated with an operation and most involving autog- enous bone grafting. Weight bear- ing was restricted until radiographic union. The 43 patients underwent a total of 59 operations. The authors concluded that 9.3% of allograft shaft fractures (4/43) may heal with immobilization, but many require treatment with internal fixation and bone grafting. Several attempts may be necessary, and sometimes ex- change of the allograft or conversion to a metallic endoprosthesis is neces- sary. Berrey et al 21 classified the frac- tures into three patterns. Type I fractures (2/43) were seen soon after surgery, with almost complete dis- solution of the graft. These were thought to be secondary to an im- mune reaction to the allograft. Type II fractures (22/43) were through the shaft of the allograft, with a mean time to fracture of 27.6 months. Type III fractures (19/43) occurred at the articular surface of osteoartic- ular allografts at a mean of 31.6 months from surgery. These are best treated with a standard resur- facing total knee arthroplasty, when feasible. In a larger series of allograft re- constructions, 22 fractures occurred at a rate of 17.7% (185/1,046). Mean time to fracture was 3.2 years. There were 8 Berrey type I fractures, 114 type II, and 63 type III. Sixty- one fractures (33%) involved a screw hole at the end of the plate. Neither adjuvant chemotherapy nor radia-

tion influenced the rate of allograft fracture. Nonunion is another common complication in the postoperative course of allograft reconstructions. All allografts have at least one os- teosynthesis site that, until healed, limits the amount of weight bearing permitted through the reconstructed limb. The location of the osteosyn- thesis affects the healing potential. Diaphyseal-to-diaphyseal osteosyn- thesis sites have a higher risk of delayed union or nonunion than do metaphyseal-to-metaphyseal sites. Supplemental autograft and stronger internal fixation are recommended at osteosynthesis sites in an effort to decrease the rate of nonunion. In the future, bone morphogenetic pro- teins may play a similar role when allograft reconstruction is per- formed. Hornicek et al 23 evaluated factors affecting nonunion of the allograft-host junction. Of 945 pa- tients, 163 (17.3%) had a nonunion. Those receiving chemotherapy had twice the rate of nonunion. Two hundred sixty-nine additional sur- geries were performed on these 163 patients. In 114 patients, treatment led to successful union. The per- centage of failure increased as the number of surgical procedures in- creased. Despite treatment, 49 pa- tients failed to demonstrate union of the osteosynthesis site. In comparing different types of allografts, intercalary allografts have better clinical outcomes than do osteoarticular allografts, allograft- prosthetic composites, and allografts used for arthrodesis 6,19,24 (Fig. 3). Ortiz-Cruz et al 24 reviewed 104 in- tercalary allografts done over an 18- year period (median follow-up, 5.6 years). Eighty-four percent (87/104) were considered successful, with retention of allograft and normal extremity function. Infection, frac- ture, stage of disease, and adjuvant therapy all had adverse effects on graft survival. Fifteen reconstruc- tions failed, most within 3 to 4 years.

Four were salvaged with a second allograft, three by another recon- struction technique; eight required amputation (two for local recur- rence). With two osteosynthesis sites, nonunions might be expected to be a common concern with inter- calary allografts. Thirty-one of the 104 allografts (30%) failed to unite at one or both junctions within 1 year, but only seven remained ununited (and were considered failures) after additional surgical intervention. Eighty-one additional surgical pro- cedures were needed to achieve sat- isfactory function in 92% of these patients. Different modes of internal fixation were used; plate fixation spanning both osteosynthesis sites was found to be superior to the use of two shorter plates at either end of the allograft. Mankin et al 19 found similar re- sults in their review of 718 allograft transplantations (mean follow-up, 78 months). Intercalary allografts yielded the greatest satisfaction, with excellent or good outcomes in 84% of cases. Osteoarticular allo- grafts, allograft-prosthetic compos- ites, and allograft arthrodeses had excellent and good outcome rates of 73%, 77%, and 54%, respectively, although they often required addi- tional surgical procedures to achieve these outcomes.

Regional Considerations

Most allograft reconstructions are for the femur, and the results of large studies primarily reflect the outcome for this region. Hornicek et al 25 reviewed the largest series to date of proximal tibial osteoarticular allografts, consisting of 38 recon- structions (38 patients) in 15 years. Fifty-five percent of the patients experienced one or more complica- tions, which were managed with multiple subsequent procedures. Three amputations were done for deep infections. About one third of the patients required removal of the original allograft and reconstruction

Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD

Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD A B C D Figure 3 A

A

Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD A B C D Figure 3 A

B

Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD A B C D Figure 3 A

C

Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD A B C D Figure 3 A

D

Figure 3 A 21-year-old man presented with thigh pain. Anteroposterior (A) and lateral (B) radiographs of the femur show a permeative diaphyseal lesion with cortical erosion (white arrows). C, Coronal T2-weighted MRI scan demonstrates the diaphyseal lesion (black arrow). Open biopsy confirmed Ewing’s sarcoma. D, Postoperative anteroposterior radiograph of the femur after wide tumor resection and intercalary allograft reconstruction stabilized with a statically locked intramedullary nail.

with a new allograft or conversion to metallic prosthesis. Ultimately, 66% had a good or excellent func- tional result. The study also com- pared outcomes and complications between the subset of patients treat- ed with chemotherapy, radiation therapy, or both to those without adjuvant therapy. The only signifi- cant (P < 0.05) difference observed between the groups was the higher incidence of fracture in the patients treated with chemotherapy. Proximal humeral osteoarticular allografts are an attractive option be- cause of their potential for soft-tissue reconstruction, healing, and func- tion. O’Connor et al 18 reported on eight patients treated with this tech- nique, a subset of 57 patients who underwent limb-sparing tumor re- sections and various forms of recon- struction. There was no nonunion or cases of instability, but half of the patients experienced subchondral

fractures and collapse of the articu- lar surface. Three of these four pa- tients were asymptomatic; the other was treated with conversion to a prosthesis. Functional rating aver- aged 71% by the MSTS system, with patients least satisfied with function and positioning of the hand. Com- pared with endoprosthetic recon- struction, osteoarticular allografts resulted in superior function after intra-articular resection of the proxi- mal humerus. Shoulder arthrodesis using an intercalary allograft com- bined with plate fixation and vascu- larized fibular grafting is an excel- lent method of reconstruction after extra-articular resection of the proxi- mal humerus. Getty and Peabody 26 reported similar results in 16 patients who underwent osteoarticular allograft reconstruction after intra-articular resection of the proximal humerus. At a mean follow-up of 47 months,

the mean MSTS functional evalua- tion score was 70%. Deterioration was noted to continue with time from surgery. The authors have stopped doing the procedure because of the unacceptable rates of epiphyseal fragmentation (4/16), instability (11/16), fracture (4/16), and infection (1/16).

Allograft-Prosthetic Composites

Clearly there are benefits and inherent drawbacks to either allo- graft or endoprosthetic reconstruc- tion. By combining the two meth- ods or using an allograft-prosthetic composite, the surgeon can tailor the procedure to help diminish the inherent risks encountered when either reconstruction is used alone. The composite helps restore as much bone stock as possible and offers joint stability that is often difficult to obtain with osteoarticu- lar allograft reconstruction. By

Malignant Bone Tumors: Limb Sparing Versus Amputation

resurfacing the allograft bone with an implant, cartilage degradation is no longer a potential problem 5 to 10 years after reconstruction (Fig. 4). Gitelis and Piasecki 14 performed 11 hip and 10 knee reconstructions and 1 elbow reconstruction in 22 pa- tients (mean follow-up, 45 months). Mean MSTS functional score was 94.3%. Five patients had a non- union, four of which healed after bone grafting; one was converted to a megaprosthesis. There were no dislocations. Graft resorption did not occur in this small number of pa- tients, and no revisions were done for implant loosening.

Techniques With Special Indications

Vascularized Bone Grafts

Vascularized bone grafts can be taken from the iliac crest, rib, scapula, or fibula. Of these options, only vas- cularized fibular grafts are suited for the large skeletal defects left after wide resection of a malignant bone tumor. Compared with allografts, vascularized autografts offer a more rapid incorporation, stronger initial construct secondary to graft hyper- trophy, and absence of immunologic problems. Vascular grafts change not the pattern of bony repair but rather the rate of repair. Final matu- ration and hypertrophy of grafts is consistent with Wolff’s law. 29 External fixation is preferable to plate fixation because it maximizes these stresses and allows for greater hypertrophy and ultimate strength of the graft. Ideally suited for chil- dren and young adults, this method of biologic reconstruction has the potential to be enduring without need for revision surgery later in life. Vascularized autografts also are used with the poorly vascularized tumor bed commonly found in previously irradiated tissue and when a delay in osteosynthesis healing is anticipated

Malignant Bone Tumors: Limb Sparing Versus Amputation resurfacing the allograft bone with an implant, cartilage degradation

A

Malignant Bone Tumors: Limb Sparing Versus Amputation resurfacing the allograft bone with an implant, cartilage degradation

B

Malignant Bone Tumors: Limb Sparing Versus Amputation resurfacing the allograft bone with an implant, cartilage degradation

C

Figure 4 A 14-year-old boy presented with knee pain of 3 months’ duration and an enlarging mass. A, Anteroposterior radiograph of the knee demonstrates an eccentric lytic proximal tibial metaphyseal lesion with cortical destruction and soft-tissue extension (arrow). Biopsy confirmed osteosarcoma. Anteroposterior (B) and lateral (C) radiographs demonstrate skeletal reconstruction with a rotating-hinge knee prosthesis and proximal tibial allograft-prosthetic composite stabilized with a dynamic compression plate.

secondary to adjuvant therapy with radiation, chemotherapy, or both. The main disadvantages of vascular- ized autograft are the increased surgery time, surgical site morbidity, and size limitations. Few published reports focus on vascularized autograft in tumor reconstruction, and long-term out- come data are lacking. 30 Hsu et al 31 reviewed a consecutive series of 30 patients who underwent skeletal reconstruction by vascularized fibu- lar transfer after resection of primary bone tumors. Mean follow-up was 36 months (range, 24 to 85 months), with union achieved in 90% (27/30) at an average of 7.6 months. The mean fibular graft length was 18.9 cm (range, 10 to 30 cm). Functional results were evaluated in 24 patients, with 9 excellent, 7 good, 6 fair, and 2 poor results. When used for inter- calary grafts (14 patients), the func- tional results were better than those seen with arthrodesis procedures (10 patients). There was a high compli- cation rate (50%), but many were managed nonsurgically and resolved

without greatly affecting the final outcome. Complications included three nonunions, three deep infec- tions, three stress fractures, two local recurrences, and an assortment of soft-tissue complications.

Arthrodesis

Arthrodesis creates a stable, painless, durable limb. Indications for arthrodesis are extra-articular joint resection or extensive muscle resection with lack of remaining muscle to power the joint, or when the desire for joint stability is para- mount. The two most common re- gions for this technique are the knee and shoulder. Knee arthrodesis can be accom- plished with allografts, nonvascu- larized autografts, vascularized rotational fibular grafts, external fix- ation with bone transport, or some combination of these techniques. Fixation is achieved with either compression plating or intramedul- lary nailing. Intramedullary fixa- tion is favored for arthrodesis be- cause of a decreased rate of graft

Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD

fracture and nonunions. The knee is aligned in 10° to 15° of flexion and 0° to 5° of valgus. In the skeletally mature individual, the limb is short- ened 1 to 2 cm to allow for foot clearance during the gait cycle. In skeletally immature patients, the limb may be lengthened with the grafting technique; the expectation is that the contralateral normal limb will continue to grow, with the result that limb length at skeletal maturity on the operated side will be equal or slightly shorter. The procedure is associated with a high rate of complications (approximate- ly 50%), including all of the inherent risks of allograft reconstruction. Despite this complication rate, how- ever, most patients achieve success- ful union and have a durable, func- tional limb. 32-34 The shoulder joint is challenging to reconstruct, given the extreme range of motion and lack of inherent static stability. The few published reports that discuss shoulder arthrodesis in tumor reconstruction have small numbers of patients (5 to 10). Notable rates of infection, frac- ture, and nonunion exist, as with knee arthrodesis. 32 Most patients obtain stable fusion, allowing satis- factory function of the upper ex- tremity. 18,32 Wolf et al 33 reviewed the long- term results in 73 patients who, from 1967 to 1985, underwent resec- tion arthrodesis of the knee with autogenous grafts. Forty patients followed for more than 10 years formed the basis of the evaluation. Intramedullary rods were used to stabilize hemicortical femoral or tib- ial allografts and nonvascularized autogenous fibular grafts to the native femur and tibia. A high inci- dence of complications (52%) was evident, yet most patients eventual- ly achieved a successful outcome with preservation of the limb, and 86% were independent ambulators at long-term follow-up. The most common complications were graft

fatigue fracture (51%), delayed union (23%), rod migration or rod fracture (25%), peroneal nerve palsy (8%), and infection and wound problems (23%). Thirty-seven of the 40 patients (93%) achieved a solid reconstruction. Two patients required an above-knee amputation, one for infection and the other for local tumor recurrence. One addi- tional patient sustained a commi- nuted traumatic fracture of the fusion and was treated with an allograft arthrodesis. The recon- structions proved to be durable, and patient satisfaction and func- tion remained high for decades, with an average MSTS functional score of 77%. Weiner et al 34 evaluated 39 pa- tients treated with resection arthrod- esis done with an intercalary allo- graft fixed with an intramedullary nail. In 31 patients, this procedure was the index reconstruction; in eight, it was done after failure of a different type of tumor reconstruc- tion. Proximal and distal osteosyn- thesis sites both healed, and function was satisfactory in 32 patients. Nonunion occurred in seven pa- tients (one junction in six patients, both junctions in one). The non- union was healed in five of the seven treated with bone grafting, repeat internal fixation, or exchange allografting; two patients went on to above-knee amputation. An addi- tional patient from the study under- went above-knee amputation for local recurrence. Fatigue fracture of the allograft occurred in five pa- tients, all within metaphyseal bone. Overall, the rate of complication was lower than that experienced with autograft arthrodesis.

Expandable Prostheses

Expandable prostheses were developed in an attempt to over- come anticipated limb-length dis- crepancies in the growing child treated with limb-sparing surgery. The first approach includes the

Lewis Expandable Adjustable Prosthesis (LEAP). 35 Expansion of the LEAP is achieved by a modified Jacob’s chuck mechanism. Rotation of the outer sleeve of the prosthesis engages the threads on the inner shaft, thereby increasing the length of the prosthetic shaft with each rev- olution. An average lengthening is 1.5 to 2 cm; the average overall extension capability of a LEAP is 6 to 9 cm. Collapse of the expansion mechanism, observed early in its use, has been addressed with the use of spacer rings. Problems with tita- nium debris and fatigue failure of expandable prostheses led to the alternative use of modular systems. These systems use a Morse taper locking system to connect segmental parts. Exchange of intercalary seg- ments can be performed as the patient grows, adding 2 cm to the length of the segment replaced. When extremity length discrep- ancy reaches approximately 2 cm or more, an expansion procedure is in- dicated. The original incision is used, and the pseudocapsule around the prosthesis is excised to prevent problems with joint stiffness after lengthening and to relieve tension on the neurovascular bundle. Eckardt et al 36 reported on their 14-year ex- perience with 32 expandable pros- theses. Nineteen of the 32 patients (59%) survived, with a median fol- low-up of 105 months. Sixteen of the patients (50%) did not undergo an expansion because of death, am- putation, or short duration of follow- up. The remaining 16 patients un- derwent 32 expansion procedures, to a maximum of 9 cm, without infection. The average time from implantation to the first lengthening was 19 months. Most of the length- enings were 1.5 to 2 cm. More than 50% of the patients had at least one complication, most frequently aseptic loosening or failure of the prosthesis, collapse of the LEAP, tem- porary nerve palsy, or flexion con- tractures. The average MSTS ratings

Malignant Bone Tumors: Limb Sparing Versus Amputation

were good to excellent at the knee, fair to good at the hip, and fair about the shoulder. The authors concluded that, in children and the skeletally immature, rehabilitation can be problematic; early loss of joint mo- tion and fixed flexion contractures can occur. With advances in tech- nology, a noninvasive prosthetic lenghtening mechanism is now being evaluated clinically.

Rotationplasty

Rotationplasty, another recon- struction option in the skeletally im- mature patient, can be done after wide resection about the knee when the sciatic nerve can be preserved. The tibia is rotated 180° and fused to the femur, with the ankle joint placed at the level of the contralateral knee. The procedure creates a func- tional below-knee amputation; out- come far exceeds that associated with above-knee ablation. The main indication for this technique is in a very young child with an extensive malignant bone tumor and several years of growth remaining. Rotation- plasty also may be used in adults when soft-tissue coverage is inade- quate after extensive tumor resec- tion. In general, the procedure is associated with a low incidence of complications and a highly func- tional and durable extremity recon- struction. 37 Advantages include the maintenance of growth and a func- tioning “knee” joint, the ability to tailor the procedure to obtain limb- length equality at skeletal maturity without further operations, an energy- efficient gait pattern, and avoidance of the problems of neuromas and stump breakdown seen with ampu- tations. With the advent of expand- able prostheses in the late 1980s, however, the indications for rota- tionplasty have narrowed. A full presurgical discussion is essential so that the patient and family under- stand the advantages and cosmetic appearance of the reconstructed limb, thus limiting postoperative

dissatisfaction or psychological problems. Meetings with other pa- tients who have had the procedure are beneficial. Kotz 37 reviewed the results of 40 patients treated with rotationplasty between 1976 and 1988. Thirty were followed for more than 3 years. No patient developed local recurrence; six died from metastatic disease, and the remaining 24 were tumor free. All patients were prosthetic ambula- tors without additional supports, and most participated in sports. Functional evaluation revealed 68% excellent, 28.5% good, 3.5% fair, and no poor results according to the system of Enneking et al. 38 Compli- cations of rotationplasty include postoperative vascular occlusion, pseudarthrosis between femur and tibia, nerve palsies, rotational mal- alignment, and diffuse osteopenia in the distal limb bones. The high level of function achieved by most pa- tients far outweighs the appearance of the limb, limiting the psychologi- cal problems associated with rota- tionplasty. 37,39 Long-term follow-up studies have shown the high durabil- ity of rotationplasty, with continued excellent or good results at 8 years. 39

Limb-Sparing Procedures Compared With Amputation

Survival and Local Recurrence Rates

In comparing limb-sparing proce- dures with amputation, the points selected as outcome measures are important. The primary goal of any oncologic procedure is local tumor control to diminish local recurrence and improve overall survival. Limb-preserving procedures have not decreased overall survival rates 4,5,11,19,41,42 (Table 3). Local recur- rence associated with limb-sparing resection and reconstruction is slightly greater than it is after ampu- tation or joint disarticulation, but this has not been found ultimately to affect patient survival. 4,41 In the largest series to date comparing limb-sparing surgery with amputa- tion in 227 patients with osteosarco- ma of the distal femur, Rougraff et al 41 found local recurrence in 8 of 73 patients treated with limb preserva- tion, in 9 of 115 patients treated with above-knee amputation, and in none of 39 patients treated with hip disar- ticulation.

Limb Lengthening

The Ilizarov bone transport pro- cedure and other techniques of limb lengthening can be used to regain bone length after resection and re- construction. Limb lengthening by distraction osteogenesis or bony transport has limited utility after resection of malignant bone tumors when used as the primary recon- struction technique. The large os- seous defect is difficult to replace and requires extended periods of treatment, which are associated with significant complications. Fre- quently, the final functional result with this technique is poor. 40 Limb- lengthening procedures are better suited as adjuncts to other methods of reconstruction or for smaller defects.

Functional Outcome

The MSTS system for assessing the function of reconstructive pro- cedures (Table 2) is designed to allow for comparison of results. 16 Functional outcome studies com- paring limb preservation and amputation have inherent limi- tations, however, including the inability to randomize treatment and the subjective nature of impor- tant outcome measures. Most func- tional outcome measures favor nonarthrodesis procedures because range of motion is measured. Most of the studies designed to assess functional outcome focus on pa- tients with perigeniculate tumor resections. Good and bad out- comes occur with whatever proce- dure is used, and there is little dif-

Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD

Table 3 Limb Sparing Versus Amputation for Extremity Bone Sarcomas

Management

Outcome Measure

Limb Sparing *

Amputation

Local recurrence 4,5,11,19,41,42

Survival 4,5,11,19,41,42

Functional outcome 41,42,44-47 Initial cost 43 Long-term cost 43

5% to 10%

70%

Good High Less than amputation

5%

70%

Good Low More than limb- sparing procedure

* 85% to 90% of patients with extremity bone sarcomas can be managed with limb-sparing surgery. Only 10% to 15% of patients require ablative surgery as initial management.

ference in quality-of-life outcomes between limb-sparing and amputa- tive surgeries. 43 Rougraff et al 41 found that their limb-preservation group had higher functional scores than did the group treated with amputation but that the limb-preservation patients fre- quently required additional surgical procedures to reach peak function. Renard et al 42 found functional re- sults to be significantly (P = 0.0001) better after limb-saving surgery compared with ablative therapy; however, complications were three times more common in the limb- saving cohort. Otis et al 44 studied the energy cost during gait by measuring oxy- gen consumption in 14 patients with custom-made knee prostheses and 12 patients who had had above- knee amputations and been fitted with an artificial limb. They con- cluded that prosthetic reconstruc- tion provides superior function because these patients had a lower energy cost during gait. In contrast, the patients studied by Harris et al 45 functioned similarly and walked with comparable velocity, efficien- cy, and rate of oxygen consumption whether they had had an amputa- tion, arthrodesis, or arthroplasty. The patients treated with endopros- theses lived more sedentary lives

and were the most protective of the limb. Kawai et al 46 evaluated clinical outcomes, length of resection, and energy cost of walking after pros- thetic knee replacement for malig- nant tumors of the distal femur. The mean free-walking velocity was 79% of normal, reflecting a decrease in both cadence and stride length. Also, mean energy cost during walk- ing was 35% greater than that of normal control subjects and correlat- ed with the percentage of femur that had been resected. Hillmann et al 47 reported on 67 patients with malig- nant tumors of the distal femur or proximal tibia who were treated by rotationplasty or endoprosthetic reconstruction. Patients with a rota- tionplasty had a mean MSTS func- tional score of 80% (24/30) com- pared with 83.3% (25/30) for patients treated with an endoprosthesis. Those with a rotationplasty had fewer restrictions in their daily activ- ities and required ambulatory assis- tive devices less frequently than did those reconstructed with a prosthe- sis. Finally, McClenaghan et al 48 compared oxygen consumption in patients treated with above-knee amputation, arthrodesis, or rota- tionplasty. Patients treated by ro- tationplasty walked the most effi- ciently.

Psychological Factors

Whether limb-sparing surgery offers a psychological outcome ad- vantage compared with amputation

for extremity sarcomas has yet to be demonstrated because no long-term prospective or comparative studies have been done. 5,49 In a small, retro- spective, one-time psychological assessment of patients treated for lower extremity sarcomas, no differ- ences between amputation and limb sparing were found regarding cog- nitive capacity, mood, body image, global physical functioning, global adjustment to illness and surgery, and lifetime prevalence of psycho- logical disorders before or after surgery. 49 Most patients adjust well to both the disease and the required surgical treatment if they have no premorbid psychological disorders. 5

Costs

Grimer et al 43 demonstrated that endoprosthetic reconstruction is less expensive than amputation, based on a 1997 cost analysis and 20-year follow-up. Their formula takes into account the projected need for revi- sion surgery, based on rates of asep- tic loosening of 2.5% per year and on rates of other causes of early fail- ure (eg, infection, implant failure) of 1.5% per year.

Future Directions

As experience is gained, the abili- ty to amend methods of treatment to improve outcomes will increase. Endoprostheses continue to be improved. Long-term results of modular rotating-hinge knee com- ponents are anticipated to yield better results than those of simple- hinge knee prostheses. A few insti- tutions have had experience with an endoprosthesis that is lengthened noninvasively by the application of external electromagnetic force, and development continues. Soft-tissue reattachment and ligament recon- struction are easier to perform be- cause of the use of osteoarticular

Malignant Bone Tumors: Limb Sparing Versus Amputation

allografts. With the development of tendon-attachment devices or en- hanced tendon-anchorage devices for prostheses, the indications and outcomes for proximal tibial pros- theses are likely to broaden and im- prove. 3 Better stability around the hip and shoulder after prosthetic reconstructions fit with these special devices should improve functional results in these regions. Extracor- tical bone-bridging fixation will likely improve the longevity of prostheses by walling off the pros- thesis-bone interface and adding additional points of fixation to improve construct strength. 3,9 For reconstructions using allo- grafts, bone morphogenetic proteins may decrease nonunion rates. A better understanding of allograft biology, as well as either closer matching of allografts to recipients

or modulation of immune respons- es, may decrease the presumed con- sequences of allograft reconstruc- tion. Using more vascularized bone grafts and combining them with allografts may help reduce or address rates of nonunion and frac- ture. The continued vigilant use of adequate soft-tissue coverage in reconstruction procedures, which reduced early postoperative wound complications, likely will decrease the incidence of late deep wounds.

Summary

The surgical management of malig- nant bone tumors of the extremities presents many challenges. With advances in chemotherapy, radio- graphic imaging, and reconstructive surgery, most patients with these

rare tumors now can be offered limb-sparing surgery. Osteoarticular allografts, modular prostheses, or composites of these two approaches form the basis for most current reconstruction efforts. However, amputation still plays an important role and offers a standard to which other approaches must be com- pared. Functional outcome and patient satisfaction appear to be at least as good, and probably better, after skeletal reconstruction than after amputation. However, the sur- gical treatment regimen associated with limb-sparing procedures is also associated with significant complica- tions and requires extensive rehabili- tation. Outcomes should continue to improve as advances are made in surgical technique, implant design, autogenous bone allograft biology, and postoperative management.

References

  • 1. Eilber FR, Eckhardt J, Morton DL: Advances in the treatment of sarcomas of the extremity: Current status of limb salvage. Cancer 1984;54(11 suppl): 2695-2701.

  • 2. Enneking WF: An abbreviated history of orthopaedic oncology in North America. Clin Orthop 2000;374:115-124.

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Matthew R. DiCaprio, MD, and Gary E. Friedlaender, MD

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  • 26. Getty PJ, Peabody TD: Complications and functional outcomes of reconstruc- tion with an osteoarticular allograft after intra-articular resection of the proximal aspect of the humerus. J Bone Joint Surg Am 1999;81:1138-1146.

  • 27. Friedlaender GE: Bone allografts: The biological consequences of immunolog- ical events. J Bone Joint Surg Am 1991; 73:1119-1122.

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  • 29. Shaffer JW, Field GA, Goldberg VM, Davy DT: Fate of vascularized and nonvascularized autografts. Clin Orthop 1985;197:32.

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  • 33. Wolf RE, Scarborough MT, Enneking WF: Long-term followup of patients with autogenous resection arthrodesis of the knee. Clin Orthop 1999;358:36-40.

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Joint Surg Am 1994;76:649-656.

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Use of Antibiotic-Impregnated Cement in Total Joint Arthroplasty Thomas N. Joseph, MD, Andrew L. Chen, MD,

Use of Antibiotic-Impregnated Cement in Total Joint Arthroplasty

Thomas N. Joseph, MD, Andrew L. Chen, MD, and Paul E. Di Cesare, MD

Abstract

The use of antibiotic-impregnated cement in revision of total hip arthroplasty pro- cedures is widespread, and a substantial body of evidence demonstrates its effi- cacy in infection prevention and treatment. However, it is not clear that

it is necessary or desirable as a routine means of prophylaxis in primary total joint arthroplasty. In the management of infected implant sites, antibiotic- impregnated cement used in one-stage exchange arthroplasties has lowered rein- fection rates. In two-stage procedures, use of beads and either articulating or nonarticulating antibiotic-impregnated cement spacers also has lowered reinfec- tion rates. In addition, spacers reduce “dead space,” help stabilize the limb, and facilitate reimplantation. Problems associated with antibiotic-impregnated cement in total joint arthroplasty include weakening of the cement and the genera- tion of antibiotic-resistant bacteria in infected implant sites.

J Am Acad Orthop Surg 2003;11:38-47

In 1970, Buchholz and Engelbrecht 1 introduced the concept of impreg- nating acrylic bone cement with antibiotic as a possible means of preventing infection in patients undergoing total joint arthroplasty. Since then, antibiotic-impregnated cement has become more commonly used for revision total joint arthro- plasty and, as antibiotic-impregnated cement spacers or beads, for treat- ment of infection during two-stage revision arthroplasty than it has for infection prophylaxis in primary total joint arthroplasty. Even with- out the contribution of antibiotic- impregnated cement, the infection rate after standard primary total joint arthroplasty in modern oper- ating rooms has been reduced to between 0.3% and 2%. A survey from 1995 concerning orthopaedic operating room practices and equip- ment suggested that this reduction has been achieved by the access to

laminar airflow (present in 49% of hospital operating rooms), body exhaust suits (in 69%), high airflow (in 85%), and ultraviolet lights (in 14%). 2 Reported infection rates after revision total joint arthroplasty vary widely because of the large number of patient variables. Several types of acrylic bone cement in current use incorporate antibiotics, either premixed by the manufacturer or added by the sur- geon in the operating room. In the United States, commonly used cements such as Palacos (Smith & Nephew, Memphis, TN), Simplex (Howmedica, Rutherford, NJ), CMW (DePuy, Warsaw, IN), and Zimmer (Zimmer, Warsaw, IN) are mixed with antibiotics by the sur- geon. Commercially prepared ad- mixtures such as AKZ (Simplex P with colistin and erythromycin), Refobacin-Palacos R (Palacos R with gentamicin cement), and Septopal

(beads of Palacos R with genta- micin) are not currently available in the United States. Some hospital pharmacies (2.2%) prepackage ce- ment with antibiotic for later use in the operating room. 3 A survey of 1,015 orthopaedic surgeons in the continental United States revealed that 56% have im- pregnated their bone cement with antibiotic for at least some cases. 2 Surgeons specializing in joint recon- struction were more likely to use antibiotic in bone cement (88%). Sixty-five percent of all surgeons surveyed reported that they adjust- ed antibiotic usage according to microbial sensitivity; of this group, 70% used tobramycin; 26%, genta- micin; 18%, vancomycin; 15%, cephalosporins; and 3%, combined antibiotics. Antibiotics in liquid

Dr. Joseph is resident, Department of Ortho- paedic Surgery, Musculoskeletal Research Center, NYU–Hospital for Joint Diseases, New York, NY. Dr. Chen is resident, Department of Orthopaedic Surgery, Musculoskeletal Research Center, NYU–Hospital for Joint Diseases, New York. Dr. Di Cesare is Associate Professor of Orthopaedic Surgery, Department of Ortho- paedic Surgery, Musculoskeletal Research Center, NYU–Hospital for Joint Diseases, New York.

Reprint requests: Dr. Di Cesare, 15th Floor, 301 East 17th Street, New York, NY 10003.

Copyright 2003 by the American Academy of Orthopaedic Surgeons.

form, generally considered to be less desirable than the powdered form (because of the effects to cement polymerization), were used by as many as 11% of the surgeons surveyed, possibly because of the general unavailability of a pow- dered form of gentamicin in the United States. In performing prima- ry arthroplasties, approximately 12% of surgeons always used anti- biotic-impregnated cement, 69% never used it, and 19% used it some- times. Of those who did use it, 68% did so in less than one third of their aseptic revision total joint arthro- plasties. However, over 80% used it more than two thirds of the time in septic revision total joint arthroplas- ty. Over half often used antibiotic- impregnated cement beads in two- stage reimplantation for infections; 32% often used antibiotic-impreg- nated cement spacers in hips; and 69% often used such spacers in knees. Of those using antibiotic- impregnated cement, 28% used a single-stage reimplantation in total joint arthroplasty infection, while 72% used a two-stage approach. 2 These data suggest that no com- monly accepted standard exists regarding the use of antibiotic- impregnated cement in orthopaedic surgery. The FDA takes no official posi- tion on the use of antibiotics in cement. A document issued July 17, 2002, requires that cement labeling contain the warning, “PMMA bone cement is contraindicated in the presence of active or incompletely treated infection, at the site where the bone cement is to be applied.” 4

Laboratory Studies

A number of criteria must be met for antibiotics to be effective when mixed with methylmethacrylate. The preparation must be sufficiently thermally stable to withstand the heat of polymerization. The antibi-

otic must not be adversely affected by body temperature and must be water soluble so that it can diffuse into surrounding tissues. The antibiotic must have a bactericidal effect at the tissue levels attained; furthermore, it must be released gradually over an appropriate time period. The preparation must evoke minimal local inflammatory or allergic reaction. Development of resistance should be rare to nonexis- tent; common pathogens must be considered, including Staphylococcus aureus, S epidermidis, coliform, and others, such as anaerobes. Finally, the antibiotic must not significantly compromise mechanical integrity, especially if the cement is used for implant fixation. In vitro analyses of antibiotic elu- tion and mechanical stability have been done with a variety of antibiot- ic-cement combinations. The stable incorporation of aminoglycoside antibiotics (eg, gentamicin and tobramycin) into cement and their elution therefrom are well estab- lished. Vancomycin is gaining pop- ularity because of its effectiveness against methicillin-resistant bacteria as well as its general availability. Although penicillins and cephalo- sporins exhibit adequate elution and stability, they are often avoided be- cause of their potential allergenicity. In one study, in vitro testing of van- comycin- and tobramycin-impreg- nated cement demonstrated elution of antibiotic for the entire 9-week study period; the highest elution rate occurred at 18 hours (between 3 and 5 times the rate that occurred at 72 hours). 5 Ciprofloxacin, a more re- cent addition to bone cement, may gain in popularity because of its wide antibiotic spectrum and gener- al availability. Ciprofloxacin elution met or exceeded the minimum inhibitory concentration for com- mon organisms associated with osteomyelitis for up to 42 days. 6 Recent studies 7,8 indicate that ciprofloxacin may inhibit bone, liga-

Thomas N. Joseph, MD, et al

ment, and soft-tissue healing; this is a concern, particularly in total knee revision surgery. Lipids may impede the leaching process from cement. The peptide antibiotics vancomycin and poly- myxin B nonapeptide have been shown to elute for a longer period than do the nonpeptide antibiotics gentamicin, novobiocin, and eryth- romycin. 9 Molecular weight also appears to play a role. One in vitro study indicated that vancomycin is eluted 10 times less efficiently than tobramycin from antibiotic-impreg- nated cement, probably because of its higher molecular weight. 10 Other in vitro studies, however, found no marked difference between the two. 11 Palacos cement appears to pro- vide the best elution profile for most antibiotics. A study of the elution characteristics of Palacos and CMW acrylic cements showed that CMW 1 released 24% less tobramycin and 36% less vancomycin than did Pala- cos; CMW 3 released 34% less tobra- mycin and 38% less vancomycin. 5 Another in vitro study, in which Palacos and Simplex beads and spacers were impregnated with 4 g of either vancomycin or tobramycin in 40 g of cement, also showed antibiotic eluting from Palacos at higher levels. 12 Concentrations re- mained above the minimum inhibi- tory concentration for S aureus longer in Palacos than in Simplex. In another study, elution of van- comycin, daptomycin, and amikacin from Palacos exceeded that of Simplex, Zimmer Dough-Type, and Zimmer LVC. 13 Commercially prepared antibiot- ic cement may be superior to intra- operatively mixed cement. Elution of gentamicin and tobramycin from laboratory-customized Zimmer, Simplex, or Palacos beads compared with elution from commercially pre- pared gentamicin-PMMA (Septopal) beads showed that more total an- tibiotic was eluted from the latter, and was maintained at higher con-

Antibiotic-Impregnated Cement in Total Joint Arthroplasty

centrations, than it was in the beads to which antibiotics were added by the investigators. 14 The results of studies of the effect on elution of combinations of antibi- otics, typically vancomycin and tobramycin, are inconclusive. In one study, elution of vancomycin was minimally affected by tobramycin, while elution of tobramycin was reduced by vancomycin. 10 In anoth- er study, the elution rate of tobramy- cin increased by 68% and that of van- comycin by 103% when these antibi- otics were combined. 15 In the first study, 10 vacuum-mixed Simplex was used, and in the second, 15 nonvacu- um-mixed Palacos. In both, the most advanced means of measuring an- tibiotic were used. An in vivo study using the prosthesis of antibiotic- loaded acrylic cement (PROSTA- LAC; Smith & Nephew, Memphis, TN) demonstrated a statistically sig- nificant (P = 0.011) increase in the elution of vancomycin when the dose of tobramycin was increased from 2.4 to 3.6 g per dose of cement; Simplex was used in 12 patients and Palacos in 37. 16 The investigators changed the cement early in their study after finding evidence in the literature suggesting better antibiotic elution from Palacos. Klekamp et al 10 demonstrated that compressive and fatigue strength decreased with the addition of van- comycin or tobramycin to cement. Cement impregnated with 1, 2, or 3 g of vancomycin failed at 90%, 70%, and 50%, respectively, of the num- ber of cycles to failure for antibiotic- free cement. Likewise, cement with 1.2 and 2.4 g of tobramycin failed at 80% and 60%, respectively, of the number of cycles to failure for con- trols. Although fatigue strength data were statistically significant (P < 0.05), the results of compressive strength tests demonstrated a de- creasing trend yet were not statisti- cally significant. Routinely used lyophilized vancomycin was found to greatly reduce cement fatigue

strength. The authors suggested using vancomycin P (an ultrafine powder) in bone cement intended for prosthesis fixation because it has less detrimental effect on cement strength. Askew et al 17 found that the addition of 1 g of either tobra- mycin or vancomycin resulted in nominal bending strength reduc- tions (6% and 1%, respectively, compared with controls). Another study confirmed that the addition of 1.2 g of tobramycin to 40 g of Sim- plex powder did not significantly de- crease fatigue strength. 18 Vancomy- cin L (lyophilized) should be finely ground when used for prosthesis fixation to prevent mechanical weakening; however, large crystals should not be completely pulver- ized when preparing beads or spac- ers because the crystals facilitate antibiotic elution. Morita and Aritomi 19 showed no reduction in tension and bending strengths of cefuzonam-impregnated cement when <3 g was used. Earlier studies showed similar results with respect to compressive and tension strengths of cement impregnated with gentamicin, oxacillin, and cefa- zolin. 20 Addition of more than 4.5 g of gentamicin has been shown to

substantially weaken cement to a level below that appropriate for implant fixation. 21 Reduction of no more than 10% in bone cement strength is considered acceptable for use in total joint arthroplasty fixa- tion; however, weaker antibiotic- impregnated cement may be used in beads and spacers. Table 1 lists ap- propriate doses of antibiotic im- pregnation in cement for prosthesis fixation and for spacers and beads. Vacuum mixing, which reduces the number of voids in bone ce- ment, improves the mechanical properties of antibiotic-impregnated cement. When cylindrical cement- vancomycin specimens were sub- jected to fatigue testing (uniaxial mode), cycles to failure were 15% to 58% greater in vacuum-mixed speci- mens than in those mixed at atmos- pheric pressure. Fracture of antibi- otic-impregnated cement specimens during cyclic testing was reduced up to tenfold with vacuum mixing or with vigorous pulverizing of the antibiotic before mixing. 10 Another study showed vacuum mixing also reduced fivefold the radiograph- ically apparent porosity of antibiotic- impregnated cement specimens but may inhibit antibiotic release. 17 In

Table 1 Reported Doses * of Antibiotics Used in Antibiotic-Impregnated

Cement 13,26,44,53-55

Antibiotic

Dose for Prosthesis Fixation

Dose for Spacers and Beads

Amikacin

1 g

2 g

Cefazolin

NR

4 to 8 g

Cefotaxime

3 g

NR

Cefuroxime

1.5 to 3 g

NR

Clindamycin

NR

4 to 8 g

Erythromycin

0.5 to 1 g

NR

Gentamicin

1 g

2 to 5 g

Ticarcillin

Not appropriate

5 to 13 g

Tobramycin

1.2 g

2.4 to 9.6 g

Vancomycin

1 g (vancomycin P)

3 to 9 g (vancomycin P or L)

* Per 40-g batch of cement P = ultrafine powder, L = lyophilized, NR = not reported in the literature

one study, vancomycin vacuum- mixed with Simplex (1:40 ratio) released slightly less than half the antibiotic that air-mixed cement did; no antibiotic release was detectable after 48 hours. 13 Another study, however, found adequate antibacte- rial activity lasting for 21 days. 17 Dextran has been used to en- hance porosity and thus improve the elution of antibiotic. One prepara- tion with dextran released approxi- mately 4 times as much antibiotic as did a dextran-free preparation, and elution remained detectable for 10 days versus 7 days, respectively. 13 However, dextran degrades the mechanical properties of cement; therefore, its use for prosthetic fixa- tion should be extremely limited. Centrifugation, another preparation technique, markedly increased the fatigue life of Simplex both with and without tobramycin by a factor of eight. Increase in the surface area of antibiotic-impregnated cement spac- ers has been shown to increase elu- tion of antibiotic in vitro. Holtom et al 22 demonstrated that fenestrated spacers with a 40% greater surface area resulted in a 20% higher elution rate of vancomycin from Palacos ce- ment than from standard or donut- shaped spacers. Masri et al 23 demon- strated a significant ( P = 0.05) in- crease in the elution of tobramycin

Thomas N. Joseph, MD, et al

over 1 week with the use of Simplex- impregnated blocks that had a 9% increased surface area-to-volume ratio. Antibiotics in liquid form mixed with cement dilute the catalyst that is needed for the cement curing process, thereby adversely affecting both the curing time and final mechanical properties of cement; accordingly, they are not recom- mended. Table 2 lists antibiotics that can be mixed with cement.

In Vivo Studies

The penetration of antibiotics re- leased from antibiotic-impregnated cement into surrounding tissues has been evaluated in both animal and human studies. Concentrations of antibiotic in hematoma, granulation tissue, and bone vary according to antibiotic. Local concentrations, however, have been found to be consistently higher than serum con- centrations and usually exceed the minimum inhibitory concentrations for target pathogens. The elution of several antibiotics from Simplex cement was measured in samples from dogs over a 28-day period. 24 Clindamycin, vancomy- cin, and tobramycin exhibited elu- tion characteristics that reached con- sistently high levels in bone and

granulation tissue. Cefazolin and ciprofloxacin were maintained at high concentrations in granulation tissue but at low levels in seroma and bone. Ticarcillin showed unfa- vorable elution characteristics in granulation tissue, seroma, and bone. Experimentally produced para- spinal wounds (fractured, infected spinous processes) in rabbits were treated with either a chain of to- bramycin antibiotic-impregnated cement beads, beads without antibi- otics, systemic antibiotics only, or nothing. 25 At 5 days, no recoverable organisms were found in six of eight animals treated with antibiotic- impregnated cement beads. Six of eight rabbits receiving systemic tobramycin had wound infections. All five animals in which nonantibi- otic-impregnated cement beads were implanted had significant infections; one died from sepsis. All four ani- mals that received no treatment were infected. Antibiotic concentrations were measured in wound drainage fluid, urine, and serum from 50 patients who underwent primary total hip arthroplasty (THA) and received tobramycin or vancomycin deliv- ered either in antibiotic-impregnated cement or by intravenous adminis- tration (not both). 26 No significant differences were found between

Table 2 Antibiotics Used in Antibiotic-Impregnated Cement

Can Be Mixed With Cement

 

Decreased Activity Because of Cement Heat

Adversely Affected by Cement Curing

Amikacin

Cefuzonam

Erythromycin

Penicillin

Chloramphenicol

Liquid gentamicin,

Amoxicillin

Cephalothin

Gentamicin

Polymyxin B

Colistimethate

clindamycin, etc (because

Ampicillin

Ciprofloxacin

(powder)

Streptomycin

Tetracycline

of aqueous content)

Bacitracin

Clindamycin

Lincomycin

Ticarcillin

Rifampin

Cefamandole

(powder)

Methicillin

Tobramycin

Cefazolin

Colistin

Novobiocin

Vancomycin

Cefuroxime

Daptomycin

Oxacillin

Antibiotic-Impregnated Cement in Total Joint Arthroplasty

Simplex and Palacos surgeon- prepared antibiotic-impregnated cement. Serum and urine antibiotic levels were significantly (P 0.05) higher in the intravenous group than in the impregnated-cement group. Wound drainage fluid levels of tobramycin were significantly (P 0.05) higher in the antibiotic- impregnated cement group than in the intravenous group, whereas the vancomycin intravenous group had higher antibiotic levels in wound drainage fluid than did the van- comycin cement group. In the cement group, tobramycin exhibited a consistently high level of bioactivity against S epidermidis in wound drainage fluid, while vancomycin lost all bioactivity by 24 hours. In 30% of cases, no vancomycin was detected in the wound drainage fluid of the cement group. Overall, tobramycin exhibited adequate local tissue levels and released antibiotic effectively, whereas vancomycin exhibited inadequate elution prop- erties.

Clinical Studies

Primary Total Joint Arthroplasty

Because of the low rates of infec- tion experienced with total joint arthroplasty procedures, researchers seeking to demonstrate statistically significant differences with the pro- phylactic use of antibiotic-impreg- nated cement require a very large sample size with multicenter partici- pation. A prospective, randomized study in Sweden combined results from nine orthopaedics departments (1,688 consecutive THAs) to com- pare the prophylactic effect of systemic antibiotics to that of genta- micin-impregnated cement alone. At a mean follow-up of 10 years, the infection rate was 1.6% in the sys- temic antibiotic group and 1.1% in the gentamicin-impregnated cement group, a difference that was not sta-

tistically significant. 11 No cases of nephrotoxicity, ototoxicity, or aller- gic reaction were reported. More than 10,000 primary ce- mented total hip replacements done for osteoarthritis and reported to the Norwegian arthroplasty registry were studied retrospectively. 27 Four groups were compared: patients receiving antibiotic prophylaxis both systemically and locally in antibiotic- impregnated cement, those receiv- ing antibiotics only systemically, those receiving only antibiotic- impregnated cement, and those receiving no antibiotic prophylaxis. The antibiotic-impregnated cement was either Palacos with gentamicin or AKZ (erythromycin and colistin with Simplex). The rate of revision done for any reason was 2.0% (94/4,586) in patients receiving only systemic antibiotics, 4.2% (10/239) for antibiotic-impregnated cement only, 1.2% (70/5,804) for the com- bined regimen, and 2.5% (7/276) for no antibiotics. Among cases that sub- sequently required revision for in- fection, the lowest revision rate, 0.14% (8/5,804), was in patients who received both antibiotic-impregnated cement and systemic antibiotics. A prospective, randomized clini- cal trial of 401 patients in two British centers compared the effect of cefuroxime-impregnated cement and cefuroxime administered sys- temically on infection after total joint arthroplasty. 28 No statistically significant difference was found between the two groups with respect to incidence of superficial wound infection or early deep infec- tion (1% in both groups). There were no late deep infections after 2- year follow-up. Hope et al 29 found at least one strain of gentamicin-resistant coag- ulase-negative staphylococcus in 30 of 34 cases of deep infection (88%) in which cement containing gentamicin had been used. In contrast, only 9 of 57 patients (16%) in whom antibi- otic-free cement was used exhibited

gentamicin-resistant coagulase-neg- ative staphylococcus.

Revision Arthroplasty

Revision arthroplasty usually is accompanied by rates of infection significantly higher than rates for primary arthroplasty. Revision arthroplasties done for infection are either one- or two-stage procedures. Two-stage revisions are more com- mon, but they can be technically demanding because of scar forma- tion, limb shortening, disuse osteo- porosis, and altered anatomy. Although advocates of two-stage

reimplantation cite infection rates lower than those of one-stage revi- sions, carefully selected patients can be treated with comparable success with one-stage revisions using antibiotic-impregnated cement. In one review of the literature, success rates of one-stage exchange with and without the use of antibiotic-impreg- nated cement were 81% and 71%, respectively; the success rates of two-stage reimplantation with and without antibiotic-impregnated cement were 93% and 82%. 30 One-Stage Revision for Infection

One-stage exchange arthroplasty using antibiotic-impregnated ce- ment has been advocated in defined instances for the treatment of an infected total joint arthroplasty. In a multicenter comparison of one- and two-stage exchange arthroplasties for infection conducted in the 1970s, a success rate of approximately 80% was found for both methods. 31 Gentamicin-loaded Palacos and 6 months of systemic antibiotics were used in all procedures. The results were slightly better for one-stage exchanges; however, follow-up was relatively short (0.5 to 3.5 years). In a study of 235 one-stage exchanges for THA infection using antibiotic- impregnated cement, 11% with per- sistent infection failed; another 3% of cases with suspected infection failed. 32 Of the 61 two-stage ex- changes, which used antibiotic-

Thomas N. Joseph, MD, et al

impregnated cement beads for peri- ods of from 6 weeks to 9 months, 5% failed from reinfection. Hope et al 29 reviewed a series of 91 patients with deep infection of a cemented THA caused by coagulase-negative staphylococcus. In this series, 72 pa- tients were treated with one-stage exchange arthroplasty; 9 (13%) failed because of recurrence of infec- tion. Gentamicin was used in com- bination with other antibiotics based on organism sensitivities. The other

  • 19 patients underwent a two-stage

exchange without any failures. Although it has been suggested that a contraindication to one-stage reimplantation is infection with a gram-negative organism, a study of

  • 15 patients with gram-negative

infection treated with one-stage THA revision found only 1 recur- rence (6.7%) at a mean follow-up of 8 years. Palacos cement with gen-

tamicin was used in 13 of 15 pa- tients, with other antibiotics added to cement as appropriate. 33 In a larger study of 183 patients with similar follow-up (mean, 7.75 years), one-stage revision with both antibi- otic-impregnated cement and sys- temic antibiotics was used for deep infection of a THA. 34 Twenty-nine of these patients (16%) had evidence of persistent infection and 154 (84%) were free of infection on follow-up. None of the 29 patients who experi- enced failure was infected with gram-negative organisms. For patients undergoing revision arthroplasty, Garvin et al 35 devel- oped a classification system of high-risk, suspicious, and definite infection categories. These were based on Gram stains, cultures, intraoperative findings, clinical diag- noses, radiographic findings, and laboratory results. 35 In a prospec- tive clinical study, gentamicin- impregnated Palacos was used for prosthesis fixation in 67 high-risk,

  • 32 suspicious, and 31 definite infec-

tions. All but one of the high-risk

patients underwent one-stage pro-

cedures; those with suspicious or definite infections underwent either one- or two-stage procedures plus 6 weeks of intravenous antibiotics. Postoperative infection occurred in 5 of the 92 one-stage patients (5.4%) and in none of the 38 two-stage patients. Of the 67 high-risk patients, 3 (4.5%) developed post- operative infections; one was then revised with a successful two-stage procedure. Of the 32 patients suspi- cious for infection, 19 underwent

one-stage implantation; one of them developed a postoperative infection. The other 13 patients with suspi- cious infection underwent success- ful two-stage implantation. Of patients with definite infection, 7 of

31 underwent one-stage implanta- tion, with one of them developing a postoperative infection; 24 patients had a successful two-stage implan- tation. To test that one-stage revisions can be successful if rigid criteria are met, Ure et al 36 prospectively fol- lowed 20 consecutive patients under- going one-stage THA for infection between 1979 and 1990. Surgical management included meticulous débridement, use of antibiotic- impregnated cement, and systemic antibiotic therapy. Patients were excluded from this treatment when they were immunocompromised, had an infection with a known resis- tant gram-negative or methicillin- resistant organism, or had a major skin, soft-tissue, or osseous defect.

At a mean follow-up of 9.9 years, no patient had experienced recurrence of infection. Two patients required revision for aseptic loosening. Parenteral antibiotics were adminis- tered postoperatively for a mean of 4.7 months.

Two-Stage Revision for Infection

By reducing dead space, cement spacers help stabilize the limb awaiting reimplantation (Fig. 1).

Complications include bone loss, dislocation, continued pain, de- creased mobility, and (rarely) frac-

ture. Local antibiotic delivery with cement spacers, cement beads, or a PROSTALAC has been used after component removal in a two-stage procedure. Additionally, antibiotic- impregnated cement can be used for prosthesis fixation during reimplan- tation in the second stage. Antibiotic-impregnated cement spacers used in the first stage of two-stage reimplantation can deliv- er a high concentration of antibiotics to the infected area. In a retrospec- tive study, Calton et al 37 treated 25 infected total knee prostheses in 24 patients with débridement, compo- nent removal, and insertion of an antibiotic-impregnated cement block. Intravenous antibiotics were admin- istered for 6 weeks; patients’ knees were kept immobilized with no weight bearing. The success rate was 92% (2 failures) at a mean fol- low-up of 36 months; 15 of 25 knees exhibited either tibial or femoral bone loss caused by invagination of the cement spacer block into the cancellous bone. Leunig et al 38 re- ported on 12 patients with deep infections of hip implants who un- derwent two-stage revision and were treated using gentamicin- loaded cement. Spacers were used for a mean of 4 months; during that period, six spacers failed, five by dislocation and one by fracture. At a mean follow-up of 27 months after reimplantation arthroplasty, all patients were mobile and infection free. An articulating spacer used in two-stage revision for infected total knee arthroplasty may improve patient mobility and allow partial weight bearing. This would pro- mote healthier soft tissues, improve wound healing, allow easier reim- plantation, improve bone quality and range of motion, and reduce complications. Hofmann et al 39 treated 26 patients who had late- infected total knee arthroplasties with two-stage revision using an articulating spacer with tobramycin-

Antibiotic-Impregnated Cement in Total Joint Arthroplasty

A B
A
B

Figure 1 Anteroposterior (A) and lateral (B) radiographs of an antibiotic-impregnated cement spacer in a two-stage revision total knee arthroplasty.

impregnated cement. The spacer was prepared by cleaning, autoclav- ing, and reinserting the femoral

component. A new tibial polyethyl- ene insert and in some cases a new all-polyethylene patellar component were used to place a large amount of antibiotic-impregnated cement between each insert and bone. Patients were treated with 6 weeks of intravenous antibiotic therapy. Reimplantation was performed 6 to

  • 12 weeks after placement of the

spacer. All but one patient (who died of systemic complications) underwent successful reimplanta- tion (96%). At a mean follow-up of 31 months, knee scores had improved and no recurrence of in- fection was found. Complications of early articulat- ing spacers included tibiofemoral instability and patellar instability; results subsequently have improved with design modifications. A recent study by Fehring et al 40 failed to

show any difference in range of motion or knee scores between articulating and static antibiotic- impregnated cement spacers used in two-stage revisions. The ar- ticulating spacers were custom-pre- pared using a stainless steel femoral component mold and stemmed tibial baseplate of antibiotic-impregnated cement. Nevertheless, reimplanta- tion was facilitated, and less bone loss occurred with articulating spac-

ers than with static antibiotic- impregnated spacers. Lai et al 41 reported on 40 infect- ed hip prostheses treated with component removal, intravenous and oral antibiotics for 8 weeks, and delayed reimplantation (mean, 48 weeks) with cementless compo- nents. At mean of 4 years’ follow- up, 5 patients (13%) had experi- enced recurrent infection: 2 of 33 from the group treated with Sep- topal (gentamicin) beads, and 3 of 6 of those treated without antibiotic-

impregnated cement beads. A pro- spective, randomized, multicenter study of 6 infected total knee and 22 infected hip arthroplasties in 28 patients compared two-stage re- implantation using gentamicin- impregnated cement beads with that using conventional parenteral systemic antibiotic therapy for 6 weeks postoperatively. 42 At a mean follow-up of 3 years, infection recurred in 2 of 15 patients treated with gentamicin-impregnated cement beads (13%) and in 4 of 13 patients treated with conventional systemic antibiotic therapy (31%); however, this was not statistically significant. Whiteside 43 used allo- graft technique with cementless revision arthroplasty for massive tibial and femoral defects in 33 chronically infected total knee arthroplasties. Treatment included implant removal, débridement, and rigidly fixed antibiotic-soaked bone graft followed by 6 weeks of antibi- otic-impregnated cement beads and intravenous antibiotics. The success rate of the two-stage procedure was 85%. Infection recurred in five knees; however, repeated procedures al- lowed successful revision in all but one, which required an above-the- knee amputation. Although use of antibiotic-impregnated cement beads or spacers is common in two-stage revisions, one study showed that their use in two-stage revisions was not correlated with cure rate for infection. 44 The PROSTALAC, introduced in 1989, is a temporary hip prosthesis composed of a thin polyethylene acetabular cup and a stainless steel femoral component, both of which are loosely cemented with antibiotic- impregnated cement (Fig. 2). Bene- fits include early mobilization, accel- erated rehabilitation, and early hos- pital discharge. The device maintains soft-tissue planes and leg lengths and has made second-stage proce- dures easier to perform. Younger et al 45 reviewed 48 patients who had

Thomas N. Joseph, MD, et al

Thomas N. Joseph, MD, et al Figure 2 Anteroposterior radiograph of the PROSTALAC in a two-stage

Figure 2

Anteroposterior radiograph of

the PROSTALAC in a two-stage revision THA.

undergone two-stage arthroplasty of an infected hip replacement using the PROSTALAC. All but three pa- tients were free from persistent infection, for an eradication rate of 94%. More recently, Younger et al 46 evaluated PROSTALACs with a cement-on-cement articulation and with a custom metal-on-polyethyl- ene articulation. Of 28 infected total hips followed for a minimum of 2 years, 96% exhibited no evidence of infection. In a retrospective study of 89 re- vision procedures for infected total knee arthroplasties, persistent infec- tion occurred in 10 knees (11.2%). 44 No standardized protocol was used for treatment. In 64 knees, antibiotic- impregnated cement was used for implant fixation; in 25, no antibiotic- impregnated cement was used. Antibiotic-impregnated beads were used in 20 patients, antibiotic- impregnated spacers in 23, both used in 4, and neither used in 42 patients. When use of antibiotic- impregnated cement for implant fix- ation was factored in, the results were statistically significant. Of the

25 knees without antibiotic-impreg- nated cement, 7 (28%) developed recurrent infection, compared with only 3 (5%) of the 64 knees treated with antibiotic-impregnated cement ( P < 0.01). Although antibiotic- impregnated cement beads or spac- ers appeared to be beneficial, their use was not statistically significant. We are not aware of any prospec- tive randomized study comparing antibiotic-impregnated cement beads or spacers to antibiotic- impregnated cement in prosthetic fixation.

Antibiotics in Revision Arthroplasty Without Infection

Although the use of antibiotic- impregnated cement in revision arthroplasty without evidence of infection has been advocated, the

literature on the subject is scant and equivocal. Lynch et al 47 reported notably better results with genta- micin-containing cement for aseptic revisions than with cement alone (systemic antibiotics not used), a reduction from 3.5% to 0.8%. A ret- rospective analysis with minimum 2-year follow-up reported that in aseptic revision THAs or conversion from upper femoral prosthesis (pro- phylactic systemic antibiotics not used), infection rates were 0.5% for gentamicin-impregnated cement and 2.8% for cement alone. 47 The authors concluded that low-viru- lence organisms that are difficult to culture may be present in some cases thought to be aseptic loosen- ing and that the local antibacterial effect is responsible for the effective prevention and treatment of infec- tion in these patients.

Experimental Cement-Antibiotic Combinations

Ceramic composites have been considered for use as a vehicle for

antibiotic delivery. In one laboratory study of a novel bioactive bone ce-

ment

(15% bisphenol- α -glycidyl

methacrylate, 15% triethylene-glycol

dimethacrylate resin, and 70% apatite- and wollastonite-containing glass-ceramic powder) containing cephalexin in the form of pellets, antibiotic release was initially rapid, slowed markedly after 24 hours, and was released continuously thereafter for 2 weeks. 48 The strength of the cement with cephalexin was approxi- mately twice that of acrylic antibiotic- impregnated cement. The authors suggested that this material may be suitable for prosthetic fixation as well as in beads or spacers. Another study tested the efficacy of a calcium hydroxyapatite ceramic with gen- tamicin in the form of blocks im- planted adjacent to stainless steel tibial inserts in rats that had been in- jected with S aureus. 49 Suppression of infection in the ceramic-genta- micin–treated animals was superior to that in controls, including those in which acrylic antibiotic-impregnat- ed cement was used. Biodegradable antibiotic-impreg- nated material offers a potential means of local antibiotic delivery for infection control or treatment with- out obligation for later removal. A biodegradable cement (composed of tricalcium phosphate and calcium carbonate with a matrix phase of polypropylene fumarate cross- linked with methylmethacrylate monomer) containing gentamicin and vancomycin was evaluated for treatment and prophylaxis of S aureus osteomyelitis in rat proximal tibias. 50 The treatment group exhib- ited significantly ( P < 0.01) fewer colony-forming units than did con- trols. Sites treated prophylactically developed no infections. No signifi- cant difference was found between biodegradable cement and PMMA used as a carrier for antibiotics. Another study showed that the ten- sile strength of the material and the biologic activity of the antibiotic were maintained when gentamicin was added to a resorbable calcium phosphate cement composed of β -tricalcium phosphate, monocal-

Antibiotic-Impregnated Cement in Total Joint Arthroplasty

cium phosphate monohydrate, and water. 51 More recently, calcium hydrox- ide has been added to PMMA beads containing tobramycin. 52 The beads released hydroxyl and calcium ions into the culture medium as well as a greater amount of antibiotic than did beads containing only tobramy- cin. Bacterial growth was more effectively inhibited when S aureus was incubated with tobramycin- and calcium hydroxide–impregnat- ed PMMA disks than with disks containing only tobramycin. The study did not, however, address the effects of the tobramycin and calci- um hydroxide combination on the strength of the cement. Future uses may include fracture healing and bone grafting in addition to osteo- myelitis treatment and implant attachment.

Summary

Since its introduction in 1970, antibi- otic-impregnated cement has been used in total joint arthroplasty in a variety of situations. In both one- and two-stage revision procedures for infection, antibiotic-impregnated cement clearly reduces the reinfec- tion rate. The antibiotic should be chosen based on the infecting organism or, if preoperative cul- tures are unavailable, by assessment of likely pathogens. In two-stage procedures, the use of articulating spacers implanted with antibiotic- impregnated cement may improve reimplantation results as well as quality of life in the period between procedures. There is some sugges- tive evidence that if cement is to be used in apparently aseptic revision surgery cases, the cement should be

antibiotic-impregnated because of the possibility that these culture- negative cases are indeed contami- nated. Because of the low rate of infections with established periop- erative and intraoperative protocols and the risk that using antibiotics will lead to the development of antibiotic-resistant bacteria, the rou- tine use of antibiotic-impregnated cement appears to be unnecessary in primary total joint replacement surgery. The future of antibiotic- impregnated cements may include stronger composites with more sus- tained release of a wide array of an- tibiotics. Bioabsorbable antibiotic- impregnated cements may further reduce reinfection rates in one-stage procedures by supplying additional local delivery of antibiotic via mate- rials that do not require later re- moval.

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