Osteoporosis and Osteopenia

Periodontology 2000, Vol. 59, 2012, 111139 Printed in Singapore.
All rights reserved
2012 John Wiley & Sons A/S
PERIODONTOLOGY 2000
Osteoporosis and osteopenia: implications for periodontal and implant therapy

J O A N O T O M O -C O R G E L
According to the National Osteoporosis Foundation, osteoporosis is a major public health threat for an estimated 44 million of the US population (55% of people 50 years of age) (163). In the USA, 10 million individuals are estimated to already have the disease and almost 34 million more are estimated to have low bone mass and thus are at risk for osteoporosis. In Europe, the USA and Japan, osteoporosis is estimated to affect 75 million people (64). One third of women and one-fth of men over 50 years of age will experience osteoporotic fractures, (103, 147). The combined lifetime risk for hip, forearm and vertebral fractures is approximately 40%, equivalent to the risk for cardiovascular disease (147). Bone mineral density is quantied using dual-energy X-ray absorptiometry scans to dene a T score. The T score compares bone mineral density with the mean peak bone density for an individual of the same gender and is reported as the number of standard deviations below that average. A T score of )2.5 or less is diagnostic for osteoporosis. Scores of )1.0 to )2.5 indicate osteopenia, and scores of 0 to )1.0 are considered normal (61). T scores are used to determine an individuals fracture risk primarily at the lumbar spine, total hip, femoral neck or trochanter. Some clinicians evaluate Z scores, which are also determined by a dual-energy X-ray absorptiometry scan, but compare the bone mineral density results with persons of the same age, weight, ethnicity and gender. Z scores are used to determine if there is an unusual reason for the alteration in bone mineral density (e.g. a systemic etiology such as thyrotoxicosis). The incidence of osteoporosis is higher in women (80%) than in men (20%). Women have a lower total bone mass than men, and peak bone levels occur at an earlier age in women (25 years of age, with 98% of the skeletal mass built by age 20) than
in men (30 years of age). Women reach menopause at a mean age of 5051 years, and a decrease in estrogen perimenopausally (35 years before menopause) and a few years after menopause (1 year without a menstrual cycle) causes accelerated bone loss (Table 1). In women, two stages of primary bone loss occur. The rst stage is rapid trabecular bone loss as a result of estrogen deciency initiated with the onset of menopause that occurs for a duration of approximately 48 years and is characterized by high bone resorption and reduced bone formation. The second stage involves slower trabecular and cortical bone loss that occurs as a result of decreased bone formation. In men, bone loss generally occurs at a slower rate, as a result of lower levels of bioavailable testosterone and estrogen. Among white women, the lifetime risk of hip fracture is one in six (compared with, for example, a one in nine risk of a diagnosis of breast cancer) (45). The greatest morbidity associated with osteoporosis is related to hip fractures, with 2024% mortality within the rst year after a hip fracture (120). Of those who survive, 4060% are unable to walk unassisted 1 year later. Although osteoporosis is more prevalent in women, the mortality rate for men with a hip fracture is double that in women of a similar age (104). Men acquire osteoporosis at a later age with a sharp increase in incidence observed at 70 years of age and older, and therefore complications of the hip fracture that result from immobility, for example thrombophlebitis, are more likely to occur in men. Risk factors for osteoporosis can be classed as nonmodiable or modiable (Table 2). Gender (female), hereditary factors, ethnicity, small body frame (<127 lbs), and early or surgical menopause are
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Table 1. Effects of estrogen on bone remodeling

Enhanced numbers of remodeling sites as a result of enhanced bone formation of osteoclasts and decreased formation of new bone in the resorption lacunae, eventually causing decreased bone mass and increased risk for osteoporosis Increased bone resorption is caused by decreased inhibition of estrogen on osteoclastogenesis and osteoclastic activity Estrogen receptors may be present in osteoclast progenitor cell and multinucleated osteoclasts. Note that marrow cells (macrophages, monocytes, osteoclast precursors and mast cells) and bone cells (osteoblasts, osteocytes and osteoclasts) have estrogen receptors a and b. Estrogen receptor-a is the dominant estrogen receptor in cortical bone and estrogen receptor-b is the dominant receptor in cancellous bone Estrogen suppresses the synthesis of cytokines responsible for stimulating osteoblast apoptosis and reducing osteoclast cell death. Stimulatory effect of estrogen on bone formation may be mediated by estrogen receptor-responsive elements on promoters in genes involved in bone matrix biosynthesis, including type I collagen or cytokine genetics Estrogen may play a role in the longevity of bone cells by controlling the rate of apoptosis and reducing osteoclast cell death
Table 2. Risk factors for osteoporosis

Nonmodiable Female Thin skeletal frame Family history History of fracture in rst relative Caucasian or Asian Advanced age Adult fracture Early menopause (<45 years of age) or bilateral ovariectomy Modiable Cigarette smoking Low body weight (<57.6 kg) Estrogen deciency Premenstrual amenorrhea (for >1 year) Inadequate calcium intake Alcoholism Physical inactivity Imbalance or vertigo Lactose intolerance
Table 3. Medications drugs associated with secondary osteoporosis

Glucocorticoids Anticonvulsants (i.e. phenytoin) Ciclosporin Cytotoxic drugs (i.e. methotrexate) Lithium Coumadin Heparin therapy (long term) Aluminum Gonadotropin-releasing hormone agonists Thyroid hormone (in excess) Excessive alcohol Proton pump inhibitors
nonmodiable risk factors for osteoporosis. Exercise, diet, alcohol intake, smoking, hormone replacement therapy, immobility and lack of weight-bearing exercise are modiable risk factors. Medications (Table 3) used routinely in clinical medicine may have detrimental effects on bone remodeling.
Recently, a prescriptiome analysis of 62,865 men of 50+ years of age with a fracture indicated that the largest impact on fracture risk at a population level was exerted by loop diuretics and analgesics (1). A multitude of systemic diseases are also associated with an increased risk of osteoporosis, including hypogonadal states (anorexia nervosa, female athletic triad, Turners syndrome and Klinefelters syndrome), endocrine disorders (Cushings syndrome, hyperparathyroidism, thyrotoxicosis, diabetes mellitus, adrenal insufciency and acromegaly), gastrointestinal disorders (severe hepatic disease, malabsorption, pernicious anemia, malnutrition and gastrectomy), rheumatologic disorders (rheumatoid arthritis), certain inherited diseases (osteogenesis imperfecta,
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hemochromatosis, hypophosphatasia and porphyria), hematologic malignant disorders (multiple myeloma, leukemia, lymphoma, hemophilia and thalassemia), and other disorders such as lactose intolerance, chronic obstructive pulmonary disease, breastfeeding, pregnancy and sarcoidosis.
Osteoporosis and osteopenia: physiology

Osteoporosis is a systemic skeletal disease characterized by loss of bone mass and micro-architectural deterioration with a consequent increase in bone fragility and susceptibility to fracture (61). It results from bone loss as a result of changes in remodeling during normal aging, but may be accelerated by extrinsic and intrinsic factors. Although bone appears inert, it is a dynamic tissue that receives about 10% of the cardiac output and remodels throughout life (129). Bone consists of both compact and trabecular bone. The extracellular bone components include a solid mineral phase associated with an organic type I (9095%) collagen matrix. This part of the organic matrix, which is noncollagenous, contains serum proteins such as albumin, cell attachment signaling proteins (thrombospondin, osteopontin and bronectin), calcium-binding proteins (matrix gla protein and osteocalcin) and proteoglycans (biglycan and decorin). The serum proteins are responsible for the organization of collagen brils, initiation of mineralization and or bonding of the mineral phase to the matrix. The mineral phase contains calcium and phosphate in the form of a poorly crystalline hydroxyapatite. Sodium, potassium and magnesium are also present in small amounts. The skeleton contains over 99% of the calcium in the adult human body. The remaining 1% is in the extracellular uid and serum, and calcium homeostasis is imperative for critical functions such as neurologic activity, clotting and muscular contraction. Skeletal calcium accretion accelerates throughout childhood and adolescence, reaches a peak in early adulthood and gradually declines thereafter at rates that rarely exceed 12% per year (129). In contrast, there are high daily rates of calcium ux into and out of bone, mediated by coupled osteoblastic and osteoclastic activity, of the 0.51.0% of freely exchangeable skeletal calcium within the extracellular uid. Calcium channels can be activated by hormones, metabolites or neurotransmitters affecting the 50% of total serum calcium that is ionized. The concentration of ionized calcium
in the extracellular uid is usually controlled by adjusting the rates of calcium movement across intestinal and renal epithelia, mediated primarily by changes in the levels of parathyroid hormone, 1,25(OH)2D-vitamin D3 and calcitonin. Current studies seek to understand vitamin D-mediated activation and to identify vitamin D-regulated genes that mediate osteoblast and osteoclast functions (179). Proteins, either uncomplexed (albumin and immunoglobulins) or loosely complexed with phosphate, citrate, sulfate or other anions, are bound to the remaining nonionized calcium. Therefore, serum proteins also directly affect the total blood calcium concentration. Bone tissues are dynamic, and healthy bone models and remodels throughout life. Modeling is a process in which the skeleton increases in size in a linear manner in response to the stresses placed upon it. This involves new bone formation that is independent of prior bone resorption, and the skeleton can thus assume a new shape or cortical thickening. On the other hand, remodeling is initiated by resorption and is followed by new bone formation at the same resorptive site. Bone remodeling repairs micro-damage in the skeleton to preserve strength and supplies serum calcium from the skeleton for mineral homeostasis. Signals from mechanical stresses are sensed by osteocytes and are then transmitted to osteoclasts or osteoblasts, or to their precursors. Bone resorption reects the sum of osteoclast recruitment and death, and the rate at which the average cell degrades matrix (171). When remodeling becomes unbalanced, osteoporosis (a loss of bone) or osteopetrosis (a gain of bone) occurs (Fig. 1) (34). This remodeling occurs at bone multicellular units. Riggs & Partt (195) estimated that the human skeleton has 12 106 of these units. In postmenopausal osteoporosis, the number of activated multicellular units is increased, leading to increased numbers of osteoclasts and resorption lacunae in the skeleton. There are also increased numbers of formation sites and osteoblasts, but as a result of estrogen deciency, the osteoblasts do not function effectively. There are estrogen receptors on osteoblasts and osteoclasts, and therefore estrogen can inhibit osteoclast formation, may indirectly affect receptor activator of nuclear factor-jB ligand (RANKL) expression by cytokine regulation and may inuence osteoclast formation by decreasing the expression of macrophage colony-stimulating factor. Decreased estrogen also results in reduced inhibition of osteoclastogenesis and more osteoclastic activity (226). The net result is decreased bone mass and reduced strength.
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A Osteoblasts Osteoclast progen. B C Osteoblast progen. D E Osteoblasts
Coupling factors? cleaning cells
Initiation
Resorption 24 weeks
Reversal
Bone formation 46 months
Remodeling completed
Fig. 1. Normal bone remodeling. (A) Bone remodeling is initiated by osteoclastic resorption, but osteoclast formation and activation are controlled by osteoblasts on the bone surface. Next, the inactive osteoblasts or pre-osteoblasts cover the surfaces of bone tissues where activation leads to osteoblastic degradation of unmineralized osteoid sandwiched between the mineralized bone. (B) Osteoblasts now increase their expression of receptor activator of nuclear factor-jB ligand (RANKL) and macrophage colony-stimulating factor, while decreasing osteoprotegerin (the inhibitor of RANK). This process creates an increase in the osteoclast
progenitor pool and initiates the differentiation that allows the development of latent multinucleated osteoclasts. Once the surface osteoblasts retract from the surface, multinucleated osteoclasts have access to the mineralized bone. Here the osteoclasts develop a rufed border and dissolve hydroxyapatite crystals forming resorption lacunae. (C) When osteoclasts leave the lacunae, mononuclear cells appear and they remove the organic matrix debris. (D) Osteoblast precursors are differentiated into active osteoblasts that ll the lacunae with new bone. (E) Remodeling is complete. Permission granted from U. H. Lerner (123).
Current clinical therapies

Clinical therapy for osteoporosis is a lifelong intervention. It is therefore important to understand not only what medications the patient is currently taking, but what medications they have previously taken, the side effects, compliance, duration and how effective the therapies have been. The current medications approved for osteoporosis include calcium, vitamin D, bisphosphonates, parathyroid hormone, selective estrogen receptor modulators, calcitonin, hormone therapy, denosumab and strontium ranelate (TaTable 4. Medications approved for the treatment of osteoporosis
Calcium supplementation Vitamin D supplementation Bisphosphonates* Selective estrogen receptor modulators Tamoxifen Raloxifen Calcitonin Hormone therapy Parathyroid hormone (teriparatide) Denosumab Strontium ranelate
*See Table 6.
ble 4). Controversies exist regarding the optimal calcium dose and calcium sources. With increasing longevity, it is important to remember that osteoporosis is not only a female disease. Owing to the increase of US veterans suffering from osteoporosis, the Veterans Administration has developed an algorithm for the treatment of male osteoporosis (Fig. 2) (53).
Calcium
Calcium intake in the USA is inadequate according to the Harvard Medical Report, which identied that only 45% of adult men and 22% of adult women receive the recommended intake of calcium (216). Among 9- to 17-year-old subjects, just 25% of boys and 10% of girls receive sufcient calcium. Calcium alone may be partially effective in preventing bone loss, especially in elderly women with an inadequate calcium intake (185, 190). In a 2002 review, 68 of 70 investigator controlled studies found that calcium supplementation resulted in greater gains in bone during growth, less loss of bone with age, and or reduced fracture risk (88). The National Academy of Sciences, National Institutes of Health and the National Osteoporosis Foundation support the recommendations in Table 5. The best sources of calcium are foods, especially dairy products (milk, yogurt, cheese and ice cream), nuts seed (peanuts, sesame paste and almonds), legumes (soy and baked beans, tofu), vegetables (spinach, broccoli, artichokes and
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Glucocorticoid therapy (5 mg daily for 3 months) Low trauma fracture after age 45 years Radiographic evidence of vertebral osteopenia or fracture Androgen deprivation therapy or other hypogonadism Anticonvulsant therapy (2 years or more) Gastrectomy, malabsorption, celiac disease, bariatric surgery Excess alcohol consumption Other conditions and medications
Indications present?
No Yes
Reassess in 2 years
Dual-energy X-ray absorptiometry (spine and hip )
T-score 2.5 or less in spine or hip
T-score between 1 and 2.5
T-score 1 or higher in spine or hip
History, examination basic laboratory analyses, serum and urine calcium, 25 hydroxy vitamin D
Abnormal
Secondary causes Consider evaluation and treatment Repeat bone mineral density scan at 12 years
Low trauma fracture Evaluate and consider treatment
No secondary causes or effects Re-evaluate in 2 years Lifestyle counseling Ensure adequate calcium/ vitamin D
No osteoporosis Lifestyle counseling Ensure adequate calcium/vitamin D
Normal
Treat abnormalities and/or refer patient
Re-evaluate for treatment
Ensure adequate calcium: 1.2 g daily Ensure adequate vitamin D: 800+ units daily Nonpharmacologic interventions to reduce fracture risk Oral bisphosphonates
For T-score less than 2.5 and multiple fracture or T-score less than 3.5, consider referral to a Metabolic Bone Specialist. Do a forearm bone mineral density if spine or hip cannot be interpreted.
Refer to metabolic bone specialist if bisphosphonates are contraindicated or patient intolerant or not responsive
Fig. 2. 2011 Veterans Administration algorithm for treating male osteoporosis. Owing to the increasing incidence of osteoporosis among patients at the Veterans Administration Hospitals, this algorithm was developed through
the ofce of the Under Secretary for Health (53). It is to be used as a guide when selecting which men need to be screened for osteoporosis, treatment recommendations and management of complications.
Table 5. Calcium recommendations

Age National Academy of Sciences Calcium intake recommendations (mg day) 210 270 500 800 1,300 1,000 1,200 1,300 1,000
Birth to 6 months 7 months to 1 year 13 years 48 years 918 years 1950 years 51 years or older Pregnant lactating 1418 years Pregnant lactating 1950 years
snow peas), fruits fortied fruit juices (fortied orange juice, rhubarb and dried fruit), sh (salmon with bones, sardines with bones, bass and ocean perch) and shellsh (steamed clams, lobster and
shrimp). Some food constituents may affect the absorption of calcium. For example, oxalic acid in spinach and rhubarb may combine with the calcium in these plants so that it is not readily absorbed. The other sources of calcium are supplements. They are usually administered as calcium carbonate or calcium citrate; however, phosphate, lactate and gluconate forms may also be found. Calcium pills are compounds in which the actual amount of calcium is elemental calcium. For example, calcium carbonate contains 40% calcium by weight; thus, a 500-mg pill of calcium carbonate contains 200 mg of calcium, and therefore the labeling will indicate that each pill contains 200 mg of elemental calcium. Calcium citrate contains 21% calcium by weight. Calcium carbonate is best taken with food because it requires stomach acid for absorption. Although it is usually tolerated by most people, it has been reported to cause bloating and constipation in some. Calcium citrate is easier to absorb, especially in the elderly, and can be taken with food or on an empty stomach. One must remember that approximately 500 mg of calcium can be absorbed at one time, so if supplementing, the dose should be spread throughout the day. Also, recom-
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mended doses should not exceed 2,500 mg day because of the possible increased risk for kidney stones.
the main predictors of vitamin D nutritional status (143, 225, 233). Vitamin D supplementation should therefore be adjusted according to these factors.
Vitamin D
Vitamin D plays a vital role in calcium absorption in the gastrointestinal tract. Vitamin D levels have been shown to be inadequate in over half of the women treated for osteoporosis in the USA and Europe (183). 7-Dehydrocholesterol is absorbed into the systemic circulation via the skin or from the diet. It is then hydroxylated in the liver to form 25-hydroxy vitamin D or calcidiol. In order to be metabolically active, 25hydroxy vitamin D is hydroxylated in the kidney to form the active hormone calcitriol or 1,25-hydroxy vitamin. Calcitriol is responsible for maintaining serum calcium and phosphate concentrations by controlling absorption in the small intestine (52). Parathyroid hormone is secreted when serum calcium levels fall in order to increase 1,25-hydroxy vitamin D synthesis and, as a result, calcium absorption from the intestine increases. Although most studies show a strong effect of vitamin D on reducing fracture risk when supplemented in conjunction with calcium, there are reports of increased bone density or reduced fracture with vitamin D alone (26, 167, 176). The recommended amount of vitamin D supplement is under constant revision. The 2006 recommended daily allowance (RDA) was 200 IU day (5.0 lg) for adults 1950 years of age, 400 IU day (10.0 lg) for those 5070 years of age and 600 IU day (15.0 lg) for those over 70 years of age. Most references at that time indicated that the current vitamin D intake was not optimal and recommendations were made to increase the guidelines. Accordingly, in 2010 the US Institute of Medicine (IOM) revised the guidelines to the following: 13 years of age, 600 IU day with an upper limit of 2,500 IU day; 48 years of age, 600 IU day with an upper limit of 3000 IU day; 9 69 years of age, 600 IU day with an upper limit of 4,000 IU day; and >70 years of age, 800 IU day with an upper limit of 4,000 IU day (204). End-points associated with improved bone mineral density, such as lower-extremity function, dental health, risk of fractures and reduction in colorectal cancer, require 1,000 IU day of vitamin D (20, 90). Also, a recent review found that the safe upper limit for vitamin D consumption by adults was 10,000 IU day or >10 times any current recommended intakes (87, 230). It is difcult to obtain an adequate intake of vitamin D from the human diet; exposure of skin to ultraviolet light provides the greatest effect. This means that geography, season, skin color and sun-related behavior are
Bisphosphonates
Bisphosphonates are analogs of inorganic pyrophosphates. They have low intestinal absorption, are excreted via the kidneys without metabolic alteration and have a high afnity for hydroxyapatite crystals (71, 217). They are powerful inhibitors of osteoclastic activity, have a high afnity to bone and are preferentially delivered to sites of increased bone formation or resorption. Clinical trials have shown that oral alendronate, risedronate and, recently, ibandronate, reduce hip fracture and increase bone mineral density in the hip, spine and wrist (30, 31, 202). Despite data that indicate good tolerance of oral bisphosphonates for up to 10 years, it is unclear as to which patients need to stay on medication in the long term. Pharmacokinetic studies in humans and animal studies have demonstrated that the tight binding of bisphosphonates to hydroxyapatite results in the retention of bisphosphonates for prolonged periods in the bone, and they become locally active again when that bone packet is resorbed (128). This property raises the possibility of both prolonged clinical effectiveness and prolonged risk of harm (44). The Fracture Intervention Trial Longterm Extension (FLEX) indicated that women who have had a good response to 5 years of bisphosphonate therapy (a 35% increase in hip bone mineral density, an 810% increase in spine bone mineral density and a T score of >)3.5) and who are not otherwise at increased risk of vertebral fracture can consider a holiday off the drug for up to 5 years (28). In experimental animals, alendronate has been shown to inhibit repair of normal microdamage, so microdamage accumulation may occur (125, 140). Note also that several bisphosphonates were approved by the US Food and Drug Administration after 2001, and the long-term effects of these drugs on bone suppression are not yet known. There are differences in the physical and chemical structure of available bisphosphonates that may explain variations in clinical observations. Potency at the enzyme level, binding afnity, distribution accumulation and release vary among the different bisphosphonates (Table 6). Low-afnity bisphosphonates do not bind as tightly and are available on the surface of the bone for removal by osteoclasts; thus, the drug comes off the bone more easily and its effects may be shorter in duration. The chemical differences between the bisphosphonates result in differences in: uptake and retention by the skeleton;
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Table 6. Dosage and US Food and Drug Administration approval dates of bisphosphonates for use in the USA
Agent Etidronate (Didronel ; Warner-Chilcott Laboratories, Rockaway, NY, USA) Clodronate (Bonefos; Bayer Healthcare, Morristown, NJ, USA) Tiludronate (Skelid; Sano-aventis, Bridgewater, NJ, USA) Pamidronate (Aredia; Novartis Cambridge, MA, USA) Alendronate (Fosamax; Merck & Co., Whitehouse Station, NJ, USA) Alendronate + D Ibandronate (Boniva ; Roche Laboratories, Burlington, NC, USA) Risedronate (Actonel; Procter & Gamble, Cincinnati, OH, USA) Risedronate + (Actonel + calcium) Zoledronate (Zometa ; Novartis Cambridge, MA, USA) Reclast

Dosage forms 200 400 mg tablets 400 800 mg tablets 60 mg ml ampules 200 mg tablets 20 60 90 mg vials 5 10 35 40 70 mg tablets 70 mg 75 ml oral solution 70 mg and 2800 U cholecalciferol tablets 2.5 mg tablets 150 mg tablets 3 mg 3 ml vials 5 30 35 mg tablets 35 mg and 500 calcium 35 mg 1,250 mg calcium carbonate 4 mg vials 5 mg vial
Approved 1977 Not approved in USA (Canada only) 1977 1991 1995 2005 2003 2005 2006 1998 2005 2005 2001 2007
Potency 1 10 10 100 100
500
2,000
10,000
diffusion of the drug within bone; release of the adsorbed drug from bone; potential recycling of the desorbed drug back onto bone surfaces; and on mineral dynamics and cellular functions (161). To date, in bisphosphonate trials, specic gains in bone quality (architecture, turnover, damage accumulation and mineralization) have not been reported in the human maxilla or mandible. Further research regarding the distribution of the medication in individual patients and distribution to oral bone is needed. The term bisphosphonate is derived from the base of the drug, namely two phosphate (PO3) groups covalently linked to a central carbon. The carbon atom confers resistance to hydrolysis and allows two R side-chains to attach. The short side-chain, R1, inuences the chemical properties and pharmacokinetics of the drug.
O OP OR1 O P OO-
R2
This chain usually has a hydroxyl moiety, which provides a strong afnity for calcium crystals and bone mineral. The long side-chain, R2, determines the
chemical properties, the mode of action and the strength of the bisphosphonate. Bisphosphonates inhibit osteoclasts by two mechanisms, depending on whether the R2 side chain contains nitrogen side groups. The nonaminobisphosphonates (etidronate, clodronate and tiludronate) lack a nitrogen in their side chains and are metabolized by osteoclasts to inactive nonhydrolyzable ATP analogs that interfere with osteoclast cellular energy and thus induce apoptosis. The more potent aminobisphosphonates (pamidronate, alendronate, ibandronate, risedronate and zoledronate), with nitrogen-containing side groups, have four activities: inactivation of ATP; inhibition of farnesyl diphosphonate synthase (part of the mevalonate pathway in cholesterol synthesis) resulting in osteoclast cytoskeletal disruption, dysregulation of intracellular transport and inhibition of cell proliferation; reduction of osteoclast recruitment; and induction of osteoblasts to produce an osteoclast-inhibiting factor. Over 750,000 prescriptions for bisphosphonates were written each week in 2006 in the USA. In 2010 the number of prescriptions had dropped to approximately 702,000 per week, although this still equates to 36.5 million per year. Bisphosphonates are available in oral doses (daily, weekly, monthly and quarterly) and in intravenous yearly doses. The longterm effects of the newer medications are unknown.
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The oral doses have been associated with gastrointestinal side effects such as dysphagia, esophagitis, esophageal ulcers and gastric ulcers. Bisphosphonates are recommended to be taken on an empty stomach with a full glass of water while remaining upright for 30 min afterwards. For this reason, compliance has been a consistent problem. In August 2007, the US Food and Drug Administration approved once-per-year intravenous zoledronic acid for the treatment of osteoporosis. In a 36-month trial, atrial brillation and arrhythmia were observed among more patients on once-per-year zoledronic acid (1.3%) than those on placebo (0.5%), but the overall incidence was not signicant (38). Also, a growing number of atypical femur fractures in patients taking oral bisphosphonates are a new concern (208). Intravenous doses of pamidronate and zolendronate for the treatment of multiple myeloma and metastatic breast prostate cancer that has metastasized to bone have also been associated with osteonecrosis of the jaw.
Parathyroid hormone
Human parathyroid hormone has shown signicant reductions in both vertebral and appendicular fracture rates. Parathyroid hormone was approved by the US Food and Drug Administration in 2002 as a recombinant parathyroid hormone 134 with the name teriparatide. It is delivered as a 20 lg subcutaneous injection indicated daily for postmenopausal women and men with osteoporosis. Most osteoporosis therapies act to primarily inhibit bone resorption and reduce bone remodeling; however, parathyroid hormone has the potential to enhance skeletal microarchitecture. The initial animal study showed that daily injection of parathyroid hormone for several weeks or months increased bone mass and strength (158). Human studies indicate that parathyroid hormone increases bone mineral density and decreases the risk of vertebral and nonvertebral fractures (130, 164, 169, 213). The current recommendation is that, to avoid decreases in bone density (27, 107), patients should be treated with an antiresorptive medication (e.g. a bisphosphonate) only after intermittent parathyroid hormone therapy has been discontinued, and that bisphosphonates should not be used concomitantly with parathyroid hormone (70).
enes. Tamoxifen is a triphenylethylene known to have estrogen antagonist activity in the breast and has demonstrated activity consistent with estrogen agonism in bone. Other triphenylethylene selective estrogen receptor modulators are clomiphene (used to induce ovulation) and toremifene (used for breast cancer treatment). The benzothiophene selective estrogen receptor modulator in clinical use is raloxifene. It was developed specically to avoid the uterotrophic effects of the other selective estrogen receptor modulators and has been approved for the treatment and prevention of postmenopausal osteoporosis (142). It has been studied extensively and acts as an antiresorptive agent, preserving both bone mineral density and bone strength in a manner identical to that of ethinyl estradiol (160), while reducing the incidence of breast cancer in a targeted population of women (67, 178). It has the following effects on bone physiology: decreased bone formation and resorption, and fracture risk reduction related to decreased biochemical markers of turnover, but no changes in bone density, no signicant change in bone volume, slight increase in mineralization density and no evidence of osteomalacia or bone toxicity (131). Note that selective estrogen receptor modulators have not shown effectiveness in reducing the vasomotor problems (i.e. hot ushes) that are associated with menopause. Droloxine, idoxifene and toremifene are similar selective estrogen receptor modulator agents, but are still considered experimental (209).
Calcitonin
Calcitonin is a naturally occurring 32-amino-acid polypeptide hormone produced by the C cells of the thyroid. It is involved in calcium and phosphate metabolism by decreasing calcium absorption by the intestines, decreasing osteoclastic activity in bones and decreasing calcium and phosphate reabsorption by the kidney tubules. Osteoclasts have calcitonin receptors, and calcitonin inhibits osteoclastic activity. Calcitonin is also associated with vitamin D regulation and enhanced bone mineral metabolism. Studies evaluated bone loss in women after menopause and found that calcitonin stopped bone loss, normalized bone turnover without subjective or objective side effects (42, 174, 188), reduced subsequent vertebral fractures in patients with established postmenopausal osteoporosis (40) and its mechanism of action appears to be related to the inhibition of bone resorption and preservation of microarchitecture without a signicant increase in
Selective estrogen receptor modulators

There are two classes of selective estrogen receptor modulators: triphenylethylenes and benzothioph-
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bone mineral density (41, 106). Calcitonin results in reduced vertebral fracture risk, but has not been demonstrated to reduce nonvertebral or hip fracture risk. Calcitonin is unique for its analgesic effect on vertebral fracture as a result of salmon calcitoninbinding sites in the central nervous system (215). Currently, research is underway to evaluate an oral type of calcitonin, as well as a form of rectal suppository. Further studies are needed to evaluate the effects of intermittent administration (1 month on and 1 month off) of calcitonin vs. daily doses, as well as the possibilities of combination therapy with other antiresorptive medications. Calcitonin-salmon is a US Food and Drug Administration-approved daily metered dose (200 IU) administered via intranasal spray or an intramuscular or subcutaneous injection.
Estrogen hormone replacement therapy

Estrogen, progesterone and androgen receptors are present in all bone cell types. Both estrogen replacement therapy and hormone replacement therapy have been shown to reduce the risk of hip and spine fractures and to reduce bone loss in postmenopausal women. For women who require drug therapy to reduce the risk for osteoporosis, including women at high risk of fracture during the next 510 years, estrogen replacement therapy hormone replacement therapy can be considered an option (29). Owing to the results of the Womens Health Initiative, many women elected to treat osteoporosis with alternative methods (241). Recent data concluded that the incidence of fractures among perimenopausal women and postmenopausal women increased signicantly in the 3 years after publication of the Womens Health Initiative and Heart and Estrogen Progestin Replacement Study II, following a decline in the use of hormone therapy, concurrent with an increase in the use of other bone-modifying agents (94). The ndings using conjugated equine estrogens and progesterone indicated an increase in the risk of venous thromboembolism, ischemic stroke, cardiovascular complications and breast cancer when receiving estrogen replacement therapy and or hormone replacement therapy. Note that these ndings are contrary to decades of previous clinical and observational trials and clinical experience that validated the rationale for hormone therapy. Current recommendations are for short-term use and the early prevention of osteoporosis. Wulf Utian, Director of the North American Menopausal Society, noted that although the North American Menopausal Society was the
rst professional body to recommend stopping the estrogen replacement therapy hormone replacement therapy group of the Womens Health Initiative, there are benets of hormone replacement therapy (241). For example, the hormone replacement therapy group showed a signicant reduction in colon cancer (127). The benecial effect was more marked in women who began therapy within 5 years after menopause (39). The net clinical effect of estrogen is that it is primarily an antiresorptive agent and therapeutically prevents osteoporosis by inhibiting bone resorption and bone turnover. It has been shown that estrogen deciency led to fragility of the trabecular structure of molar alveolar bone that was inversely correlated with lumbar bone mineral density in ovariectomized monkeys (14). Currently, low-dose estrogen therapy for prevention of bone loss in postmenopausal women as a monotherapy is seen as a viable option in clinical medical practice (194). Note that treatment with androgens stimulates new bone formation and results in higher bone mineral density than estrogen therapy alone (166). Alternative estrogens need further research. The effect of phytoestrogen on bone and menopausal vasomotor symptoms has yet to be conrmed (196). The risk benet ratio of hormone replacement therapy needs to be assessed with greater knowledge of the effects of other treatments that exist for menopausal symptoms.
Denosumab
Denosumab is a human monoclonal antibody that binds RANKL. It therefore blocks interaction with the RANK receptor on osteoclasts and osteoclast precursors. Data also indicate that it is similarly effective in various stages of renal function impairment: it does not impair fracture healing processes or contribute to atherosclerosis progression in patients with high cardiovascular risks (72). The result is inhibition of osteoclast-mediated bone resorption. Clinical trials indicate that subcutaneous administration of 60 mg of denosumab every 6 months for 36 months reduces bone turnover and increases bone mineral density signicantly more than alendronate at the lumbar spine and hip in osteoporotic female patients (46). Clinical data also indicate that it inhibits structural damage in patients with rheumatoid arthritis when added to methotrexate (124). Nearmaximal reductions in the mean levels of serum C-telopeptide from baseline were evident 3 days after administration of denosumab, and suppression of
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bone turnover appeared to be dose-dependent (141). This is a promising new treatment for osteoporosis and rheumatoid arthritis that reduced bone resorption by a median of 86% at 1 month, which is greater than that seen when using other antiresorptive drugs (45). Note that Aghaloo et al. (4) have reported ONJ associated with denosumab.
Strontium ranelate
Strontium ranelate is a new oral drug that reduced the risk of all nonvertebral fractures and, in a highrisk subgroup, of hip fractures over a 3-year period (189). It is well tolerated and is a possible alternative to current bisphosphonates. It acts by dissociating bone remodeling by increasing bone formation and decreasing bone resorption and in a Phase 3 trial led to early and sustained reductions in the risk of vertebral fractures (149, 189).
Periodontal implications
The evidence supporting the relationship between osteoporosis and periodontitis is increasing. However, confounding factors play a signicant role as a result of the chronicity of both problems. Studies on tooth loss, alveolar crestal height and clinical attachment loss have been performed; however, problems in extrapolation and application of data arise owing to small sample sizes, study design variations and inadequately controlled confounding factors, which have limited our understanding of the relationship between the two diseases. There are data which relate bone mineral density of the spine, trochanter and other skeletal bones with that of the maxilla and mandible. The preponderance of evidence shows an association between systemic measures of osteoporosis (such as dual-energy X-ray absorptiometry) and oral bone mineral density (98). Animal models indicated fragility of the trabecular structure of molar alveolar bone (222), as well as increased vertical loss of mandibular alveolar bone (168, 224). In one study, the fragility of the monkey alveolar bone trabecular structure inversely correlated with lumbar bone mineral density when ovariectomized (14). In a 28-month longitudinal study of postmenopausal women, mandibular bone loss, assessed by dual-energy X-ray absorptiometry, was much higher than in other skeletal sites (56). Also, Inagaki et al. (92) found that periodontitis and tooth loss may be a useful indicator of metacarpal bone mineral density loss in Japanese women. It has
been suggested that radiographic examination of the facial skeleton may lead to early detection of osteoporosis (115). Although there are no current standard methodologies to evaluate maxillary and mandibular bone mineral density, research with newer technologies may permit dental practitioners to assess oral bone quality. Evaluation of dental panoramic radiographs for identication of osteoporotic changes has yielded mixed results. In an evaluation of mandibular panoramic radiographs, it was found that osteoporotic patients were more likely to have altered inferior cortex morphology, but no statistically signicant differences in cortical width, degree of alveolar crest resorption, fractal dimension or number of mandibular teeth were identied compared with nonosteoporotic patients. The authors recommended training practitioners to use specic evaluation techniques to detect signicant radiographic changes, especially at the inferior mandibular cortex, to help identify postmenopausal women with currently undetected low bone mineral density, as well as undetected spinal fractures (220). Dental panoramic radiographs may be useful for identifying women under the age of 65 with osteoporosis by observation of a thin cortical width and or a severely eroded cortex (66, 221). Panoramic studies indicate that the relative bone density of the mandible is statistically signicantly lower in patients with osteoporosis (32, 170). However, when panoramic-based indices were used to correlate bone mineral density of the mandible and hip, it was found that they were not able to distinguish normal from osteopenic osteoporotic mandibles (58). Four different dental radiographic techniques were compared for detecting osteoporosis: fractal dimension (measuring loss of trabecular continuity and dimensions of space); microdensitometry (light transmission through a selected area on a radiograph); pixel intensity (blackness or whiteness); and panoramic analysis (cortical bone thickness at the gonial angle). They were compared with standard bone density measurement techniques used to diagnose osteoporosis in bones other than the jaws: quantitative computed tomography, and single- and dual-photon absorptiometry. Pixel intensity was the most effective dental method, and only panoramic analysis was ineffective (119). Digitized bitewings may be a more reliable method of monitoring changes in bone density. Jonasson et al. (100) found that subjects with sparse mandibular trabeculation on digitized radiographs had an increased risk of fracture. Therefore, high-risk subjects may be identiable prior to fracture.
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A study using a novel computed tomography micro-computed tomography-based hard-normalsoft classication system proposed a formula to convert ordinary computed tomography values, expressed in Hounseld units, into bone volume percentages for objective measurements of bone density (184). Computed tomography scanners can determine the percentage of calcication in localized sites, and this could be used in treatment planning and may predict periodontal disease progression before clinical attachment loss. This determination would also enhance dental implant therapy. Standardization of radiographic methods would be needed to permit chairside determination of bone mineral density, and although there is potential for dentists to identify signs of osteoporosis in dental radiographs, clear methodologies and criteria for assessing bone have not yet been dened.
Tooth loss and alveolar crestal loss

Studies show the greatest associations between tooth loss alveolar ridge atrophy and osteoporosis (47, 57, 66, 85, 154, 246). There is also less risk of tooth loss when postmenopausal women are placed on hormone replacement therapy (84, 219). Krall et al. (114) found that the odds of being edentulous were reduced by 6% for each 1-year increase in duration of hormone replacement therapy use. It is also apparent that there is increased alveolar ridge resorption in edentulous patients with osteoporosis (54), and greater alveolar crestal height loss is noted with osteoporosis and osteopenia (155, 228, 236).
Periodontal disease
Current knowledge regarding the effects of osteoporosis osteopenia on periodontal diseases and alveolar bone loss is inconclusive. The association of osteoporosis in postmenopausal women with periodontitis, attachment loss and gingival recession has been reported (33, 80, 93, 112, 228, 237). Several studies have indicated that reduced bone mineral density was associated with increased clinical attachment loss (156, 201, 245). Others have found weak or no signicant associations between systemic bone mineral density and clinical attachment loss (68, 180, 239). However, recent studies provide stronger evidence of an association between osteoporosis and clinical attachment loss in humans (6, 135, 214, 218, 219, 221). The relationship between periodontal disease and plasma cytokines, vitamin D and bone mineral density in postmenopausal women, with and without osteo-
porosis, has been investigated, and it was found that periodontal disease was more common in women with osteoporosis and was associated with lower vitamin D and higher concentrations of RANKL and osteoprotegerin (95). Sub-antimicrobial doses of doxycycline in postmenopausal women have shown a possible benet in reducing the progression of attachment loss with an effect on serum biomarkers of bone loss (79, 177, 192). Most studies indicate improved periodontal status in women on hormone replacement therapy estrogen replacement therapy (43, 193, 219), characterized by increased alveolar bone mass and improved alveolar crest height, reduced clinical attachment loss and reduced periodontal inammation. Also, estrogen receptor-alpha gene polymorphism was shown to be a possible indicator for bone mineral density variation of lumbar spine L2L4 and Wards triangle in both premenopausal and postmenopausal Chinese women with periodontitis (248). The lipoxygenase gene Alox 15 is shown to be a negative regulator of peak bone mineral density in mice (111) suggesting future therapeutic approaches to reduce periodontal disease may impact osteoporosis. A recent study found that hypergonadotropic hypogonadism in men contributed to the progression of periodontal disease (229). The effect of daily administration of teriparatide vs. placebo was studied in conjunction with periodontal regeneration in patients with severe periodontal disease. Radiographic linear resolution of osseous defects was signicantly greater after teriparatide therapy than after placebo at 6 months, with a mean linear gain in bone of 29% at 1 year vs. 3% in those receiving placebo (P < 0.001) (21). A recent review suggested that reduced bone mineral density is a shared risk factor for periodontitis rather than a causal factor, but more prospective studies are required to fully determine what, if any, relationship truly exists between periodontal disease and reduced bone mineral density (144).
Bisphosphonates: patient management and their effect on the periodontium

Thus far, animal studies have shown resistanceconferring benets of oral bisphosphonates in experimentally induced periodontitis models (7, 8, 9, 35, 173, 187, 212, 238, 243). Topical (25, 81, 148, 243) and systemic (108) alendronate applied during periodontal ap elevation reduced alveolar bone loss in rats. In contrast, a recent study, in which aggressive periodontal disease was induced in conjunction with potent bisphosphonate therapy (zoledronic acid),
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induced osteonecrosis of the jaws in rats (5). Recent studies on rats suggest that alendronate and or doxycycline may inhibit the expression of matrix metalloproteinase-8, increase the levels of tissue inhibitors of matrix metalloproteinases in gingiva (37), increase serum osteocalcin and provide slight inhibition of lipopolysaccharide-induced alveolar bone resorption (36). A 2003 systematic review stated that preliminary data on patients taking bisphosphonates reported impacts on periodontitis management (186). Human studies also showed a positive effect of bisphosphonates on the progression of periodontal disease (222, 223). Lane et al. (117), in a randomized, doublemasked, placebo-controlled 12-month study, and Rocha et al. (199), in a controlled, double-masked, prospective 6-month study, showed that bisphosphonate treatment improved the clinical outcome of nonsurgical periodontal therapy and may be an appropriate adjunctive treatment to preserve periodontal bone mass. Jeffcoat et al. (97) also showed a signicant gain, over 2 years, in baseline alveolar bone height in a group with low mandibular bone mineral density treated weekly with alendronate relative to a placebo group receiving nonsurgical therapy. Other investigators also showed positive gains on alveolar bone density and height with weekly alendronate therapy; however, these gains did not last for longer than 6 months (65, 198, 200). Given the potential for bisphosphonate-induced osteonecrosis of the jaw, the use of bisphosphonates as an adjunctive treatment for periodontal disease is not indicated. Further research on comparisons of long-term bisphosphonates and the possible effect on the periodontium and periodontal therapies are warranted. There are no studies evaluating bisphosphonate therapy to improve surgical outcomes. In clinical practice, the therapist should: Identify patients at risk for osteoporosis if not diagnosed. Review medications, including length of time on the medication(s), compliance, method of delivery and dosages if the patient has been diagnosed with osteoporosis. Evaluate lifestyle (i.e. exercise and diet). Explain to the patient the possible impact of bisphosphonates on periodontal and implant therapies. Institute a comprehensive oral hygiene program. Eliminate periodontal dental inammation. Consult with the physician if there is a question regarding recommended periodontal implant treatment and bisphosphonates.
Figure 3 presents an algorithm to help dental clinicians make the right decisions about how to manage their patients who are taking bisphosphonates, and to provide advice on when to consult with medical colleagues.
Bisphosphonates: dental implant implications

There is currently an assumption that osteoporosis will affect successful integration of dental implants in the maxilla or mandible, and it is not clear whether successful implant therapy can be expected in patients with osteoporosis. There are no reliable data showing that systemic bone dualenergy X-ray absorptiometry scans accurately reect the bone mineral density of the maxilla or mandible (96, 235). Becker et al. (22) found no association between peripheral dual-energy X-ray absorptiometry scores and the risk of implant failure. This exploratory study suggested that a simple visual assessment of bone quality at the site of implant placement may be more informative regarding implant failure than peripheral bone mineral density dual-energy X-ray absorptiometry (22). In a review by Mombelli et al. (157), data from 17 papers showed low evidence for an association between osteoporosis and implant failure. Most published studies are case reports or crosssectional, have biased sampling, or used varying criteria for measuring osteoporosis. However, most show implant success despite skeletal osteoporosis (24, 48, 51, 62, 7376, 82, 132). Animal studies provide mixed results in this regard. The compact layer of bone in the rabbit tibia was 28% thicker in controls than in animals in which osteoporosis had been induced, and this could potentially affect implant placement (132). Ovariectomized rats had signicant osteoporosis around implants, but no difference in the extent of implantbone contact (175). In rabbits with steroidinduced osteoporosis, signicant correlations were demonstrated between the bone density of the femur and the torque required to remove implants placed in the tibia. However, there was no signicant difference in the torque required to remove the implants placed in the mandible, suggesting that steroid administration, which results in lower bone mineral density, could have less effect on the osseointegration of titanium implants in the mandible than in skeletal bone (77). Most data, however, do not suggest increased risk of implant
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Intravenous bisphosphonates
Intravenous bisphosphonate for multiple myeloma, metastatic cancer and/or severe osteoporosis (once a month pamidronate or zoledronic acid) Intravenous zoledronic acid 5 mg once a year for up to 2 years >65 year old woman >23 years on oral bisphosphonate History of steroid therapy Other medical risks*
Oral bisphosphonates
>65 year old woman >23 years on oral bisphosphonate No steroid therapy No medical risks* <65 year old woman <23 years on oral bisphosphonate No steroid therapy No medical risks*
Thorough oral examination, and consultation with prescribing physician
Follow guidelines for oral route
Consultation with prescribing physician Advise patients of risks of ONJ
Comprehensive periodontal examination Currently, no contraindications to periodontal or implant therapy Close periodontal maintenance Sound oral hygiene practices
Prior to initiation of bisphosphonate
Bisphosphonate therapy already initiated
ONJ
No ONJ
Comprehensive periodontal examination and treatment to achieve optimal periodontal health Periodontal therapy needed to enhance control of disease Extraction of poor to hopeless teeth with reduction of irregular osseous contours Bisphosphonate therapy (if systemic conditions permit) should be delayed 1421 days Assess restorative needs: Removable appliances should be stable with no rough areas that could traumatize mucosa Caries control Complete all invasive dental procedures Frequent periodontal/dental maintenance visits and monitoring
Non-surgical periodontal therapy Close periodontal maintenance Antimicrobial mouthrinse and antibiotics as needed Prevent osseous injury No extractions No dental implants Nonrestorable teeth require endodontic therapy of the remaining roots Good oral hygiene practices
Follow guidelines in Box 2 (AAOMS Staging and Treatment Strategies for ONJ)
Collaborate with prescribing physician
Treat periodontal disease/periapical pathoses as soon as possible Treat in sextants if assessing bone healing nonsurgically if possible Discuss options to avoid extractions Extractions should be conservative with primary closure Systemic antibiotics to avoid risk of infections Antimicrobial rinses Sound oral hygiene Close periodontal monitoring NB No validated diagnostic technique to currently assess increased risk for developing ONJ NB Discontinuing bisphosphonates (time-outs) should be through the prescribing physician
Comprehensive periodontal examination Clear treatment plan with the physician, if extensive Initiate treatment in a single site or sextant to assess healing potential Close periodontal maintenance Sound oral hygiene
ONJ
Consult with prescribing physician regarding proposed treatment, drug holiday, antibiotic regimen Antibiotic therapy Pain reduction as needed Antimicrobial mouthrinses Gentle debridement of loose or sharp bone segments Follow Box 2 AAOMS
Close periodontal maintenance with gentle debridement
*Medical risks
Cancer Smoker Dialysis Low hemoglobin Diabetes Obesity Chemotherapeutic agents Head/neck radiation therapy
Fig. 3. Decision tree for managing patients who are taking bisphosphonates. According to the medical and medication history, the dental clinical treatment can follow pathways for the dental and periodontal treatment of patients who are taking bisphosphonates, including the management requirements if bisphosphonate-induced osteonecrosis of the jaws is identied. All patients prescribed bisphosphonates should be informed of the risks and possible effects of the bisphosphonate on oral bone
and treatment outcomes. Discussions should be documented, the options reviewed and consent obtained for the elected course of treatment. Please note that this algorithm does not apply to all patients in all situations. The clinician must base decisions on their best clinical judgment for individual patients at the time of treatment. AAOMS, American Association of Oral & Maxillofacial Surgeons; ONJ, Osteonecrosis of the jaw.
failure as a result of decreased bone mineral density, although the long-term biomechanical stability of implants under masticatory forces is as yet unknown (109). Only a few studies have evaluated the effect of hormone replacement therapy or oral bisphosphonates on implant success in humans, but most of these noted minimal complications. Qi et al. (182) found that estrogen therapy may promote bone healing around titanium implants. Minsk et al. (153) showed that hormone therapy did not improve outcomes of implant therapy, while Moy et al. (159) indicated that women on hormone replacement therapy had an increased relative risk for implant failure of 2.55. August et al. (15) found that postmenopausal estrogen status could have an impact on implant healing in the maxilla, but not in the mandible. A recent animal study showed that alendronate may prevent the negative inuence of
estrogen deciency on bone healing around titanium implants (59). Jeffcoat (97) also showed 3-year results of a single-blind controlled study with oral alendronate or risedronate on implant placement. Implants were >99% successful in both groups and no occurrences of osteonecrosis of the jaw were noted. A recent study showed that estrogen replacement therapy and alendronate were effective in preventing bone mass loss around integrated implants in ovariectomized rats (78). Studies with adjunctive systemic alendronate have also shown reduced vertical bone resorption postextraction and suppression of free bone graft resorption in Wistar rats (79) and in human wisdom teeth extraction sites (83). Currently, many patients may have taken oral bisphosphonates for approximately 3 years and hence may have experienced signicant impacts on the quality of oral and alveolar bone. The clinician must evaluate the length of the time the patient has been
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on an oral bisphosphonate, together with assessment of case complexity, the patients overall systemic health and risk factors (231). Currently, the American Association of Oral and Maxillofacial Surgeons recommends that patients should be informed of the small risk of compromised bone healing following implant placement after oral bisphosphonate therapy, especially if the implant is placed within 3 years of bisphosphonate therapy. The American Association of Oral and Maxillofacial Surgeons recommendations for implant placement are (3): If the patient has been taking an oral bisphosphonate for less than 3 years without any other clinical risk factors (e.g. steroids, chemotherapy, thalidomides, or genetic perturbations) then no alteration or delay in the planned implant surgery is necessary. It is important to note that: s Informed consent should be provided regarding possible future implant failure and possible osteonecrosis of the jaws if the patient continues taking oral bisphosphonates and s The prescriber of the oral bisphosphonates should be contacted to suggest monitoring, alternate dosing of the bisphosphonates, drug holidays, or an alternative to the bisphosphonate therapy. If the patient has been taking an oral bisphosphonate for less than 3 years and is also taking concomitant corticosteroids then the prescriber should be contacted and asked to consider discontinuing the oral bisphosphonates for at least 3 months prior to implant placement (or oral periodontal surgery). If systemic conditions permit, bisphosphonates should not be restarted until osseous healing has occurred. If the patient has been taking oral bisphosphonates for more than 3 years, with or without concomitant corticosteroids, the prescriber should be contacted to discontinue the bisphosphonates for 3 months prior to the oral surgery, if systemic conditions permit. The oral bisphosphonate should not be restarted until osseous healing is complete. Note that dental implants are contraindicated in patients taking monthly intravenous bisphosphonates for multiple myeloma, metastatic breast or prostatic cancer of the bone, severe osteoporosis or Pagets disease. There are many questions yet to be answered with respect to osteoporosis and dental implants. Currently, there are no convincing data to contraindicate dental implant placement in the osteoporotic patient. However, limited case reports have shown osteone-
crosis of the jaws after implant therapy (23). One study compared a control group of female patients with dental implants taking no oral bisphosphonates with a test group who were taking a bisphosphonate. The bisphosphonate group had an 86% success rate vs. a 95% success rate in the group not taking the medication (105). In contrast, a recent animal study showed that single-dose zoledronic acid improved osseointegration in estrogen-decient rabbits (244). A second animal study showed that strontium ranelate increased mechanical xation of the implant in rats (134). Controlled studies are required to assess implant outcomes in varying bone densities, in people taking different bisphosphonates, in atrophic alveolar ridges, in two-stage vs. early-loading vs. immediateloading situations, and in different implant systems and implant surfaces. It has been noted that increased function of the mandible 2 years after implant overdentures were placed seemed to cause a load-related bone formation that minimized, or in some cases counteracted, the physiologic age-related bone mineral density loss leading to osteoporosis (234).
Osteonecrosis of the jaw

Bisphosphonate-induced osteonecrosis of the jaw (Osteonecrosis of the jaw [ONJ], Bisphosphonate osteonecrosis [BON], Bisphosphonate-related osteonecrosis of the jaw [BRONJ], Antiresorptive osteonecrosis of the jaw [ARONJ]) was described by Marx in 1983 (136). It may, however, be the same disease that was described in 1899 as an industrial disease seen in phosphate miners and match factory workers and referred to as phossy jaw (49, 50, 89). This condition refers to exposure of bone in the mandible or maxilla persisting for more than 8 weeks in a patient who has previously, or is currently receiving, treatment with a bisphosphonate and who has no history of radiation therapy to the jaws (152). Osteonecrosis of the jaw originates in the alveolar bone, but may spread to the basal bone. Early radiographic ndings include sclerosis or loss of the lamina dura, and or widening of the periodontal ligament space (136). Osteonecrosis of the jaw is frequently observed in the jaw as a result of the rapid rate of bone remodeling. The alveolar crest remodels at 10 times the rate of the tibia, at ve times the rate of the mandible at the level of the mandibular canal and at 3.5 times the rate of the mandible at the inferior
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border (55). Thus, there is a higher uptake and concentration of bisphosphonates in the alveolar bone compared with other sites. It appears that alveolar bone depends more on osteoclastic bone resorption-remodeling and renewal than any other bone in the adult skeleton. Sedghizadeh et al. (210) also see the unique nature of the oral biolm as a potential source of osteonecrosis of the jaw. Histopathologic and scanning electron microscopy examination of osteonecrosis of the jaw vs. osteomyelitis specimens revealed that subjects with osteonecrosis of the jaw had a greater diversity of bacteria, in addition to fungal organisms not seen in osteomyelitis of the jaws (210). Bisphosphonates are used to prevent and reduce the bone resorption that occurs in metabolic bone diseases, such as osteoporosis, osteitis deformans (Pagets disease), metastatic bone diseases (i.e. multiple myeloma, metastatic breast cancer, metastatic prostatic cancer and other metastatic cancers), or other diseases that can reduce bone mineral density secondarily (hyperthyroidism and diabetes mellitus). It has become apparent that the intravenous nitrogenous bisphosphonates are implicated in osteonecrosis of the jaw. Their potent anti-osteoclastic and or antiresorptive effects occur via inhibition or cell death of the osteoclast, which resorbs bone and ingests the bisphosphonates. They become bound to the mineral crystals on bone surfaces and, with increased doses, accumulate in the bone matrix. When bone resorption is inhibited, old bone is not removed and new osteoid is not formed. The osteocyte that acts as a mechanoreceptor to maintain the mineral matrix of the bone outlives normal bone remodeling (44). The result is hypermineralization or a hypodynamic bone that has a reduced biomechanical competency. Some authors warn that prolonged oral bisphosphonate use needs to be weighed against such long-term suppression of bone metabolism (126, 171, 172). Others say that long-term use may retard fracture healing, but not affect bone mineralization or bone mechanics (126). According to Marx, repeated bisphosphonate dosing is a biologic catch-22, in that the drug accumulates in bone matrix and can be removed only by osteoclast-mediated resorption as part of the bone turnover cycle. The problem is that bisphosphonates are toxic to osteoclasts and prevent bone turnover. Bisphosphonates are also antiangiogenic (150), may be comorbid medications in immunocompromised patients and may indirectly modulate the osteoblastosteoclast balance (122, 205). Numerous reports in recent years have raised concern about the serious nature of osteonecrosis of
the jaw (17, 18, 60, 86, 99, 101, 137, 145, 146, 181, 206, 207, 247). A systematic review reported on 368 cases of osteonecrosis of the jaw. The primary medical diagnoses were multiple myeloma (162 cases), metastatic breast cancer (134 cases) and metastatic prostatic cancer (23 cases), which together constituted 91.5% of the reported cases. Over 94% of patients were taking intravenous zoledronic acid, pamidronate, or both (240). Sixty per cent of patients with osteonecrosis of the jaw had received dentoalveolar surgery, but 40% of the cases of osteonecrosis of the jaw appeared spontaneously, often in denture wearers, in which 39% were associated with exostoses. Osteonecrosis of the jaw was more frequently located in the mandible (65%) than in the maxilla (26%) or both the mandible and maxilla (9%). Multifocal or bilateral involvement was more common in the maxilla than in the mandible (31% vs. 23%, respectively). There were 17 cases reported in patients using oral bisphosphonates. Of those, 15 were taking alendronate (4.2%), one was taking risedronate (0.3%) and one was taking ibandronate (0.3%). The most important predisposing factor for development of osteonecrosis of the jaw was the type and dose of the bisphosphonates, followed by a history of trauma, dental surgery or dental infection. Badros et al. (16) retrospectively reviewed 90 multiple myeloma patients with osteonecrosis of the jaw and found it to be time-dependent, with a higher risk in older multiple myeloma patients after long-term use of bisphosphonates, often after dental extractions. Bamias et al. (18) found that the duration of exposure to bisphosphonates was strongly related to development of osteonecrosis of the jaw. Those who developed osteonecrosis of the jaw received a median of 35 (range, 1368) infusions of bisphosphonates vs. 15 (range, 674) infusions for patients without osteonecrosis of the jaw. Also the median time for exposure to bisphosphonates was 39.3 (range, 1186) months for patients with osteonecrosis of the jaw compared with 19 (range, 484.7) months for patients without osteonecrosis of the jaw (18). Note that bisphosphonate doses for oncologic purposes are often 12 times higher than doses for treating osteoporosis (191). It is becoming increasingly evident that the cumulative dose of the bisphosphonate, its potency, the stereochemistry of the nitrogen side chain (monthly intravenous zolendronate and pamidronate), patients age, medical status, history of dental trauma, pre-existing dental disease and other pharmacologic agents (corticosteroids, cytotoxic drugs and multimodal antiretroviral therapies) all increase the risk for osteonecrosis of the jaw.
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A B
Fig. 4. Bisphosphonate-induced osteonecrosis of the jaw in a 73-year-old woman with multiple myeloma, type II diabetes, myocardial infarction and total hip replacement. The patient had been taking intravenous zolendronate for 1 year, and there was a history of extraction
1 year before this clinical presentation of nate-induced osteonecrosis of the jaw. appearance. (B) Radiographic appearance. exposure to reveal the extensive necrosis bone defect.
bisphospho(A) Clinical (C) Surgical and alveolar
Clinically, osteonecrosis of the jaw may present as exposed alveolar bone occurring spontaneously or after dental surgery. The sites usually are painful, have soft tissue swelling or ulceration, mobile teeth and induration with drainage (Fig. 4). Radiographically, if teeth are present, there may be sclerosis of the alveolar lamina dura, loss of the alveolar lamina dura and or widening of the periodontal ligament space, particularly at molars (138).
Intravenous bisphosphonates and osteonecrosis of the jaw: prevention and therapy

Before placing patients on intravenous bisphosphonates, the oncologist and dental team need to develop management protocols similar to those developed by the radiation therapist oncologist before initiation of full-course irradiation therapy to the head and or neck. Although osteochemonecrosis and osteoradionecrosis are different, because of a lack of blood supply in the latter, pre-oncologic therapy should be aggressive in order to prevent postcancer therapy sequelae. However, once intravenous bisphosphonates have been given to the patient, it is imperative that meticulous monitoring and home care are implemented and that periodontal maintenance is provided at frequent intervals. Surgical therapy should be avoided if possible. Even extractions should ideally not be performed unless teeth are extremely mobile (12) or there is spreading infection that cannot be controlled by conservative therapy. However, Adornato et al. (2) have reported successful treatment of osteonecrosis of the jaw with bone resection and autologous platelet-derived growth factors. A recent review states that laser application at low intensity
may improve the reparative osteonecrosis of the jaw process and can be used for conservative surgery, whereby necrotic bone is vaporized until healthy bone is reached (232). Ozone therapy was also discussed for treatment of osteonecrosis of the jaw during and after oral surgery to stimulate cell proliferation and soft tissue healing. Marx et al. (138) recommends the treatments in Box 1 for therapy with intravenous bisphosphonates specic to the stage of osteonecrosis, in which effective control to a pain-free state without resolution of the exposed bone was 90.1%. The American Association of Oral and Maxillofacial Surgeons has revised their Staging and Treatment Strategies for osteonecrosis of the jaw, as shown in Box 2 (12). Medical researchers have been actively engaged in trying to identify ways to manage the sequelae of osteonecrosis of the jaw (69, 91, 102, 110, 197). A recent consensus statement recommended that intravenous bisphosphonates should be discontinued after 2 years of therapy for multiple myeloma patients who achieve a complete response and or plateau. If their disease is still active, they have not achieved a response, or have threatening bone disease beyond 2 years of therapy, the frequency of treatment can be decreased to every 3 months. The consensus statement recommended dental evaluation, good dental hygiene, attention to reducing periodontal and periapical infections, extracting teeth as necessary, but withholding bisphosphonate treatment for at least 1 month before the procedure, and resuming treatment when the patient has fully recovered and the wound fully healed (116). It was recently noted that surgery is more successful in patients with osteoporosis or multiple myeloma than in those with solid tumors, and that discontinuation of bisphosphonate therapy favored the surgical outcome (242).
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Box 1. Recommendations for dental treatment of patients receiving intravenous bisphosphonates (monthly), specic to the stage of osteonecrosis
Stage 0 Patients at risk (osteoclast hypocellularity, apoptosis with a reduction in endosteal osteoblasts and their osteoid production) (12) Eliminate existing inammatory dental pathologies Withhold intravenous bisphosphonate therapy for 23 months, if systemic conditions permit, to allow dental providers to obtain optimum dental health: s Remove abscessed, nonrestorable or periodontally unsalvageable teeth s Perform caries control, restorative, root canal and periodontal therapy (including periodontal surgery) s Provide xed or removable partial dentures s Leave impacted teeth undisturbed unless they have oral communication s Leave small single tori undisturbed; remove large, multilobular lingual tori and large midline palatal tori s Prophylactic antibiotic coverage is recommended for invasive dental procedures in cancer patients Stages 1a and 1b (Stage 1a, bone exposure <1 cm and painless; Stage 1b, largest area of exposure is >1 cm and painless) Asymptomatic exposed bone requires either no treatment or maintenance with a 0.12% chlorhexidine oral rinse three times daily Stages 2a, 2b and 3a (Stage 2a, a single exposed area of bone measures <2 cm and is accompanied by pain and or clinical infection; Stage 2b, exposure area is >2 cm; and Stage 3a, exposed bone >3 cm in area or showing signicant osteolysis or an orocutaneous stula) These scenarios require an antibiotic regimen and 0.12% chlorhexidine rinses administered through one of three regimens: Rinse three times daily, plus penicillin VK 500 mg four times per day ongoing
Rinse three times daily, plus penicillin VK 500 mg four times per day until pain is controlled (for those concerned about long-term penicillin problems) Rinse three times daily plus an alternative to penicillin because of allergy or nonresponsiveness: doxycycline 100 mg once daily, levooxacin 500 mg once daily or erythromycin ethylsuccinate 400 mg three times daily Note: metronidazole 500 mg three times daily in addition to penicillin, doxycycline or levooxacin has been shown to control pain and infection in cases refractory to any of the antibiotics alone, but is recommended for only 10 days on an intermittent basis because of toxicity Stage 3b (Stage 3a plus a pathologic fracture) The clinician may duplicate Stage 3a, but to choose a more interventional approach: alveolar resection or a continuity resection may be performed. Titanium reconstruction plates should not be placed immediately and deferred until 3 months or when infection is resolved
Oral bisphosphonates and osteonecrosis of the jaw: prevention and therapy

Most osteoporotic patients who present in dental practice are taking oral bisphosphonates, such as alendronate, risedronate or ibandronate (as opposed to an intravenous infusion of zolendronate or pamidronate). Recently, intravenous zoledronate, 5 mg once a year for 2 years, has increased in use as a result of ease of compliance. It is now 18 years since alendronate (Fosamax) was approved by the US Food and Drug Administration, 8 years since risedronate (Actonel) was approved and just 3 years since ibandronate (Boniva) was approved. Currently, alendronate poses a higher risk for osteonecrosis of the jaw than risedronate as a result of the numbers of patients who have been prescribed alendronate over the years, whereas ibandronate has been available only for a short period of time. Some alternatives to bisphosphonates may not be a safe option in light of new reports of osteonecrosis of the jaw in patients taking denosumab (4). Patients with, or at high risk of, osteopenia should be counseled regarding the importance of weightbearing exercise, dietary vitamin D, calcium and
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Box 2 American Association of Oral and Maxillofacial Surgeons staging and treatment strategies for management of osteonecrosis of the jaw
BRONJ* Staging At-risk category: No apparent necrotic bone in patients who have been treated with either oral or intravenous bisphosphonates Stage 0: No clinical evidence of necrotic bone, but nonspecic clinical ndings and symptoms Stage 1: Exposed and necrotic bone in patients who are asymptomatic and have no evidence of infection Treatment strategies No treatment indicated Patient education Systemic management, including the use of pain medication and antibiotics Antibacterial mouth rinse Clinical follow-up on a quarterly basis Patient education and review of indications for continued bisphosphonate therapy Stage 2: Exposed and necrotic bone associated with infection Symptomatic treatment with oral antibiotics as evidenced by pain and erythema in the region of the ex Oral antibacterial mouth rinse posed bone with or without purulent drainage Pain control Supercial debridement to relieve soft tissue irritation Stage 3: Exposed and necrotic bone in patients with pain, Antibacterial mouth rinse infection and one or more of the following: exposed and necrotic bone extending beyond the region of alveolar bone Antibiotic therapy and pain control (i.e. inferior border and ramus in the mandible, maxillary Surgical debridement resection for longer term sinus and zygoma in the maxilla) resulting in pathologic palliation of infection and pain fracture, extra-oral stula, oral antral oral nasal communication, or osteolysis extending to the inferior border of the mandible or sinus oor
*Exposed bone in the maxillofacial region without resolution in 812 weeks in persons treated with a bisphosphonate who have not received radiation therapy to the jaws. Regardless of the disease stage, mobile segments of bony sequestrum should be removed without exposing uninvolved bone. The extraction of symptomatic teeth within exposed, necrotic bone should be considered because it is unlikely that the extraction will exacerbate the established necrotic process. Discontinuation of the intravenous bisphosphonates shows no short-term benet. However, if systemic conditions permit, long-term discontinuation may be benecial in stabilizing established sites of bisphosphonate-related osteonecrosis of the jaw, reducing the risk of new site development and reducing clinical symptoms. The risks and benets of continuing bisphosphonate therapy should be made only by the treating oncologist in consultation with the Oral Maxillofacial surgeon and the patient. Discontinuation of oral bisphosphonate therapy in patients with bisphosphonate-related osteonecrosis of the jaw has been associated with gradual improvement in clinical disease. Discontinuation of oral bisphosphonates for 612 months may result in either spontaneous sequestration or resolution following debridement surgery. If systemic conditions permit, modication or cessation of oral bisphosphonate therapy should be performed in consultation with the treating physician and the patient.
magnesium, and therapies to improve the balance of the body, before taking oral bisphosphonates. The medical histories taken by clinicians should include questions on lactose intolerance, hormone replacement therapy, hysterectomy (date of), menstrual history, menopause (at what age and if hormone replacement therapy was prescribed), medications that alter the calcium balance (especially corticosteroids or chemotherapy), diet and exercise balance histories. If a patient is taking oral bisphosphonates, they need to be questioned regarding the type of bisphosphonate, length of time they have been taking it, compliance and side effects. There are many new therapies available that may be better alternatives to t the individual patient to their individual needs at that particular time, but current data do support oral
bisphosphonates as being effective in preventing hip and spine fractures. The risks for osteonecrosis of the jaw when the patient is taking oral bisphosphonates have been reported to be as low as 0.7 100,000 (202) and as high as 4% (211). However, a new study by Barasch et al. (19) found that oral bisphosphonates were a potent risk factor for osteonecrosis of the jaw with an odds ratio of 12.2 (95% CI: 4.335.0). Currently, there are no clear guidelines to determine precisely which patients on oral bisphosphonates are at risk for osteonecrosis (a variety of guidance documents and Web resources are indicated in Box 3). There are recommendations indicating increased risk of osteonecrosis of the jaw in patients treated with oral bisphosphonates for
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Box 3. Guidance documents and web resources for clinicians to seek information relating to management of dental patients who are taking bisphosphonates
American Academy of Endodontists Position Statement Endodontic Implications of Bisphosphonate-Associated Osteonecrosis of the Jaws 2006 http://www.aae.org/dentalpro/ guidelines.htm (10) Ruggiero et al. (206), Practical Guidelines for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaw in Patients with Cancer, 2006. American Society of Clinical Oncologists (13). Updated Recommendations for the Prevention, Diagnosis, and Treatment of Osteonecrosis of the Jaw in Cancer Patients, 2006. Migliorati et al. (151), Managing the care of patients with bisphosphonate-associated osteonecrosis. An Academy of Oral Medicine position paper, 2005. American Academy of Periodontology Statement on Bisphosphonates http://www.perio. org/resources-products/bisphosphonates.htm (11) American Dental Association Report of the Council on Scientic Affairs Expert Panel Recommendations: Dental Management of Patients on Oral Bisphosphonate Therapy, 2008 (63) American Association of Oral and Maxillofacial Surgeons Position Paper on BisphosphonateRelated Osteonecrosis of the Jaws 2009 Update (12) Canadian Consensus Practice Guidelines for Bisphosphonate Associated Necrosis of the Jaw, 2008 (102). National Institutes of Health Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, 2001 (165).
23 years or longer with concomitant use of steroids (138). In one study, patients on oral bisphosphonates had increased complications and incidence if they were taking them for longer than 3 years (139). A recent study indicated risk within 2 years of bisphosphonate initiation that increased four-fold after 2 years (19). This study also found that suppuration,
dental extractions, steroid use and head neck radiation signicantly increased the risk for osteonecrosis of the jaw. Patients with periodontal disease and dental abscesses are also at higher risk. Miglioratis study indicated that 84% of patients with osteonecrosis of the jaw also had periodontal disease (151). Marx proposed the potential of an indicator of bone turnover, C-terminal cross-linking telopeptide, to measure higher risk after 3 years on oral bisphosphonates; however, the American Dental Association Report of the Council on Scientic Affairs concluded the current screening and diagnostic tests are unreliable for predicting a patients risk of developing osteonecrosis of the jaw (63). Owing to the aforementioned risk factors, the clinician should work closely with their medical colleagues before prescribing oral bisphosphonates. Ideally, optimal periodontal dental health state should be established before the patient commences bisphosphonate therapy. This involves closely evaluating radiographs, extracting teeth with a hopeless prognosis, removal of multilocular tori, appropriate periodontal therapy, root canal therapy and provision of necessary restorative treatment. Also, the patient should be informed of the risks associated with 23 years or longer of continuous oral bisphosphonate therapy. Finally, the treating physician should be updated regarding the patients oral status. If the patient has already been on an oral bisphosphonate, there is minimal risk of osteonecrosis of the jaw if they have been taking the medication for less than 23 years, there are no medical risk factors and they have no dental problems. One source has stated that it is safe to proceed with periodontal and oral surgical procedures as needed (138). The latter did not, however, differentiate between length of time of treatment with the oral bisphosphonates. It has also been recommended that patients with active periodontitis should receive appropriate forms of non-surgical therapy which should be combined with a prolonged phase of initial therapy for observation if the disease does not resolve, surgical treatment should be aimed primarily at obtaining access to root surfaces with modest bone recontouring being considered and necessary (63). There are no data on the risk of osteonecrosis of the jaw with periodontal regenerative therapy. With regard to implants, there is consensus that the recommendations are to obtain documented consent from the patient after reviewing the risks, benets and treatment alternatives. There are no clear data to guide the clinician
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regarding the impact of oral bisphosphonate therapy on implant placement and occurrence of osteonecrosis of the jaw. Two recent studies found that oral bisphosphonate therapy did not alter implant outcomes and there were no reported cases of osteonecrosis of the jaw (82, 133). The American Dental Association states that the risk for osteonecrosis of the jaw increases when augmentation of atrophic ridges or extensive implant placements are performed (63). Patients with implants and receiving therapy with oral bisphosphonates should be monitored and maintained closely. If the patient has been taking oral bisphosphonates for longer than 3 years, the treating physician should be contacted. The physician needs to be informed of the patients periodontal dental status and of the dental treatment plan. If a surgical procedure is warranted, current American Association of Oral and Maxillofacial Surgeons recommendations are that the patient discontinues the oral bisphosphonates for 3 months before the procedure. However, this is controversial and the American Dental Association, states discontinuing bisphosphonate therapy may not eliminate any risk for developing osteonecrosis of the jaw (63). Drug holidays have been recommended following a 10-year alendronate study, indicating that stopping the medication after 3 years diminished bone mineral density minimally, had no increase in fractures, and improved bone remodeling (30). Biochemical markers of bone turnover may be used to complement measurement of bone mineral density; however, their clinical utility is limited. Current markers of bone resorption include serum collagen type 1 cross-linked telopeptide, cross-linked Ntelopeptides of type I collagen, and pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen. There are also biochemical markers of bone formation, such as specic-alkaline phosphatase, osteocalcin and procollagen type I N- and C-propeptides (227). Urinary cross-linked N-telopeptides of type I collagen and serum pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen correlate with risk for skeletal complications, disease progression and overall survival. Rosen et al. identied serum CTX as a marker of bone resorption that was useful specically to assess the efcacy of antiresorptive treatments (203). Marx recommended that a test for collagen type 1 cross-linked telopeptide should be performed at the initial consultation and immediately before performing a procedure (138). Therefore, serum collagen type 1 cross-linked telopeptide might provide the clinician with information regarding bone suppression and risk of
Table 7. Laboratory risk assessment for patients taking oral bisphosphonates

Telopeptide CTX (pg ml) 300600 150299 101149 <100 Risk for osteonecrosis of the jaw None None or minimal Moderate High
osteonecrosis of the jaw (Table 7). His recommendation is therefore: Take a baseline initial serum measurement of collagen type 1 cross-linked telopeptide. If it is less than 150 pg ml, consult with the medical doctor. Recommend to discontinue the oral bisphosphonate for 3 months with the consent of the prescribing physician. If the patient has severe osteoporosis, the physician may elect to prescribe an alternative drug (see Table 4). Repeat the measurement of serum collagen type 1 cross-linked telopeptide in 3 months. If the level of serum collagen type 1 cross-linked telopeptide is 150 pg ml, it is permissible to proceed with dental procedures. Restart the oral bisphosphonate 3 months after the procedures. For each month in which the patient is not taking the oral bisphosphonate, the collagen type 1 cross-linked telopeptide value will increase by approximately 25 pg ml. The American Dental Association and others, however, indicate that the collagen type 1 crosslinked telopeptide may be of questionable value and is not based on strong clinical evidence (63, 113). If a patient has established oral bisphosphonateinduced osteonecrosis of the jaw, the treating physician should be contacted. The medication should be discontinued and it is recommended that the prescribing physician should provide an alternative medication. There is also an opinion that discontinuing the bisphosphonate should not be recommended once necrosis of the jaws has occurred (122); however, this was based on four case reports. If the physician elects to not prescribe a substitute drug, stringent periodontal maintenance and monitoring is necessary. Oral bisphosphonate-induced osteonecrosis of the jaw has been reported to be less extensive and more responsive to discontinuation of the medication without debridement. Marx states that
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approximately 60% of patients will have recovering osteoclasts that will resorb bone around the necrotic area in order to sequestrate it from adjacent viable bone within 6 months to 1 year. The 40% that do not sequestrate will require surgical debridement, including extraction of teeth in necrotic sites with alveolar resection and primary closure (138). He also states that the remaining bone should be viable and restored with nonimplant-supported appliances; however, if an alternative osteoporosis drug is prescribed, bone augmentation and implants are viable. It is imperative that dental clinicians treat these patients in partnership with medical professionals. Patients need to be aware of the risks vs. benets of the procedures. Recently, case reports indicate healing of osteonecrosis of the jaw after therapy with teriparatide after other treatments have failed (118, 162). Clinical trials are urgently needed to evaluate the most effective treatment protocols for patients with different stages of osteonecrosis of the jaw. Cases of oral bisphosphonate-induced osteonecrosis of the jaw are seldom reported, so it may appear to be a rare occurrence. A randomized clinical trial may not have adequate numbers of cases of osteonecrosis of the jaw or the drug may have been taken for too short a duration to present adverse effects. A database should be developed for clinicians to easily report cases, citing the type of bisphosphonate, duration of use, compliance, medical history and nature of the reported osteonecrosis of the jaw. Currently, it is imperative that clinicians report cases of osteonecrosis of the jaw to the US Food and Drug Administration at http://www.fda.gov/MedwWatch/report.htm.
bisphosphonates, we must monitor other potential oral side effects. We must stay current with medical technologies that enhance earlier diagnostics to prevent or treat complications. The clinician needs to understand the mechanisms of actions of the various therapies. Periodontal therapy, augmentation and placement of dental implants are still viable options for the clinician predicated on best clinical judgment for that individual patient. Preventive care, especially oral hygiene reinforcement, monitoring and periodontal maintenance therapy, is of paramount importance. Periodontal professionals can potentially play a pivotal role in the early detection of osteoporosis via diagnostic tests (e.g. radiographs), clinical monitoring and continual updating of patient risk. With the advent of genomic, experimental, mechanistic and clinical trials we must continually interpret the data in the context of the healthcare needs of our patients at a given time. There is no single therapy that is safe and effective for all people and therefore it is vital that data from population-based studies do not get lost in translation when applied to individuals (121). Because osteoporotic patients are at higher risk for periodontal disease and patients with periodontitis are at higher risk for osteonecrosis of the jaw, periodontal intervention and disease prevention are imperative. Close periodontal maintenance, meticulous monitoring, understanding of periodontal and implant therapy for the individual patient at a given time and collaboration with medical professionals will provide patients with the highest level of care.
Conclusion
Clinical periodontal and implant therapy in the osteoporotic osteopenic patient provide new challenges. The numbers of patients with low bone mineral density and the numbers of patients who are taking bisphosphonates for long periods of time are rising dramatically. As the treatment of osteoporosis evolves, we need to present options to our patients and to recognize the impact of osteoporosis osteopenia on our clinical therapy. Decisions regarding periodontal treatment and implant placement in patients taking bisphosphonates depend on a host of variables: length of time on the drug, patient age, type of drug, dosage, dosing (continuous or intermittent), compliance, oral vs. intravenous delivery, dental periodontal status and overall systemic health. With the development of alternative medications to oral
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Osteoporosis and Osteopenia

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Osteoporosis and Osteopenia

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Periodontology 2000, Vol. 59, 2012, 111139 Printed in Singapore.

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Osteoporosis and osteopenia: implications for periodontal and implant therapy

Table 1. Effects of estrogen on bone remodeling

Table 2. Risk factors for osteoporosis

Table 3. Medications drugs associated with secondary osteoporosis

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Osteoporosis and osteopenia: physiology

Coupling factors? cleaning cells

Bone formation 46 months

Current clinical therapies

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Dual-energy X-ray absorptiometry (spine and hip )

T-score 2.5 or less in spine or hip

T-score between 1 and 2.5

T-score 1 or higher in spine or hip

Low trauma fracture Evaluate and consider treatment

No osteoporosis Lifestyle counseling Ensure adequate calcium/vitamin D

Treat abnormalities and/or refer patient

Re-evaluate for treatment

Table 5. Calcium recommendations

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Potency 1 10 10 100 100

Selective estrogen receptor modulators

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Estrogen hormone replacement therapy

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Tooth loss and alveolar crestal loss

Bisphosphonates: patient management and their effect on the periodontium

Bisphosphonates: dental implant implications

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Thorough oral examination, and consultation with prescribing physician

Follow guidelines for oral route

Consultation with prescribing physician Advise patients of risks of ONJ

Prior to initiation of bisphosphonate

Bisphosphonate therapy already initiated

Close periodontal maintenance with gentle debridement

Osteonecrosis of the jaw

Osteoporosis and osteopenia: implications for periodontal and implant therapy

bisphospho(A) Clinical (C) Surgical and alveolar

Intravenous bisphosphonates and osteonecrosis of the jaw: prevention and therapy

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Oral bisphosphonates and osteonecrosis of the jaw: prevention and therapy

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Table 7. Laboratory risk assessment for patients taking oral bisphosphonates

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Osteoporosis and osteopenia: implications for periodontal and implant therapy

87. 88. 89.

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Osteoporosis and osteopenia: implications for periodontal and implant therapy

Osteoporosis and osteopenia: implications for periodontal and implant therapy

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