Back pain in an elderly woman: Osteoporosis and related fractures

Prof Annie Kung Department of Medicine University of Hong Kong

Pathogenesis of osteoporosis
Resorbed cavity too large Newly formed packet of bone too small

Formation does not match resorption

Increased numbers of remodeling units

INCREASED BONE LOSS

Bone turnover
Trabecular bone
20% of the skeletal mass 80% of bone turnover

Cortical bone
80% of the skeletal mass 20% of bone turnover

Bone remodeling
Bone marrow precursors

Mesenchymal cells

Hematopoietic cells

Osteoblast

Osteoclast Lining cells

Regulation of osteoclastogenesis by factors from osteoblast/stromal cells

Osteoclast precursor Mature osteoclast

Differentiation

M - CSF

RANK

Inhibition

OPG
RANKL
RANKL
"decoy receptor"

Osteoblast / stromal cell

Hofbauer LC & Heufelder AE, J Mol Med, 2001;79:243-253

Estrogens: mechanism of action in bone

Precursor (Osteoblast)
Cytokines IL-1, TNF-a IL-6, TGF-b,....

Precursor (Osteoclast)

Estrogens
apoptosis TGF- Cytokines RANK-L

apoptosis TNF-

osteoblast

osteoclast

Regulation of RANKL and OPG by systemic hormones

RANKL
Dexametasone 1,25-(OH2)D3 PTH PGE2

OPG
17-Estradiol

Stimulation

17-Estradiol

Inhibition

Hydrocortisone 1,25-(OH2)D3 PTH PGE2

Aubin JE & Bonnelye E, Osteoporos Int, 2000;11:905-913

Age-related bone loss

Dietary calcium intake Vitamin D intake and synthesis

Calcium absorption

Estrogen deficiency

Plasma calcium

PTH secretion

Bone turnover and resorption

BONE LOSS

Secondary osteoporosis

Endocrine

Nutritional

Drug-induced

Immobilization

Others

Hyperthyroidism Hypogonadism Cushing Syndrome

Glucocorticoids Immunosuppressly Anticonvulsants

Rheumatoid A. Diabetes Tumors

(Myeloma, etc.)

Osteomalacia
Equivalent to Rickets in children Abnormal histology: unmineralized osteoid Cause: vitamin D deficiency, very low level of serum 25(OH)D New conception: osteoporosis and osteomalacia a continuum

Clinical Diagnosis of Osteoporosis

Wrist fracture

Spinal fracture

Hip fracture

Clinical Diagnosis of Osteoporosis

Previous fragility fracture Back pain Height loss (>2cm since age 25) Kyphosis Occiput to wall distance Gap between costal margin and iliac crest <3 finger breaths

WHO Definition of Osteoporosis

A condition characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and increase susceptibility to fracture.
1994, WHO Working Group

Diagnosis Based on BMD

Kanis JA et al. Osteoporos Int. 1994; 4:368

WHO Definition of Osteoporosis

Prevalence estimate of osteoporosis in a population Results expressed as SD from mean of young adult Caucasian women (T score) Evaluated in postmenopausal Caucasian women 1 SD reduction in BMD (using DXA of spine, hip or forearm) corresponds to a 2fold increased risk in hip fracture

WHO Definition of Osteoporosis

Normal Ostopenia T score -1 T score < -1 and > -2.5

Osteoporosis
Established osteoporosis

T score -2.5 T score -2.5 with fracture

T scores allow comparison using the same diagnostic criteria for different machines.

T-score
Young normal adult reference of same ethnicity Patients BMD Young Adult Mean BMD 1 SD of Young Adult BMD (a large population SD can affect the T score value)

Why Cut-off at T score -2.5

This cutoff value identifies approximately 30% of postmenopausal women as having osteoporosis using measurements made at the spine, hip or forearm. This is approximately equivalent to the lifetime risk of fracture at these sites.
Kanis JA et al. JBMR 1994;9:1137

Prevalence of Osteoporosis and Lifetime Fracture Risk in White Women

40.0% 35.0% 30.0% 25.0% 20.0% 15.0% 10.0% 5.0% 0.0%
lumbar spine femoral neck forearm any of three

T-score equal to or lower than -2.5 Lifetime fracture risk

** Clinical vertebral fractures

Melton LJ III, et al. J Bone Miner Res. 1995;10:175. Melton LJ III, et al. J Bone Miner Res. 1992;7:1005.

WHO Diagnostic Criteria, and BMD Profile in a Population

1.2 1.1
+1 SD T-Score +2 SD

Total Hip BMD (g/cm2)

Mean

0.9
-1 SD

-2 SD

0.7 0.6 0.5 0.4

30

40

50

60

70

80

90

Age (years)

OSTEOPOROSIS

-2.5 SD

LOW BONE MASS

0.8

NORMAL

1.0

New Definition of Osteoporosis

Osteoporosis is a skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength reflects the integration of bone density and bone quality.
NIH Consensus Conference 2001

Normal bone

Osteoporotic Bone
NIH Consensus Development Panel on Osteoporosis. JAMA 285 (2001): 785-95

Determinants of bone strength

Bone Remodeling

Microarchitecture

Mass (Size, Geometry)

Tissue Properties Mineralization Collagen

(structure, cross-links)

Micro damage

Bone Strength

BMD and Risk of Fracture

Osteoporosis is a disease characterised by low bone mass and increased fracture risk 1 SD reduction in BMD corresponds to a 2-fold increased risk in hip fracture BMD measurement can diagnose osteoporosis before fracture occurs

Prevalence of Osteoporotic Fractures in Hong Kong Women

60 - 69 years
70 - 79 years

1:6
1:5

80 and above

1:4

Osteoporosis Risk Factors

Nonmodifiable
gender race heredity, body frame age

Modifiable
low estrogen level low dietary calcium or vitamin D sedentary smoking alcoholism medications (glucocorticoids, etc)

Recommended Intakes (USA)

Age range
19 - 50 51 - 70 > 70 Upper limit Osteoporosis

Ca (mg)
1,000 1,200 1,200 2,500 2,500

Vit D (IU/d)
200 (5 mcg) 400 600 2,000 800

Clinical Evaluation of Patient with Established Osteoporosis

A. History Risk factors Evidence for secondary osteoporosis Medications that cause bone loss Medications / illness that increase the chance to fall Family history

Clinical Evaluation of Patient with Established Osteoporosis (2)

B. Physical Examination Height and weight Dental exam (loss of teeth, dentures) Evidence of hyperthyroidism, Cushings disease Estimate degree of kyphosis, observe posture, sites of tenderness Factors that influence propensity to fall (agility, hearing, eyesight, postural sway) Gait, mobility muscle strength

Clinical Evaluation of Patient with Established Osteoporosis (3)

C. Laboratory Tests Serum calcium, phosphate 24 hour urine calcium 25 OH vitamin D PTH , TSH Biochemical Markers of Bone Turnover

Clinical Evaluation of Patient with Established Osteoporosis (4)

D. Radiologic Evaluations/Non-invasive Bone Mass Quantitations X-ray thoracolumbar spine Dual-energy X-ray absorptiometry Computed tomography

Treatment Options

1. Lifestyle modification

2. Therapeutic Agents

Life Style Modification

1. Adequate Dietary Calcium Intake 2. Weight bearing exercise

3. Avoid vitamin D deficiency

Therapeutic Agents
Resorption Inhibitors Estrogen SERM Bisphosphonates Calcitonin RANKL Ab Formation Stimulators PTH

Alter Bone Turnover Strontium Ranelate

HRT

Inhibits bone resorption calcium excretion in urine cytokines production by stromal cells Additional advantage CVD risk factors e.g. cholesterol, but outcome events (i.e. MI, stroke) not reduced menopausal symptoms Disadvantage Endometrial cancer (additional progestogens if uterus intact) Slight risk of breast cancer Venothrombolic disease

Selective Estrogen Receptor Modulators (SERMS)

Selective stimulatory action on bone Decreases LDL Little effect on breast and uterus Raloxifene vertebral fracture risk by 50% but not non-vertebral fracture

Bisphosphonates

Derivatives of pyrophosphates Inhibit osteoclast activity, specific inhibition of bone resorption Bound onto surface of osteoclast, inhibit farnesyl pyrophosphate synthase (FPPS), the key enzyme in the mevalonate pathway and induce apotosis of osteoclast e.g. etidronate, alendronate, risedronate, ibandronate, zolendronate fracture risk (both vertebral and nonvertebral, including hip) by about 50%

Bisphosphonates

Oral/IV preparation Poor intestinal absorption Selective uptake at active bone sites
Short plasma half-life No active metabolites Renal excertion

Side-effects: oesophagitis, first phase reaction (fever, muscle/bone pain) Action persist, may cause adverse effect of oversuppression of bone turnover and atypical fractures (5 in 10,000) and osteonecrosis of jaw (1 in 10,000)

Calcitonin

Inhibits osteoclast activity Intramuscular or Intranasal BMD 2 - 3 % vertebral fracture risk by 30% but not non-vertebral fracture Additional benefit on pain relief

RANKL Ab
Human monoclonal Ab to RANKL Interfere with RANKL and decrease osteoclast differentiation and activation Given as SC injection q 6 months Decrease vertebral fracture by 50%, non-vertebral fracture 30%

PTH

High level, continuous: bone resorption cortical > trabecular bone Low dose, intermittent: anabolic action e.g. daily IMI can BMD and vertebral fracture risk by 70%

Strontium Ranelate
Strontium belongs to Group 2 compounds in chemistry periodic table, same as calcium Act through Ca-sensing receptor Alter bone turnover, increases bone formation and decreases bone resorption

Biochemical Bone Markers

Bone Formation Osteocalcin Alkaline phosphatase PINP (Type I ProCollagen Peptide) Bone Resorption Hydroxyproline Deoxypyridinoline Pyridinoline II (PYD) C-telopeptides (CTx) urine N-Telopeptide (NTx)

Usefulness of Biochemical Markers

Study of normal bone metabolism Diagnosis and monitoring of bone disease

Evaluate effectiveness of therapeutic agent, monitor treatment progress

Not useful as a screening agent

Major Secondary Causes of Osteoporosis

Disease Myeloma Hyperparathyroidism Hyperthyroidism Cushings Syndrome Hypogonadism Ix SIEP Ca2+, PTH TSH Cortisol, ACTH E2, testosterone

Mechanisms for Steroid Induced Osteoporosis

1. Decreases osteoblast function,

decreases bone formation 2. Increases osteoclast resorption 3. Causes negative calcium balance ( GI absorption, renal excretion) 4. Induces hypogonadism

Glucocorticoid-Induced Osteoporosis
Progressive

demineralization

Trabecular
Bone

>> cortical bone

loss greatest within first year (can loss up to 20% of trabecular bone) of loss greatest in those subjects with high bone remodeling rates

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