Osteoporosis

Elizabeth Holt, M.D., Ph.D.
Silvio E. Inzucchi, M.D.
Yale University School of Medicine

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

• Loss of bone mass, including loss of trabecular bone microarchitecture and connectivity and thinning of cortical bone, leading to increased risk of fracture
• Bone mass density > 2.5 SDs below that of normal, young adult control population (dual x-ray absorptiometry [DXA] T score < -2.5)
• Histomorphology
  • Decreased cortex thickness
  • Decreased number and size of trabeculae in cancellous bone
  • Decreased trabecular connectivity
  • Increased number of perforations in trabecular plates
• Primary osteoporosis
  • Occurs in the elderly, particularly women in 6th decade and older
  • Bone fracture, pain, and spinal deformity
  • Both appendicular and axial skeleton are involved, with fractures occurring frequently in thoracic vertebrae (compression fractures), hip, and distal radius (Colles fracture)
• Secondary osteoporosis is associated with the following:
  • Endocrine disorders (hyperparathyroidism, hyperthyroidism, Cushing syndrome, hypogonadism, growth hormone deficiency)
  • Systemic inflammatory disease (e.g., rheumatoid arthritis)
  • Bone mineral and metabolic defects
  • May be seen in younger women with amenorrhea, especially those with anorexia nervosa, and in athletes
  • Renal, liver, and intestinal diseases (e.g., malabsorption)
  • Use of some medications, including glucocorticoids
  • Other chronic illnesses (e.g., multiple myeloma)

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Differential Diagnosis

• Metastatic cancer
• Osteomalacia
• Osteogenesis imperfecta
• Paget disease

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Best Tests

• DXA of proximal femur, lumbar spine, or nondominant distal radius
  • Positioning of patient may affect results, particularly at the hip and wrist
  • Degenerative disease or scoliosis in the lumbar spine can make the bones appear denser
  • Comparison studies should be performed on same densitometer if possible
• Plain radiographs
  • Only able to identify significant osteoporosis
  • May be useful to assess for silent fractures
  • May help to assess for classical roentgenographic features of certain metabolic bone diseases, such as osteomalacia and hyperparathyroidism

• Risk of fracture is not only predicted by T-score; relative contribution of other risk factors such as age (and others below) is significant
• Once osteoporosis is diagnosed, consider causes of secondary bone loss (other than estrogen deficiency) using a comprehensive history and physical exam to exclude relevant diseases; this should be followed by laboratory testing for any conditions suspected

• Spontaneous high thoracic or cervical fractures with minimal trauma should raise suspicions of malignancy
• Risk of death within 1 yr of hip fracture is significantly increased

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Best Therapy

Modifiable Risk Factors

• Smoking cessation
• Moderation of alcohol consumption
• Weight-bearing physical activity
• Physical therapy evaluation to improve safety and stability
• Home safety evaluations to prevent falls
• Review medication lists for frail elderly patients to eliminate medications that may cause dizziness or sedation

• Consider drug therapy for postmenopausal women with DXA T-score < –2.5 in the absence of risk factors for fracture and for postmenopausal women with DXA T-score < –1.5 in the presence of risk factors for fracture
• Most important risk factors for fracture
  • Personal history of fracture after age 40 yr
  • Family history of osteoporosis in a first-degree relative
  • Current cigarette smoking
  • Low body weight, < 127 lb, regardless of height
• Calcium supplementation
  • May help prevent further bone loss but not effective alone as therapy
  • Should be used in conjunction with other therapeutic agents below
  • In elderly patients, those on proton pump inhibitors or H₂ receptor blockers, and patients with pernicious anemia, calcium citrate may be better absorbed than calcium carbonate
  • Take calcium carbonate with food
  • Take calcium citrate on empty stomach
    • Dose: 1,000–1,500 mg/day
    • Cost/mo: $3
• Vitamin D supplementation
  • May help prevent further bone loss but not effective alone as therapy
  • Vitamin D deficiency is associated with increased risk of falls
  • Should be used in conjunction with other therapeutic agents (see below)
  • Excessive intake may result in hypercalcemia
  • Patients taking medications (e.g., phenytoin) that increase vitamin D metabolism may need higher doses
    • Dose: 400–800 IU/day
    • Cost/mo: $3
• Bisphosphonates: antiresorptive agents
  • Preferred agents for most patients with osteoporosis
  • Alendronate and risedronate (but not ibandronate) have been demonstrated to reduce both vertebral and nonvertebral fractures
  • Risk reduction for fracture is ~ 35–50%
  • Contraindicated in patients with esophageal dysmotility, stricture or varices, or active esophagitis/gastritis; creatinine clearance must be above 35 ml/min
  • Use with caution in patients with history of esophagitis or gastroesophageal reflux disease
  • Osteonecrosis of the jaw is a rare side effect of agents in this class
  • Use with caution in women of childbearing age
  • Concern for adynamic bone: consider a 1- to 2-yr drug holiday after 5–10 yr of oral bisphosphonate therapy
  • Take first thing in the morning on empty stomach with full glass of water, remain upright, and do not consume other drinks, medications or food for 30 min
    • Alendronate
      • FDA-approved for hip fracture prevention
      • Dose
        • Prevention: 35 mg p.o. once a wk
        • Treatment: 70 mg p.o. once a wk for osteoporosis defined by BMD or fractures
      • Cost/mo: $69 (35 mg/wk); $78 (70 mg/wk)
    • Risedronate
      • Not FDA-approved for hip fracture prevention
      • Dose: 35 mg p.o. once a wk for prevention or treatment
      • Cost/mo: $68
    • Ibandronate
      • Not FDA-approved for hip fracture prevention
      • Dose
        • Prevention and treatment: 150 mg once/mo
      • Cost/mo: $76
• Raloxifene: antiresorptive agent
  • Not FDA-approved for hip fracture prevention
  • Selective estrogen receptor modulator (SERM)
  • Does not increase risk of breast cancer
  • Increased risk of thromboembolic disease
  • May cause/worsen hot flashes
  • Reduces vertebral fractures but not nonvertebral fractures
  • Usually used only if bisphosphonates not tolerated or contraindicated
    • Dose: 60 mg/day p.o.
    • Cost/mo: $85
• Calcitonin: antiresorptive agent
  • Reduces vertebral fractures but not nonvertebral fractures
  • May provide pain relief in those with acute vertebral fractures
  • Tachyphylaxis is a concern
  • Usually used if other agents not tolerated or contraindicated
    • Dose: 200 IU/day intranasally
    • Cost/mo: $93
• Estrogen: antiresorptive hormone
  • Should be limited to those who require relief of menopausal symptoms
  • Reduces both vertebral and nonvertebral fractures
  • Risk reduction for fracture is ~ 50%
  • ERT should be accompanied by a comprehensive screening program consisting of regular lipid profiles, breast examinations, mammography, and gynecologic assessments
  • Contraindicated in those with history of breast or uterine cancer or thrombotic disorders
  • Increases the incidence of breast cancer, cardiovascular events, and stroke
  • In women with an intact uterus, must be used in conjunction with progestational agent
  • When used without progestins, also increases the risk of uterine cancer
    • Dose: 0.625 mg oral conjugated estrogen/day or 0.1 mg 17 b-estradiol transdermal for days 1 to 21
    • Cost/mo: oral, $32; transdermal, $86
• Teriparatide (recombinant human PTH [1-34]): anabolic agent
  • Reduces both vertebral and nonvertebral fractures
  • Has not been shown to prevent hip fracture
  • Black box warning from FDA because of association with osteosarcoma in rats
  • Use for patients with the following:
    • Severe osteoporosis
    • History of vertebral fracture, T-score –3.0 or below, or age > 69 yr
    • Fracture or unexplained bone loss in patients on antiresorptive therapy
    • Intolerance of oral bisphosphonate therapy
  • Side effects include flushing, hypercalcemia, and hypercalciuria
  • Serum calcium and 24-hr urine calcium levels must be monitored and calcium intake adjusted as needed
  • Can be administered for no longer than 2 yr
  • Contraindicated in patients with active malignancy, hypercalcemia, Paget disease, history of irradiation to the skeleton, sarcoma, or malignancy involving bone
  • Simultaneous use with antiresorptive agents appears to reduce its efficacy
  • When bisphosphonate therapy follows treatment with teriparatide, the effects of teriparatide are enhanced and maintained
    • Dose: 20 mg S.Q./day
    • Cost/mo: $587

• Reduce fracture risk through the following measures:
  • Maintaining body weight
  • Weight-bearing physical exercise
  • Avoiding drugs that may cause sedation or falls
  • Treating impaired vision
  • Hip protectors have been shown to be effective in some clinical trials
• Osteoporosis in men is idiopathic in about half of cases; identifiable causes include the following:
  • Hypogonadism
  • Alcohol abuse
  • Liver or intestinal disease
• Men benefit from calcium repletion, adequate vitamin D intake, appropriate exercise regimen, and antiresorptive agents, if applicable

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Best References