Osteoporosis

Carolyn B. Becker, MD
Harvard Medical School

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 mineral density (BMD) > 2.5 SD below that of normal, young adult control population (dual x-ray absorptiometry [DXA] T score ≤ −2.5)
• Histomorphology
• Decreased cortical 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 sixth 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 (hyperparathyroidism)
• 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; immobilization)

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Differential Diagnosis

• Other Diagnoses to Consider for Low Bone Density or Nontraumatic Fractures

  • 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 assess for classic roentgenographic features of certain metabolic bone diseases, such as osteomalacia and hyperparathyroidism

Clinical Pearls

• 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 examination to exclude relevant diseases; this should be followed by laboratory testing for any conditions suspected
• FRAX calculator may help in treatment decision making

Red Flags

• 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

Drug Treatment for Osteoporosis*

• Consider drug therapy for postmenopausal women with DXA T score ≤ –2.5 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 with or without food

• Dose: 1,000–1,200 mg/day

• Vitamin D supplementation
• May help prevent further bone loss but not effective alone as therapy
• 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: 600–800 IU/day

• 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, Barrett esophagus, 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 week
• Treatment: 70 mg p.o. once a week for osteoporosis defined by BMD or fractures
• Risedronate
• Not FDA approved for hip fracture prevention
• Dose: 35 mg p.o. once a week for prevention or treatment
• Ibandronate
• Not FDA approved for hip fracture prevention
• Dose
• Prevention and treatment: 150 mg once/mo

• Raloxifene: antiresorptive agent
• Not FDA approved for hip fracture prevention
• Selective estrogen receptor modulator (SERM)
• Decreases risk of estrogen receptor–positive breast cancer
• Increased risk of thromboembolic disease
• May cause/worsen hot flashes
• Reduces vertebral fractures but not nonvertebral fractures
  •  Dose: 60 mg/day p.o.
• 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
• 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%
• Estrogen replacement therapy 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
• 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 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 bisphosphonates appears to reduce its efficacy
• Very expensive
• Daily subcutaneous injections
• When bisphosphonate therapy follows treatment with teriparatide, the effects of teriparatide are enhanced and maintained
  • Dose: 20 mg SC/day
• Denosumab: antiresorptive agent: reduces both vertebral and nonvertebral fractures; monoclonal antibody against RANK ligand; given SC every 6 months; side effects: infections, rashes, hypocalcemia
  
  Clinical Pearls

• 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
• Glucocorticoids
• Men benefit from calcium repletion, adequate vitamin D intake, appropriate exercise regimen, and antiresorptive or anabolic agents, if applicable

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Best References

Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Available at: http://www.iom.edu/vitamind (accessed November 30, 2010).

Kanis JA, Oden A, Johannson H, et al. FRAX and its applications to clinical practice. Bone 2009;44:734–43.

Khosla S. Update in male osteoporosis. J Clin Endocrinol Metab 2010;95:3–10.

MacLean C, Newberry S, Maglione M, et al. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008;148:197.

National Osteoporosis Foundation. Clinician’s guide to the prevention and treatment of osteoporosis. Washington (DC): National Osteoporosis Foundation; 2008. Available at: http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf.

Shane E, Burr D, Ebeling BR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2010;25:2267–94.

U.S. Preventive Services Task Force. Screening for osteoporosis: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2011;154:356–64.

Vega D, Maalouf NM, Sakhaee K. The role of receptor activator of nuclear factor-KB(RANK)/RANK ligand/osteoprotegerin: clinical implications. J Clin Endocrinol Metab 2007;92:4514–21.

World Health Organization. FRAX WHO fracture risk assessment tool. Sheffield (UK): World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield; 2008. Available at: http://www.shef.ac.uk/FRAX/index.htm.

* To obtain additional drug information, click on the DrugInfo tab in the left column, or click on the following link: http://search.medscape.com/drug-reference-search?queryText=

October 2011