Osteoporosis

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

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

Definition

• A disease characterized by low bone mass, microarchitectural deterioration of bone tissue, or both, leading to skeletal fragility
• Osteopenia is a precursor to osteoporosis.

Key Clinical Features

• Bone mass density > 2.5 SDs below that of normal, young control population (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
  • Secondary osteoporosis associated with the following:
    • Endocrine disorders (hyperparathyroidism, hyperthyroidism, Cushing syndrome),
    • Systemic inflammatory disease,
    • Bone mineral and metabolic defects,
    • Renal, liver, and intestinal diseases (i.e., malabsorption),
    • Other chronic illnesses
  • Bone fracture, pain, and deformity
  • Both appendicular and axial skeleton are involved, with fractures occurring frequently in thoracic vertebrae (crush fractures), hip, and distal radius (Colles fracture)
  • May be seen in younger women with amenorrhea, especially those with anorexia nervosa and athletes

Differential Diagnosis

• Metastatic cancer
• Osteomalacia
• Osteogenesis imperfecta

Best Tests

• Dual x-ray absorptiometry (DEXA) of proximal femur, lumbar spine, or distal nondominant radius
  • Results can be affected by positioning of patient, particularly at the hip, and by osteophytes, especially at the lumbar spine
  • Ideally, comparisons should be made on same machine
• Plain radiographs
  • Insensitive to subtle changes in mineral density in early osteoporosis
  • May be useful to assess for silent fractures (e.g., thoracic spine)
  • Can occasionally be helpful to assess for classical roentgenographic features of certain metabolic bone diseases, such as osteomalacia and hyperparathyroidism

Clinical Pearls

• Once diagnosis is made, evaluate patient to exclude secondary causes of bone loss (other than estrogen deficiency) using a comprehensive history and physical exam to exclude other diseases
• No characteristic lab abnormalities
  • Perform routine blood chemistry studies
    • Serum calcium and phosphorous
    • BUN
    • Serum creatine
    • Liver enzymes
    • CBC

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

Best Therapy

• Consider drug therapy for postmenopausal women with T-score < -2.5 in the absence of risk factors for fracture and for postmenopausal women with 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

Drug Treatment for Osteoporosis

• Calcium supplementation
  • Take calcium carbonate with food
  • Take calcium citrate on empty stomach
  • May help prevent further bone loss but not effective alone as therapy
  • Should be used in conjunction with other therapeutic agents below
    • Dose: 1,000-1,500 mg/day
    • Cost/mo: $2.50
• Vitamin D supplementation
  • Much larger doses, especially if administered parenterally may result in hypercalcemia
  • May help prevent further bone loss but not effective alone as therapy
  • Should be used in conjunction with other therapeutic agents below
    • Dose: 400–800 IU/day
    • Cost/mo: $3.00
• Bisphosphonates
  • Take first thing in the morning, remain upright, and do not consume food for 1 hr
  • Contraindicated in patients with active esophagitis, achalasia, or esophageal stricture
  • Use with caution in patients with history of esophagitis or gastroesophageal reflux disease
  • An antiresorptive agent
  • Demonstrated to reduce both vertebral and nonvertebral fractures
  • Risk reduction for fracture is approximately 50%
  • Preferred choice in most patients
    • Alendronate
      • Dose
        • Prevention: 5 mg/day for perimenopausal women with low bone mass
        • Treatment: 10 mg/day or 70 mg/wk (postmenopausal women with osteoporosis defined by BMD or fractures); 10 mg/day p.o. for men with osteoporosis
      • Cost/mo: $66.99 (5 mg/day); $133.97 (10 mg/day)
    • Risedronate
      • Dose: 5 mg/day or 35 mg once/wk
      • Cost/mo: $62.99
• Raloxifene
  • Selective estrogen receptor modulator (SERM)
  • Does not carry with it same implications for uterine or breast cancer as do conventional estrogens
  • Increased risk of thromboembolic disease
  • An antiresorptive agent
  • Has been shown to reduce vertebral fractures but not nonvertebral fractures
  • Usually used if bisphosphonates not tolerated or contraindicated
    • Dose: 60 mg/day p.o.
    • Cost/mo: $70.99
• Calcitonin
  • An antiresorptive agent
  • Has been shown to reduce vertebral fractures but not nonvertebral fractures
  • May provide pain relief in those with acute vertebral fractures
  • Tachyphylaxis is a concern
  • Usually used if bisphosphonates not tolerated or contraindicated
    • Dose: 200 IU/day intranasally
    • Cost/mo: $34.50
• Estrogen
  • An antiresorptive hormone
  • Should be limited to those who require relief of menopausal symptoms
  • Contraindicated in those with history of breast or uterine cancer or thrombotic disorders
  • Increases the incidence of breast cancer and may increase the incidence of cardiovascular events
  • 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
  • Demonstrated to reduce both vertebral and nonvertebral fractures
  • Risk reduction for fracture is approximately 50%
    • Dose: 0.625 mg oral conjugated estrogen/day or 0.1 mg 17β-estradiol transdermal for days 1 to 21
    • Cost/mo: oral, $23.99; transdermal, $85.99
• Teriparatide (recombinant human PTH [1-34])
  • An anabolic agent
  • Demonstrated to reduce both vertebral and nonvertebral fractures
  • Should not be used with bisphosphonates or, most likely, with any antiresorptive agent
  • Usually reserved for women with severe osteoporosis
    • Dose: 20 μg S.Q./day
    • Cost/mo: $515.96
      

Clinical Pearls

• Reduce fracture risk through the following measures:
  • Maintaining body weight
  • Weight-bearing physical exercise
  • Avoiding long-acting benzodiazepines
  • Minimizing caffeine intake
  • Treating impaired vision
• Men benefit from calcium repletion, adequate vitamin D intake, appropriate exercise regimen, and antiresorptive agents, if applicable.
• For men, testosterone injections or patch should be used if patient is hypogonadal.
• A secondary cause for men with osteoporosis is found more commonly than in women
  • Hypogonadism
  • Alcohol abuse
  • Liver or intestinal disease

Best References

Body, et al: J Clin Endocrinol Metab 87:4528, 2002

Liberman, et al: N Engl J Med 333:1437, 1995

Maricic, et al: Arch Intern Med 162:1140, 2002

McClung, et al: N Engl J Med 344:333, 2001

NIH Consensus Panel: JAMA 285:785, 2001

Women's Health Initiative Investigators: JAMA 288:321, 2002

July 2004