Osteoporosis

Osteoporosis is a skeletal condition in which the loss of bone mineral density leads to decreased bone strength and an increased susceptibility to fractures. The disease typically affects postmenopausal women and the elderly, as an abrupt decrease in estrogen and age-related processes play a key role in the development of osteoporosis. Further risk factors include inactivity, smoking, and alcohol consumption. Osteoporosis usually remains asymptomatic until the first occurrence of fragility fractures (following minor trauma), particularly of the vertebrae. After repeated vertebral fractures, patients may also develop thoracic hyperkyphosis and lose height. Osteoporosis is diagnosed through a bone density test (dual-energy x-ray absorptiometry), while fractures are usually confirmed through conventional x-ray. Management of osteoporosis includes prophylactic measures and medical therapy. The prophylaxis consists mainly of adequate intake of calcium and vitamin D and regular physical activity with strengthening exercises. Both help to maintain or even increase bone mass and improve balance, thereby reducing the risk of falling. Medical therapy is indicated in cases of severely reduced bone density or osteoporotic fractures. The most commonly used drugs are bisphosphonates, which inhibit bone resorption and can significantly decrease the risk of fractures. There are several other possible medical therapies (e.g., teriparatide, raloxifene), which may be indicated in special cases (e.g., severe osteoporosis, breast cancer prophylaxis required) or if patients have contraindications to bisphosphonates.

• Osteoporosis: loss of trabecular and cortical bone mass which leads to bone weakness and increased susceptibility to fractures
• Osteopenia: decreased bone strength but less severe than osteoporosis

• Sex: ♀ > ♂ (∼ 4:1)
• Age of onset: 50–70 years
• Demographics: higher incidence in individuals of Asian, Hispanic, and northern European ancestry ^[1]

Epidemiological data refers to the US, unless otherwise specified.

• Primary osteoporosis (most common form)
  • Type I (postmenopausal osteoporosis): postmenopausal women ^[2][3]
    • Estrogen stimulates osteoblasts and inhibits osteoclasts.
    • The decreased estrogen levels following menopause lead to increased bone resorption.
  • Type II (senile osteoporosis): gradual loss of bone mass as patients age (especially > 70 years)
  • Idiopathic osteoporosis
    • Idiopathic juvenile osteoporosis ^[4]
    • Idiopathic osteoporosis in young adults ^[5]
• Secondary osteoporosis
  • Drug-induced/iatrogenic
    • Most commonly due to systemic long-term therapy with corticosteroids (e.g., in patients with autoimmune disease) ^[6]
    • Long-term therapy involving: ^[7]
      • Anticonvulsants (e.g., phenytoin, carbamazepine)
      • L-thyroxine
      • Anticoagulants (e.g., heparin)
      • Proton pump inhibitors
      • Aromatase inhibitors (e.g., anastrozole, letrozole)
      • Immunosuppressants (e.g., cyclosporine, tacrolimus)
  • Endocrine/metabolic: hypercortisolism, hypogonadism, hyperthyroidism, hyperparathyroidism, renal disease
  • Multiple myeloma
  • Excessive alcohol consumption
  • Immobilization
• Risk factor for osteoporosis
  • Cigarette smoking
  • Malabsorption, malnutrition (e.g., a vegan diet low in calcium and vitamin D), anorexia ^[8]
  • Low body weight
  • Family history of osteoporosis ^[9]

• Mostly asymptomatic
• Fragility fractures: pathological fractures that are caused by everyday-activities (e.g., bending over, sneezing) or minor trauma (e.g. falling from standing height) ^[10]
  • Common locations: vertebral (most common) > femoral neck > distal radius (Colles fracture) > other long bones (e.g., humerus)
  • Vertebral compression fractures
    • Commonly asymptomatic but may cause acute back pain and possible point tenderness without neurological symptoms
    • Multiple fractures can lead to decreased height and thoracic kyphosis.
    • See “Vertebral fractures” for more information.

Imaging

DXA (dual-energy x-ray absorptiometry)

• Definition: : a noninvasive technique that calculates bone mineral density (BMD) by using two x-ray beams ^[11]
• Measurement sites: lumbar spine and femoral neck
• Indications ^[12]
  • General recommendation for women ≥ 65 years; and men ≥ 70 years (one-time screening test)
  • In younger individuals, if additional risk factors are present: e.g., prolonged glucocorticoid use, low BMI (< 21 kg/m²) or weight < 127 lb, alcohol use, smoker, amenorrhea
• Results: T-score is defined as the difference in standard deviations between the patient's BMD and the BMD of a young adult female reference mean.
  • Osteoporosis: T-score ≤ -2.5 SD
  • Osteopenia: T-score of -1 to -2.5 SD

Osteoporosis is diagnosed if T-score ≤ -2.5 SD and/or a fragility fracture is present.

Plain radiography

• If osteoporosis is diagnosed: Radiographic assessment of the whole skeletal system is recommended, particularly if a fracture is already suspected or height loss has occurred.
• Increased radiolucency is detectable in cortical bones once 30–50% of bone mineral has been lost ^[13]
• Osteoporosis can be diagnosed if vertebral compression fractures are present ; commonly an incidental finding because such fractures are typically asymptomatic.

Quantitative computed tomography (QCT) ^[14]

Used for the measurement of true bone volume density in g/cm³

Clinical chemistry

Usually normal findings, but some markers may be used for assessing the risk of fracture . See “Laboratory evaluation of bone disease” for more information.

• Urine: ↑ cross-links (e.g., deoxypyridinoline) , markers of bone turnover ^[15]
• Blood tests ^[16]
  • Primary osteoporosis
    • Normal serum calcium, phosphate, and parathyroid hormone (PTH) levels
    • Alkaline phosphatase possibly elevated
  • Secondary osteoporosis: abnormal results depending on underlying disease (e.g., hypercalcemia in hyperparathyroidism)

Pathology

• Thin, disconnected trabecular structures
• Attenuated, pitted cortical bone
• Increased osteoclast number and activity

• Osteomalacia
• Hyperparathyroidism
• Metastases
• Multiple myeloma
• Intraosseous hemangioma

The differential diagnoses listed here are not exhaustive.

Medical therapy ^[17]

Indications

• History of fragility fractures
• T-scores ≤ -2.5
• T-score between -1 and -2.5 with severely increased risk of fracture

Drug of choice

• Bisphosphonates: e.g., alendronate, risedronate
  • Mechanism of action: inhibition of osteoclasts → bone resorption
  • Side effects ^[18]
    • Hypocalcemia
    • Esophagitis, esophageal cancer
    • Osteonecrosis of the jaw

Bisphosphonates should be taken in the morning and evening at least 30 minutes before meals, with plenty of water, and the patient should maintain an upright position for at least 30 minutes following intake to prevent esophagitis. ^[19]

Alternative drugs ^[9]

Used in the case of contraindications/unresponsiveness to bisphosphonates.

• Teriparatide: parathyroid hormone analog
  • Mechanism of action: increases osteoblastic activity → increased bone growth
  • Mainly used for the treatment of osteoporosis and as an alternative for severe osteoporosis (T-score ≤ -3.5) or for patients with contraindications to bisphosphonates ^[17]
  • Administered in a pulsatile fashion
  • Side effects
    • Hypercalcemia (usually transitory)
    • Increased risk of osteosarcoma in patients with:
      • Paget disease of the bone (or an unexplained elevation of alkaline phosphatase)
      • Prior cancers or radiation therapy
• Raloxifene: (selective estrogen receptor modulator, SERM) for patients with contraindications to bisphosphonates or those who also require breast cancer prophylaxis (but increases the risk of thromboembolism) ^[17][20]
• Denosumab (monoclonal antibody against RANKL)
  • Mechanism of action: targets the RANKL by mimicking osteoprotegerin → interference in osteoclast maturation → ↓ osteoclast activity
  • Indicated in patients with impaired renal function or in whom bisphosphonates therapy failed
• Calcitonin
  • Rarely used today due to the availability of more effective alternatives ^[21]
  • Indicated in postmenopausal osteoporosis
• Hormonal therapy ^[9]
  • Estrogen: for women with intolerance to first-line or second-line treatment options or with persistent menopausal symptoms
    • Usually in combination with progestin
    • Contraindications: breast cancer, coronary heart disease, deep vein thrombosis
  • Testosterone: for men with hypogonadism ^[22]

Denosumab makes you dance.

• Diet
  • Avoid alcohol and nicotine.
  • Sufficient intake of calcium; and vitamin D
• Physical activity: with strength and balance training
• Drug intake: Avoid or minimize use of glucocorticoids.