Osteoporosis

Osteoporosis is a skeletal condition in which the loss of bone mineral density (BMD) leads to decreased bone strength and increased susceptibility to fractures. Postmenopausal women and older adults are often affected, as an abrupt decrease in estrogen and age-related processes play a key role in the development of osteoporosis. Additional risk factors include physical inactivity, a diet low in calcium and vitamin D, smoking, and alcohol consumption. Osteoporosis usually remains asymptomatic until the first occurrence of a fragility fracture (typically following minor trauma). Patients may also present with thoracic hyperkyphosis and height loss secondary to multiple vertebral compression fractures. Diagnostic evaluation includes BMD assessment (e.g., dual-energy x-ray absorptiometry), fracture risk assessment, and workup for common causes of secondary osteoporosis. Fractures are usually confirmed through conventional x-ray. Pharmacotherapy is indicated in patients who fulfill the diagnostic criteria for osteoporosis. Bisphosphonates, which inhibit bone resorption and can significantly decrease the risk of fractures, are the preferred first-line treatment. Nonbisphosphonates are indicated in patients who are unable to take bisphosphonates and those in whom bisphosphonate therapy has been unsuccessful. Prevention mainly comprises of adequate calcium and vitamin D intake and regular physical activity with strengthening exercises to maintain or even increase bone mass and improve balance, thereby reducing the risk of falls and fragility fractures. High-risk individuals should be offered screening for osteoporosis and pharmacotherapy should be initiated in those with osteopenia at a high risk of fractures.

• 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)

• 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) ^[3]
  • Long-term therapy involving: ^[6]
    • 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)
    • Androgen deprivation therapy (ADT)
• Endocrine/metabolic: hypercortisolism, hypogonadism, hyperthyroidism, hyperparathyroidism, renal disease
• Multiple myeloma

Additional risk factors ^[7]

• Excessive alcohol consumption
• Cigarette smoking
• Immobilization or inadequate physical activity
• Malabsorption (e.g., celiac disease), malnutrition (e.g., diet low in calcium and vitamin D), anorexia ^[8]
• Low body weight
• Family history of osteoporosis
• Personal history of fracture

• 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) ^[9]
  • Common locations of major osteoporotic fractures: 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.

Approach ^[10]

Osteoporosis is typically identified during screening in high-risk individuals (see “Screening for osteoporosis”).

• Assess BMD and estimate the risk of major osteoporotic fracture.
• The diagnosis is confirmed if any of the following diagnostic criteria for osteoporosis are fulfilled. ^[10]
  • T-score ≤ -2.5 standard deviations (SDs) on dual-energy x-ray absorptiometry (DXA)
  • T-score -1 to -2.5 SD in patients at increased risk of major osteoporotic fracture
  • History of a major osteoporotic fragility fracture (regardless of BMD)
• Once confirmed:
  • Consider screening all patients for common causes of secondary osteoporosis.
  • Evaluate high-risk patients for vertebral fractures.
• Consider bone turnover markers (BTMs) to assess fracture risk and monitor treatment response.

Osteoporosis is diagnosed in patients with a T-score ≤ -2.5 SD and/or a fragility fracture. ^[10]

Bone mineral density (BMD) assessment ^[10][11]

Indications

• Evaluation of suspected osteoporosis
• Screening for osteoporosis in asymptomatic high-risk individuals

Preferred modality: dual-energy x-ray absorptiometry

DXA measures BMD; at the lumbar spine and hip/femoral neck using two x-ray beams. Findings are represented in terms of BMD scores that compare results to a reference population.

DXA evaluates bone quantity. The trabecular bone score uses data from DXA images to evaluate bone quality and may sometimes be used to further stratify fracture risk. ^[12]

Alternatives ^[11][13]

These studies are most commonly used when conventional DXA is unavailable.

• Peripheral DXA: measures BMD at the distal forearm
• Quantitative computed tomography
  • Provides a volumetric measurement of BMD at the lumbar spine and hip
  • Can measure density of trabecular bone
  • May be superior to DXA in patients with: ^[11]
    • Very tall or very short stature
    • Significant degenerative disk disease
    • BMI > 35 kg/m²
    • Close monitoring of trabecular bone density changes (e.g., chronic glucocorticoid use, parathyroid hormone therapy)

Fracture risk assessment ^[10]

• Several calculators are used to estimate fracture risk during the diagnostic workup or screening for osteoporosis.
• FRAX (commonly used; see “Tips and Links”): estimates the 10-year probability of a major osteoporotic fracture ^[10][14]

Laboratory studies ^[7][10]

Consider screening all patients with newly diagnosed osteoporosis for common causes of secondary osteoporosis and potential contraindications for certain pharmacotherapy.

• Routine studies
  • CBC, CMP, PTH, phosphate, and serum 25-hydroxyvitamin D
  • 24-hour urine to measure calcium, creatinine, and sodium levels
• Additional studies
  • Evaluate for specific etiologies of secondary osteoporosis as guided by clinical assessment (e.g., celiac antibodies, TSH, myeloma screen).
  • Consider BTMs to assess fracture risk and monitor treatment response. ^[10][15]
• Findings
  • Primary osteoporosis: Serum calcium, phosphate, and parathyroid hormone (PTH) levels are usually normal
  • Secondary osteoporosis: See “Laboratory findings in common bone disorders” and/or relevant articles for details.

Treat vitamin D deficiency and ensure at least 2 weeks of recommended daily intake of calcium before obtaining 24-hour urine calcium. ^[10]

Screening for vertebral fractures ^{[10][11][16][17]}

Vertebral fractures are common in patients with osteoporosis, asymptomatic in up to two-thirds of cases, and associated with a high risk of future fractures.

• Indications: T-score ≤ -1.0 in individuals with one or more of the following ^[10][16]
  • Women ≥ 70 years of age or men ≥ 80 years of age
  • Height loss of ≥ 4 cm (> 1.5 inches)
  • Undocumented (self-reported) prior vertebral fracture
  • Kyphosis
  • Recent long-term glucocorticoid therapy
• Modalities ^[10][11]
  • Vertebral fracture assessment (VFA): uses DXA to assess for vertebral fractures
  • Lateral thoracic and lumbar spine x-ray
• Supportive findings (on x-ray)
  • Increased radiolucency and cortical thinning ^[18]
  • Vertebral compression fractures

Imaging for other skeletal fractures ^[10][19]

• Indications
  • Symptoms of fracture (e.g., pain, limited mobility)
  • Thigh or groin pain in patients on long-term (∼ 5 years) bisphosphonate therapy ^[20]
• Modalities
  • First line: plain x-ray
  • Second-line : Consider MRI or CT.
• Supportive findings
  • Radiographic signs of a fracture
  • Atypical femoral fractures: Transverse noncomminuted fracture of the subtrochanteric region or shaft of the femur ^[21]
  • Increased radiolucency (on x-ray/CT) and cortical thinning ^[18]

• 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.

Approach ^[7][10]

• All patients: Optimize bone health.
• Older patients: Assess for and manage risk factors for falls. ^[7][22]
  • Discuss fall prevention strategies.
  • Identify and manage risk factors for falls using the CDC STEADI algorithm for falls.
  • Recommend individual and/or group exercise interventions that incorporate strength and balance training.
  • Refer to physical and/or occupational therapy as needed.
• Start pharmacotherapy in the following situations:
  • Diagnostic criteria for osteoporosis fulfilled
  • Patients with osteopenia at increased risk of major osteoporotic fracture in the next 10 years
• See also “Introduction to geriatrics” for general information on the prevention of falls in older individuals.

Pharmacotherapy for osteoporosis ^[10][23]

Indications ^[10]

• Treatment: patients who fulfill any of the diagnostic criteria for osteoporosis
• Prevention: patients with osteopenia and an increased probability of a major osteoporotic fracture in the next 10 years (as determined on a clinical risk assessment tool such as the FRAX)

General principles ^[10]

• Bisphosphonates are preferred first-line agents.
• Consider nonbisphosphonates as first-line alternatives in certain situations or as second-line agents if bisphosphonate therapy is unsuccessful or not tolerated.
• Combination therapy with agents of different classes is currently not recommended.
• Agents approved for osteoporosis treatment in men ^[24]
  • Alendronate, risedronate, zoledronic acid, and teriparatide
  • Denosumab is approved for men receiving ADT for prostate cancer.
• Agents approved for glucocorticoid-induced osteoporosis ^[7][10][25]
  • Bisphosphonates, denosumab, and teriparatide
  • Teriparatide may be more effective at preventing vertebral fractures in this patient group than the other agents.

Bisphosphonates for osteoporosis ^[7][10]

• Indications: preferred initial treatment in all patients ^{[7][10][20][25]}
• Mechanism of action: inhibition of osteoclasts, which are involved in bone resorption
• Agents: The following are approved for both prevention and treatment of osteoporosis.
  • Alendronate ^[7][10]
  • Risedronate ^[7][10]
  • Ibandronate (only FDA-approved for postmenopausal women) ^[7][10]
  • Zoledronic acid ^[7][10]
• Adverse effects ^[7][26]
  • Osteonecrosis of the jaw
  • Atypical femoral fractures
  • Esophagitis
  • Hypocalcemia
• See also “Contraindications to bisphosphonate therapy” and “Duration of pharmacotherapy for osteoporosis.”

Oral bisphosphonates should be taken in the morning with plenty of water at least 30 minutes before food and other medication, and the patient should maintain an upright position for at least 30 minutes after intake to prevent esophagitis. ^[14]

Alendronate, risedronate, and zoledronic acid reduce hip, vertebral, and nonvertebral fracture risk; ibandronate reduces vertebral fracture risk only. ^[7]

Nonbisphosphonates ^[7][10][20]

• General indications
  • Alternative first-line agents in patients with contraindications to bisphosphonate therapy
  • Second-line agents in those who do not improve with bisphosphonates or are unable to tolerate bisphosphonate therapy (e.g., due to adverse effects)
• Specific indications: detailed below

Estrogen is not approved for the treatment of osteoporosis in women; if estrogen is prescribed to a patient with a uterus, it should always be combined with progesterone therapy to reduce the risk of endometrial hyperplasia. ^[10][20]

Monitoring and follow-up ^[10][14][20]

• Regularly review patients to assess for problems with adherence; see “Managing chronic conditions.”
• Consider BTMs to assess treatment efficacy and adherence. ^[10]
• Measure height yearly; if there is a ≥ 2 cm height loss, repeat imaging for vertebral fractures.
• Obtain DXA every 1–2 years for patients on treatment to monitor response. ^[10]
• Markers of improvement: stable or increasing BMD, no new fractures, normal or low BTMs
• If there is inadequate improvement : ^[10]
  • Consider alternative agents or reevaluate for secondary osteoporosis.
  • Consider referral to a clinical endocrinologist or osteoporosis specialist, if available.

The benefits of nonbisphosphonates are lost rapidly after discontinuation; initiate another treatment for osteoporosis after cessation. ^[10][14]

• Optimize calcium and vitamin D intake.
  • Recommended daily intake of calcium: 1000–1200 mg ^[14]
  • Recommended daily intake of vitamin D: 800–1000 IU ^[14]
• Treat vitamin D deficiency.
• Encourage physical activity, including strength (resistance) and balance training.
• Avoidance or minimization of the following:
  • Tobacco use: See “Counseling on smoking cessation.”
  • Excessive alcohol consumption: See “Counseling on alcohol abuse.”
  • Glucocorticoid use; see also “Measures to prevent complications of steroid therapy” ^[35]

Indications

Screening recommendations vary. The following recommendations are mainly consistent with the 2018 US Preventive Services Task Force (USPSTF). ^[13]

• Screening is recommended in:
  • Women ≥ 65 years of age
  • Women < 65 years of age at increased risk of osteoporosis as determined by a clinical risk assessment tool (e.g., osteoporosis risk assessment instrument, osteoporosis self-assessment tool, FRAX)
  • Individuals with a history of low-trauma fracture after 50 years of age ^[10]
• There is insufficient evidence to recommend routine screening for osteoporosis in men; consider screening:
  • Younger men with risk factors for osteoporosis (e.g., long-term corticosteroid use; ADT for prostate cancer) ^[24][36]
  • Men ≥ 70 years of age ^[7][14][24]

Screening modality and further management ^[13]

• Modality: BMD assessment; DXA of lumbar spine and hips is preferred ^[10][11][13]
• Diagnostic criteria for osteoporosis fulfilled: Start treatment for osteoporosis.
• Diagnostic criteria not fulfilled ^[37]
  • High-risk individuals
    • Optimize bone health and discuss fall prevention.
    • Start pharmacotherapy for osteoporosis prevention.
      • Preferred: bisphosphonates (see “Bisphosphonates for osteoporosis” for dosages) ^[10]
      • Alternatives for postmenopausal women in whom bisphosphonates are inappropriate or who desire pharmacotherapy for management of menopause symptoms ^[10][38][39]
        • Raloxifene ^[10]
        • Consider estrogen or conjugated estrogen/bazedoxifene; see “Hormone replacement therapy” for dosages and details.
  • Reassess BMD.
    • There is a paucity of data on the value and optimal timing of repeating the BMD assessment.
    • Determine the need for and frequency of screening intervals on an individual basis based on the initial BMD (T-score) and development of new risk factors for osteoporosis or fractures.

Short-interval (within 2–3 years) reassessment of BMD in individuals who do not fulfill the diagnostic criteria for osteoporosis is not routinely recommended. ^[7][37]