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Feb.24.2022

Postmenopausal Osteoporosis

Synopsis

Key Points

  • Osteoporosis is a systemic skeletal disease involving low bone mass and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and consequent increased fracture risk r1
  • Diagnosis of postmenopausal osteoporosis may be met in 1 of 4 ways:
    • Bone mineral density t score of −2.5 or less in the lumbar spine, femoral neck, total hip, and/or distal third of radius
    • Presence of fragility fracture in absence of other metabolic bone disease, even with normal bone density
    • Bone mineral density t score from −1 to −2.5 and a fragility fracture of proximal humerus, pelvis, or distal forearm
    • Bone mineral density t score from −1 to −2.5 and elevated 10-year risk of hip or major osteoporotic fracture using FRAX (Fracture Risk Assessment Tool)
  • Bone mineral density test results determine whether a patient has normal bone density, osteopenia, osteoporosis, or severe osteoporosis
    • Preferred method for diagnosis of osteoporosis is DXA applied to femoral neck
  • Lifestyle measures to improve bone health include increasing weight-bearing and resistance physical activity, reducing fall risk, ensuring proper nutritional status with adequate calcium and vitamin D intake, stopping smoking, and moderating alcohol intake r2
  • Preferred initial pharmacologic agents for most patients with postmenopausal osteoporosis at high risk of fracture include alendronate, denosumab, risedronate, and zoledronic acid (to reduce the risk for hip and vertebral fractures) r3r4r5
  • Preferred initial pharmacologic agents for most patients with postmenopausal osteoporosis at very high risk of fracture include abaloparatide, denosumab, teriparatide, and zoledronic acid
  • Complications of osteoporosis include fractures of hip (femoral neck), vertebrae, wrist, and pelvis r6
  • Osteoporosis is associated with elevated rates of mortality; for each standard deviation decrease in bone mineral density, mortality risk increases 1.17-foldr7
  • Screening for osteoporosis is suggested for all postmenopausal patients aged 50 years or older using history, examination, and FRAX score; bone mineral density testing is suggested for those aged 65 years or older r8r9

Pitfalls

  • Bone density reports can produce incorrect results if interpreted incorrectly; examples of circumstances that can yield misleading conclusions are inclusion of measurements from fractured vertebrae with severe osteoarthritis and measuring extraskeletal calcifications r10
  • Discontinuation of denosumab is often followed by rapid bone loss and can lead to multiple vertebral fractures if a potent bisphosphonate or antiresorptive medication is not prescribed at time of denosumab discontinuation r11r12

Terminology

Clinical Clarification

  • Osteoporosis is a systemic skeletal disease involving low bone mass and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and consequent increased fracture risk r13
    • Compromised bone strength reflects the integration of bone density and bone quality r14
      • Bone density corresponds to the amount of mineral within a volume, and bone quality depends on architecture, bone turnover, bone matrix composition, damage accumulation, and mineralization r15
  • Osteoporosis develops silently over years before it becomes apparent through bone mineral density screening or fractures
    • Fragility fractures are the main physical manifestation and occur at diverse sites such as the proximal femur, vertebral bodies, and distal radius
  • A formal diagnosis of osteoporosis is made in a postmenopausal patient when 1 or more of the following criteria are met:
    • Bone mineral density t score of −2.5 or less in the lumbar spine, femoral neck, total hip, and/or distal third of radius
    • Fragility fracture of the spine or hip, in the absence of metabolic bone disease, regardless of bone mineral density
    • Bone mineral density t score between −1 and −2.5 and a fragility fracture of the proximal humerus, pelvis, or distal forearm
    • Osteopenia or low bone mass (t score from −1 to −2.5) and high FRAXr16 (Fracture Risk Assessment Tool) score, such as high probability of fracture
  • Fractures are associated with serious clinical consequences, including pain, disability, loss of independence, and death
    • Most major fractures are associated with reduced relative survival, with an impact persisting more than 5 years after the event r17
      • Major osteoporotic fractures are fractures that occur at spine, proximal femur, distal forearm, and proximal humerus. Other skeletal sites are prone to fragility fractures, including pelvis, ribs, and proximal tibia r18

Classification

  • Osteoporosis is commonly classified operationally on the level of bone mass, measured as bone mineral density r2
    • Risk of fracture increases approximately 2-fold for each 1 standard deviation decrease in bone mineral density r19
  • WHO definitions of osteopenia and osteoporosis are traditionally used for making decisions about health policy r20
    • Normal bone health: bone mineral density value more than 1 standard deviation below young adult female reference mean (t score −1 or more)
    • Osteopenia: bone mineral density value more than 1 but less than 2.5 standard deviations below that of young adult female reference mean (t score less than −1 and greater than −2.5)
    • Osteoporosis: bone mineral density value 2.5 or more standard deviations below that of young female adult reference mean (t score −2.5 or less)
      • Within the category of osteoporosis, WHO identifies an additional subset of severe based on very high risk of fracture: r20
        • Severe osteoporosis: bone mineral density value 2.5 standard deviations or more below that of young female adult reference mean (t score of −2.5 or less) and 1 or more documented fragility fractures
  • Additional defining criteria for osteoporosis beyond bone mineral density measurements have been proposed and adopted. These include: r21r22r23r24
    • Low-trauma spine or hip fracture, regardless of bone mineral density
    • Low bone mineral density that falls within the range for osteopenia (ie, t score between −1.1 and −2.5) and fragility fracture of proximal humerus, pelvis, or distal forearm
    • Low bone mineral density that falls within the range for osteopenia (ie, t score between −1.1 and −2.5) and high FRAX score based on country-specific thresholds
  • Newly proposed classifications use a set of clinical predictors to further estimate the level of risk of fracture in patients with established (diagnosed) osteoporosis
    • Stratification of osteoporosis severity, according to high-risk and very-high-risk features, assists with selection of first line therapy and also suggests length of therapy r4
      • Very-high-risk category meets definition for osteoporosis and 1 of the following: r4
        • Recent fracture (within past 12 months)
        • Fractures even while on approved osteoporosis therapy
        • Multiple fractures
        • Glucocorticoid use
        • t score less than −3
        • High risk of falls
        • History of injurious falls
        • FRAX probabilities of more than 30% for a major osteoporosis fracture or more than 4.5% for hip fracture
      • High-risk category meets definition for osteoporosis but does not have indicators of very high risk r4
    • Risk stratification for selection and duration of therapy.FRAX, Fracture Risk Assessment Tool (of the Centre for Metabolic Bone Diseases, University of Sheffield).Data from Camacho PM et al: American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis--2020 update. Endocr Pract. 26(suppl 1):1-46, 2020.
      High riskVery high risk
      t score between −1 and −2.5 and high 10-year probability of fracture by FRAX: major osteoporotic fracture risk of 20% or more or hip fracture risk of 3% or moreRecent fracture, within past 12 months
      t score between −1 and −2.5 and history of fragility fracture of hip or spineFractures during approved osteoporosis therapy
      Any patient with an osteoporosis diagnosis who does not meet criteria for very high risk as defined in this tableMultiple fractures
      Fractures while on therapy with drugs causing skeletal harm (eg, glucocorticoids)
      Very low t score (less than −3)
      High risk for falls or history of injurious falls
      Very high 10-year probability of fracture by FRAX: major osteoporotic fracture risk of 30% or more or hip fracture risk of 4.5% or more

Diagnosis

Clinical Presentation

History

  • Osteoporosis is asymptomatic in absence of a fracture; it is usually diagnosed on routine screening or after a fracture occurs c1
  • History of fracture with minimal trauma (ie, fragility) is strongly suggestive of osteoporosis r25c2
    • Fragility fracture is defined as a fracture sustained from force similar to a fall from a standing position or less that would not have occurred in healthy bone r25
  • Vertebral fractures are the most common form of osteoporotic fracture
    • New vertebral fractures, even those not recognized clinically, are associated with substantial increases in back pain and limited mobility r6c3c4
    • A vertebral fracture may occur after a fall or a spinal flexion-loading event; patients might report hearing a "pop" and complain of sharp midline back pain, possibly radiating to the flanks r25c5c6c7c8c9c10
    • Patients also may present with back "tiredness," which improves when they sit or lie down r25c11
      • This symptom is likely related to paraspinal weakness or spasm from abnormal spinal curvature that occurs with chronic vertebral compression
  • Hip fractures also commonly occur with falls, although these fractures rarely may occur with limited force such as twisting r25c12c13

Physical examination

  • Complete examination of the spine includes measuring height and assessing pain, paraspinal muscle contraction, thoracic kyphosis, lumbar lordosis, scoliosis, and the gap between the costal margin and iliac crest. Also evaluate for the abdominal protrusion that can occur with multiple vertebral fractures r15
  • A kyphotic deformity of the upper thoracic spine may be present; it is important to distinguish it from accentuated cervical lordosis with associated prominence of T1 r25c14
  • Measured height loss of more than 4 cm since young adult maximum height is suggestive of prior vertebral fractures; it is best measured with a calibrated device (eg, stadiometer) r25
    • Height loss also occurs with scoliosis and aging (approximately 0.8 cm of height is lost each decade after age 50 years) c15c16c17
  • Acute vertebral compression fracture can cause spinal tenderness to palpation and percussion c18
  • Physical examination also may find underlying processes contributing to secondary osteoporosis
    • Common secondary causes include hyperparathyroidism, hypercalciuria, calcium malabsorption, vitamin D deficiency, and hyperthyroidism r26

Causes and Risk Factors

Causes

  • Postmenopausal osteoporosis is a complex disease with a multifactorial origin r27
    • Adult bone mass is determined by 2 processes: acquisition of peak bone mass during adolescence and subsequent bone loss after maturity
    • Changes in bone mass result from physiologic and pathophysiologic processes in the bone remodeling cycle, and ultimately this can lead to skeletal fragility r28
    • Abrupt decline of estrogen levels at menopause causes loss of bone and contributes to development of osteoporosis r28c19c20
      • Menopause induces accelerated bone loss within 5 to 8 years, followed by a linear rate of bone loss that accelerates after age 75 years r6
  • Numerous diseases and treatments may cause or contribute to osteoporosis, either as comorbid primary diseases or as causes of secondary osteoporosis r15r29
    • Endocrine disorders
      • Hypogonadism c21
      • Hyperthyroidism c22
      • Hyperparathyroidism c23
      • Diabetes mellitus c24
      • Hypopituitarism c25
    • Glucocorticoid medications c26
      • Glucocorticoid-induced osteoporosis is the most common secondary form of the disease r30
      • Consistent evidence indicates that glucocorticoids impair bone formation r6
      • With oral corticosteroids (eg, prednisone), increased fracture risk starts with dosages as low as 2.5 mg/day r30
      • Increased fracture risk partially offsets on cessation of therapy but not back to baseline r30
    • Other medications
      • Medications that may cause or contribute to osteoporosis include anticonvulsants, aromatase inhibitors, methotrexate and other chemotherapeutic agents, heparin, and cyclosporine r29c27c28c29c30c31c32
    • Autoimmune diseases
      • Rheumatoid arthritis c33
      • Ankylosing spondylarthritis c34
      • Systemic lupus erythematosus c35
      • Inflammatory bowel disease c36
    • Diseases resulting in malabsorption c37
      • Celiac disease c38
      • Gastrectomy c39
    • Conditions associated with immobilization
      • Parkinson disease c40
      • Poliomyelitis c41
      • Cerebral palsy c42
      • Paraplegia c43
    • Bone marrow disorders, including myeloproliferative disorders (eg, multiple myeloma, leukemia) and anemias c44c45c46c47
    • Disorders of connective tissues
      • Osteogenesis imperfecta c48
      • Marfan syndrome c49
    • Other
      • Pompe disease c50
      • Gaucher disease c51
      • Total parenteral nutrition c52
      • Homocystinuria c53
      • Hypercalciuria c54
      • Mastocytosis c55
      • Hemochromatosis c56
      • Anorexia nervosa c57
      • Chronic liver diseases c58
      • Turner syndrome c59
  • Pregnancy and lactation are stressors of calcium homeostasis and can (uncommonly) contribute to osteopenia or osteoporosis r31c60c61

Risk factors and/or associations

Age
  • In the United States, it is estimated that more than 10 million Americans older than 50 years have osteoporosis r32c62
    • Combined, osteoporosis and low bone mass at femoral neck or lumbar spine affect more than half of older adults in the United States
  • Prevalence rises in people after menopause c63c64c65
    • A 50-year-old female is estimated to have a 17% lifetime risk of hip fracture and about a 50% risk of any osteoporotic fracture r33
    • By age 80 years, 27% of females have low bone mass (osteopenia) alone, and 70% have osteoporosis at hip, spine, or forearm c66c67c68c69
Genetics
  • Peak bone mass, which is reached in early adult life, primarily depends on genetic factors r6c70
    • Genetic factors account for 60% to 80% of the variance in peak bone mineral density r25
    • Bone mass at a given age is a function of the achieved peak bone mass and of the amount of bone lost later through menopause, aging, disease processes, or medications; therefore, the level that can be achieved at the end of bone growth is critical for future risk of fracture
  • Parental history of hip fracture is a significant risk factor for future fracture that is largely independent of bone mineral density r2c71
Ethnicity/race
  • More common in populations of European and Asian ancestry; peak bone mass values are highest in populations with African ancestry, followed by populations with European ancestry and then those with Asian ancestry r6c72c73c74
Other risk factors/associations r34
  • Alcohol use c75
  • Tobacco use c76
  • Physical inactivity c77
  • High caffeine intake c78

Diagnostic Procedures

Primary diagnostic tools

  • Diagnosis of osteoporosis is assigned using a combination of history, measurement of bone mineral density by DXA, and estimation of fracture risk using the FRAX tool of the University of Sheffield r2r15c79
  • Diagnostic criteria
    • A diagnosis of osteoporosis in postmenopausal patients may be met in 1 or more of 4 ways: r4r14r21r24
      • Bone mineral density that is 2.5 standard deviations or more below the young adult mean for females (ie, t score of −2.5 or less) at the lumbar spine, femoral neck, total hip, or distal third of radius
      • Presence of fragility fracture at spine or hip, in the absence of other metabolic bone disease, even with normal bone density
      • Bone mineral density t score between −1 and −2.5 and a fragility fracture of proximal humerus, pelvis, or distal forearm
      • Bone mineral density t score between −1 and −2.5 and increased 10-year risk of fracture using FRAX toolr16
  • Bone mineral density measurement
    • Bone mineral density measurement can be used to determine categories of normal bone density, osteopenia, or osteoporosis
      • Bone mineral density measurements also are used in monitoring response to therapy
      • Bone mineral density testing is indicated for all postmenopausal patients with risk factors for low bone mineral density or fracture r35
    • DXA of lumbar spine, total hip, and proximal femur is the preferred method for diagnosis r19r36r37
  • Fragility fracture history (present or earlier)
    • Fragility fracture is one that is sustained from a force similar to a fall from a standing position or less that would not occur in healthy bone
    • Documentation of a fragility fracture at any of certain sites (ie, spine, hip, proximal humerus, pelvis, distal forearm) meets criteria for osteoporosis regardless of bone mineral density measurements
      • Bone mineral density testing is still indicated for these patients, to be used for monitoring purposes
  • Fracture risk assessment
    • Perform risk assessment on all patients at time of initial evaluation for osteoporosis; this assessment is warranted even for those that meet the diagnostic criteria by virtue of bone mineral density or fracture history
    • FRAX tool computes an estimate of 10-year probability of hip fracture or a major osteoporotic fracture r2
      • It is an internet-accessible computerized algorithm that uses country-specific data on clinical risk factors and femoral neck bone mineral density to calculate fracture probability
        • Calculation also may be performed without data entered for the values obtained from bone mineral density testing
      • Risk score is based on the following parameters: age, sex, weight, height, previous fracture, parental history of hip fracture, smoking status, glucocorticoid use, rheumatoid arthritis, secondary osteoporosis, alcohol intake, and (where available) femoral neck bone mineral density r38
      • FRAX score predicts 10-year probability of hip fracture and major osteoporosis fracture (major fractures include hip, spine, humerus, and forearm)
      • From history and physical examination plus FRAX score, recommendations can be made about whether pharmacologic intervention is appropriate
    • FRAX shortcomings
      • FRAX score underestimates risk of all future fractures, given that it estimates only for hip and major fractures, which comprise about half of all fragility fractures r39
      • FRAX score underestimates risk for patients with multiple prior fractures, those with recent fracture, those whose lumbar spine bone mineral density is much less than at femoral neck, those with secondary osteoporosis, those with diabetes, and those at high risk of falls r40
        • For patients with diabetes, rheumatoid arthritis may be entered into the FRAX algorithm as a surrogate to adjust for the elevated risk r41
  • Evaluation for causes of secondary osteoporosis
    • An evaluation is indicated for all females diagnosed with postmenopausal osteoporosis to identify coexisting medical conditions that cause or contribute to bone loss
      • Undiagnosed metabolic bone and mineral diseases are present in about one-third of females with osteoporosis r26
      • Common secondary causes include hyperparathyroidism, hypercalciuria, calcium malabsorption, vitamin D deficiency, and hyperthyroidism r26
    • Routine laboratory investigation of osteoporosis needs to include CBC, serum chemistry panel (with levels of calcium, albumin, total protein, creatinine, phosphate, alkaline phosphatase, and liver transaminases), thyroid function tests, and 25-hydroxyvitamin D level r4
    • 24-hour urine collection for calcium, sodium, and creatinine levels is also recommended to assess for calcium malabsorption or hypercalciuria
    • Additional tests beyond the aforementioned ones may be helpful, depending on initial results, and may be useful in considering unusual secondary causes or conditions in the differential diagnosis. They include: r2r4
      • Serum intact parathyroid hormone level, for possible hyperparathyroidism
      • Thyroid function tests, for possible hyperthyroidism
      • Tissue transglutaminase antibodies test, for suspected celiac disease
      • Serum protein electrophoresis and free kappa and lambda light chains test, for suspected multiple myeloma
      • 24-hour urine free cortisol test or 1 mg overnight dexamethasone suppression test, for suspected endogenous hypercortisolemia
      • Serum tryptase or urine N-methylhistidine test, for mastocytosis
  • Evaluate for prevalent vertebral fractures
    • Vertebral fracture assessment is densitometric spine imaging performed for the purpose of detecting vertebral fractures that might otherwise go unidentified r42
      • Detecting vertebral fractures requires specific imaging techniques that can be done at same time as DXA
      • Finding vertebral fractures, regardless of results of bone mineral density testing or FRAX score, meets a criterion for the diagnosis of osteoporosis
    • Indications for vertebral fracture assessment include advanced age, history of height loss, use of systemic glucocorticoid therapy, and self-reported but undocumented prior vertebral fracture r43
  • Utility of bone turnover markers
    • Bone turnover markers are not used for diagnosis, but baseline levels are sometimes obtained before start of therapy because they can be useful for initial evaluation and for monitoring response to therapy
      • Elevated levels can predict more rapid rates of bone loss
      • High bone turnover levels are associated with increased fracture risk independent of bone mineral density
    • Bone turnover markers respond quickly to therapy, and comparing levels over time can allow for insights into drug adherence and absorption
    • Most useful bone turnover markers are PINP (N-propeptides of type I collagen), which derive from bone formation osteoblast products, and CTX (C-terminal cross-linking telopeptides of type 1 collagen), which derive from bone resorption products of collagen degradation

Laboratory

  • Laboratory tests are most helpful when a secondary cause of osteoporosis is suspected or to identify conditions in the differential diagnosis r2r6
  • Routine laboratory investigation of osteoporosis includes CBC; serum chemistry panel (with levels of calcium, albumin, total protein, creatinine, phosphate, alkaline phosphatase, and liver transaminases), thyroid function tests, and 25-hydroxyvitamin D level r4c80c81c82c83
  • Bone turnover markers r44c84
    • Bone turnover markers, including CTX (C-terminal cross-linking telopeptides of type 1 collagen), are used primarily as a means to measure metabolic activity of bone in patients on osteoporosis therapies
      • These markers also have a role in monitoring patients on a drug holiday, to ensure persistence of antiresorptive effect
    • Bone turnover markers can be measured in serum, plasma, and urine, and their levels relate to the activity of osteoblasts (bone formation markers) and osteoclasts (bone resorption markers)
      • Bone formation markers include proteins that are rather specific to bone (eg, osteocalcin) and those that are less specific to bone, such as PINP (N-propeptide of type I collagen, fragments of type I procollagen released during formation of type I collagen) and bone ALP (the bone isoform of alkaline phosphatase)
      • Bone resorption markers include fragments released from the telopeptide region of type I collagen after its enzymatic degradation, including NTX (N-telopeptide of type I collagen) and CTX (C-terminal cross-linking telopeptides of type 1 collagen), deoxypyridinoline, and tartrate-resistant acid phosphatase
      • In cohort studies of females, the higher the bone turnover marker levels, the more rapid the bone loss and the greater the risk of fracture
    • Interpretation of results
      • Suppression of bone resorption markers is seen on initiation of bisphosphonate therapy, whereas with treatment cessation, bone resorption marker levels increase; the changes in bone mineral density lag far behind
        • An appropriate level of CTX (C-terminal cross-linking telopeptides of type 1 collagen) or bone resorption marker suppression is at or below a healthy premenopausal mean; the lower half of the premenopausal reference intervals have been used as a target for those on bisphosphonate therapy and gives an indication of appropriate suppression of bone turnover by bisphosphonate
        • Another criterion for response evaluation is whether the minimum significant changes are exceeded; minimum significant changes are twice the mean morning day-to-day variation seen in premenopausal people r45
      • Increased levels of bone formation markers in response to anabolic therapy are reassurance that the drug is effective
    • Practical issues
      • Ideally, blood sample for bone turnover markers is collected in early morning in fasting state
      • Avoid collecting specimen during acute phase after a fracture
      • Some bone turnover markers are affected by renal impairment, whereas others are unaffected

Imaging

  • DXA c85c86
    • DXA of lumbar spine, total hip, and proximal femur is the preferred method for diagnosis r19r36r37
      • Central DXA, measuring axial sites, is preferred over peripheral DXA for diagnosis, although distal third of radius also may be used as an alternative diagnostic site if central sites are unavailable r46
      • Femoral neck is the site with the highest predictive value for fracture risk r2
      • Spine is ideal site for assessing treatment response, provided that lumbar spine does not have significant degenerative or artifactual changes that render it invalid for analysis r2
    • DXA is also the preferred method by which to monitor bone mineral density over time r47
    • DXA results are categorized by WHO diagnostic criteria for osteopenia and osteoporosis r20
      • Normal: bone mineral density value more than 1 standard deviation below young adult female reference mean (t score −1 or more)
      • Osteopenia: bone mineral density value more than 1 but less than 2.5 standard deviations below that of young adult female reference mean (t score less than −1 and greater than −2.5)
      • Osteoporosis: bone mineral density value 2.5 or more standard deviations below that of young female adult reference mean (t score −2.5 or less)
  • Quantitative CT and quantitative ultrasonography c87c88
    • Alternative techniques to assess bone mineral density
      • Ultrasonography (often of calcaneus) is portable and is sometimes used in nonclinical settings (eg, community health fairs)
      • Peripheral bone density measurement methods can identify patients at increased risk for fracture, but the DXA diagnostic criteria established by WHO and supported by multiple professional society guidelines apply only to axial measurements r2r3r4r18
  • Vertebral fracture assessment r6r43
    • Test evaluating vertebral morphology that uses either lateral lumbar and thoracic spine radiographs or lateral spine DXA from upper thoracic to lower lumbar spine c89c90
      • It is a useful study in some cases to identify patients at risk whose bone mineral density may be above treatment thresholds r47
    • Significant loss in vertebral height may be indicative of vertebral fracture, which can be missed using DXA alone r6
    • Lateral spine imaging with standard radiography or densitometric vertebral fracture assessment is indicated when t score is less than −1 and of 1 or more of the following factors are present: r42
      • Females aged 70 years or older; males aged 80 years or older
      • Historical height loss greater than 4 cm
      • Self-reported but undocumented prior vertebral fracture
      • Glucocorticoid therapy equivalent to 5 mg or more of prednisone or equivalent per day for 3 months or longer
      • Kyphosis
  • Skeletal radiography r6c91
    • Anteroposterior and lateral views are required for both the thoracic and lumbar spine to evaluate potential vertebral fractures
    • Vertebral fractures include wedge deformities, end-plate (biconcave) deformities, and compression (or crush) fractures
    • Vertebrae from T4 to L4 are graded on visual inspection as follows:
      • Normal (grade 0)
      • Mildly deformed (grade 1: 20%-25% loss in anterior, middle, and/or posterior height)
      • Moderately deformed (grade 2: 25%-40% loss in anterior, middle, and/or posterior height)
      • Severely deformed (grade 3: 40% or more loss in anterior, middle, and/or posterior height)
  • Trabecular bone score r48c92
    • Obtained using software compatible with DXA systems; provides information about bone microarchitecture
    • Can predict fracture risk independently of bone mineral density values and improves the ability of FRAX to predict fracture
    • High scores indicate homogeneous, normal bone and reduce the FRAX estimated risk, whereas low scores correlate with weaker bone texture and increase the FRAX risk
    • Adjusting FRAX interpretation with trabecular bone score has the greatest clinical utility in people whose fracture risk is close to the therapeutic intervention threshold. For example:
      • A low trabecular bone score in a female with osteopenia might lead to favoring treatment with a pharmacologic agent
      • A high trabecular bone score in a female with diabetes might also favor pharmacologic intervention

Differential Diagnosis

Most common

  • Osteomalacia c93
    • Condition defined by impaired skeletal mineralization, usually due to low calcium or phosphorus levels
    • Vitamin D deficiency is one of the most common causes of osteomalacia; most patients with mild to moderate vitamin D deficiency are asymptomatic d1
    • Patients with osteomalacia may present with musculoskeletal pain, bony tenderness, hyperalgesia or paresthesia, proximal muscle weakness, waddling gait, history of fracture, and coexisting hypocalcemia r49
    • Classic findings of osteomalacia on plain radiographs are pseudofractures (radiolucent bands) ranging from a few millimeters to a few centimeters in length, most visible near the femoral neck or pelvis r50
    • Differentiated from osteoporosis by clinical presentation in the setting of a low serum level of 25-hydroxyvitamin D, calcium, or phosphorus r51
  • Pathologic fractures due to other causes
    • Malignant vertebral compression fractures can be caused by metastatic cancers or primary tumors of bone r52c94
      • Cancers with a propensity to metastasize to bone (eg, breast, prostate, thyroid, lung) can lead to malignant vertebral compression fractures
      • Primary tumors of bone and lymphoproliferative or myeloproliferative diseases (eg, lymphomas, multiple myeloma) also can be the cause of malignant vertebral compression fractures
    • Consider possible malignant vertebral compression fractures after a vertebral fracture in a patient with known history of cancer or one whose laboratory test results point to possible malignancy (eg, abnormal serum protein electrophoresis results). In very unusual cases, a vertebral compression fracture can be the first manifestation of malignancy
      • Most often, these patients have back pain at site of tumor, often worse at night
    • Advanced imaging is often necessary to distinguish benign from malignant vertebral compression fractures
      • MRI is the technique of choice, but other modalities (eg, CT, PET, SPECT) can provide additional information, as guided by radiologist evaluations r52
    • Acute (less than 2 weeks) and subacute (2 weeks to 3 months) benign vertebral compression fractures often have large areas of MRI signal alteration or increased metabolism on nuclear medicine scans; these areas can mimic malignancy r53
    • Chronic (more than 3 months) benign vertebral compression fractures have small areas of usually linear signal alteration and show restoration of fatty marrow and normal metabolism r53
    • MRI findings suggestive of metastatic vertebral compression fracture are as follows: expansion of fractured vertebral body, epidural and/or paraspinal soft tissue mass, abnormal signal intensity of pedicle or posterior element, epidural mass, encasing epidural mass, and other spinal metastasis r54
    • MRI findings suggestive of acute osteoporotic vertebral compression fracture are as follows: a band of low signal intensity on T1- and T2-weighted images, preservation of normal bone marrow signal intensity, retropulsion of a posterior bone fragment, and multiple levels of compression fractures r54

Treatment

Goals

  • Prevent fragility fractures r14
  • Maintain quality of life r14

Disposition

Recommendations for specialist referral

  • Patients with any of the following factors may benefit from referral to endocrinologists or other physicians with expertise in osteoporosis: r55r56
    • Fracture or significant ongoing loss of bone mineral density despite adherence to first line therapy
    • Complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease)
    • Unusual features including young age or abnormal laboratory test results (eg, low phosphorus level)
    • Artifacts on DXA that are unexplained

Treatment Options

An estimate of the baseline fracture risk should guide the selection of initial osteoporosis therapy for people who are postmenopausal; stratification drives both choice of initial osteoporosis agent and duration of therapy

Bone health–preserving nonpharmacologic measures are indicated for all postmenopausal people with osteoporosis and osteopenia

  • Encourage adequate intake of calcium and vitamin D
  • Employ measures to avoid falls
  • Limit alcohol consumption
  • Encourage weight-bearing, resistance, and balance exercises
  • Advise smoking cessation

Indications for pharmacologic therapy

  • Pharmacotherapy to reduce fracture risk is indicated in most patients with formal diagnosis of osteoporosis and/or in the following circumstances: r3r4
    • t score of −2.5 or less (ie, or worse) in spine, femoral neck, total hip, or distal third of radius
    • t score from −1 down to −2.5 in spine, femoral neck, total hip, or distal third of radius and fragility fracture of spine or hip
    • t score from −1 down to −2.5 in spine, femoral neck, total hip, or distal third of radius and FRAX score shows that 10-year probability of a major osteoporotic fracture is 20% or more or that 10-year probability of hip fracture is 3% or more

Pharmacotherapy

  • 3 major classes of drugs are antiresorptive agents, parathyroid hormone analogues or parathyroid hormone–related protein analogues, and monoclonal antibodies
    • Choice of therapy is individualized according to patient's clinical situation and the trade-off between benefits and harms
    • Although there is general guidance on the selection of a drug according to risk of fracture (high or very high), it is important to weigh risks, benefits, and patient preferences and to consider individual patient circumstances when selecting a drug r3
      • Individual considerations for drug therapy.
        Patient circumstanceReasonable choice of drug
        Female with history of breast cancerBisphosphonate or denosumab
        Female with recent vertebral fracturesAn anabolic agent, such as teriparatide or abaloparatide
        Female with severe gastroesophageal reflux diseaseAn injectable therapy, such as denosumab or zoledronic acid
        Any patient with chronic kidney disease stage 4Denosumab, carefully monitoring for hypocalcemia
        Female with painful vertebral fracture(s)Calcitonin is optional for analgesic effects
    • Menopausal hormone therapy is no longer recommended to treat osteoporosis; however, it may be beneficial to prescribe on a short-term basis in specific circumstances, such as in people younger than 60 years or within 10 years of menopause who are in need of therapies to treat vasomotor symptoms of menopause r57r58
  • Initial treatment for high-risk postmenopausal people with osteoporosis
    • Preferred medications for initial treatment include alendronate, denosumab, risedronate, and zoledronate r4
    • Alternative medications for initial treatment include ibandronate and raloxifene, which are appropriate when reduction of hip fracture risk is a lower priority r4
    • Intranasal calcitonin has weak antifracture efficacy and is largely used to ameliorate pain of vertebral fractures r59r60
  • Initial treatment for very-high-risk postmenopausal people with osteoporosis
    • Females at very high risk include those with a recent fracture, multiple fractures, fractures during treatment, long-term glucocorticoid therapy, high risk of falls, or very high fracture probability by FRAX (defined as 30% or more for major osteoporotic fracture or 4.5% or more for hip fracture)
    • Preferred medications for initial treatment include abaloparatide, denosumab, teriparatide, or zoledronate r4
      • Romosozumab is highly effective for preventing fractures, but some experts reserve it as a second line option in the near term because there is a black box warning regarding the possible association of an elevated risk for cardiovascular events found in initial clinical trials r61
    • Alternative medications for initial treatment for very-high-risk category include alendronate and risedronate r4
  • The various drug classes yield differing amounts of risk reduction
    • Pharmacologic agents and expected fracture reduction.Dash (—) indicates that no effect was observed; the lack of demonstrable effect at these sites should be considered in the context that individual studies may have not been powered to detect an effect. Asterisk (*) indicates that fracture reduction was found only at a medium dose of 200 international units of nasal calcitonin daily.Data from Barrionuevo P et al: Efficacy of pharmacological therapies for the prevention of fractures in postmenopausal women: a network meta-analysis. J Clin Endocrinol Metab. 104(5):1623-30, 2019; Cosman F et al: Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 375(16):1532-43, 2016; and Saag KG et al: Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med. 377(15):1417-27, 2017.
      Drug classDrugReduction in vertebral fracture risk (%)Reduction in hip fracture risk (%)Reduction in nonvertebral fracture risk (%)
      Bisphosphonates
      Alendronate444017
      Risedronate362620
      Ibandronate31
      Zoledronate564218
      Monoclonal antibodies
      Denosumab683919
      Romosozumab73
      Estrogens or selective estrogen receptor modulators
      Menopausal hormone therapy342921
      Raloxifene40
      Bazedoxifene39
      Parathyroid hormone analogues or parathyroid hormone–related protein analogues
      Teriparatide74
      Abaloparatide87
      Other
      Calcitonin46*
  • Romosozumab for osteoporosis
    • Romosozumab represents a new class of drug, a humanized monoclonal antibody directed against sclerostin, which is a protein secreted by osteocytes to reduce bone formation
      • It has an early anabolic effect along with some antiresorptive properties
    • Romosozumab is indicated for females with history of osteoporotic fracture, those with multiple risk factors for fracture, those who cannot take other osteoporosis medications, and those for whom other osteoporosis therapies have failed
      • It is also useful for patients who were previously treated with a parathyroid hormone analogue for maximum duration but still need anabolic effect, as well as for patients who are receiving injectable antiresorptive therapy but have poor treatment response (as shown by worsening bone mineral density or by fracture that occurs during pharmacotherapy)
    • In the FRAME trial, postmenopausal people with t score of −2.5 to −3.5 for total hip or femoral neck who were treated with romosozumab for 12 months showed a 73% lower risk of new vertebral fracture compared with placebo
    • In the ARCH trial, postmenopausal people with osteoporosis and a fragility fracture who were treated with romosozumab for 12 months and then treated with alendronate showed a 48% lower risk of new vertebral fracture compared with alendronate alone
      • Females in the study arm assigned to romosozumab had a 19% lower risk of nonvertebral fracture and 38% lower risk of hip fracture
      • Risk of serious cardiovascular events was higher for females receiving romosozumab (2.5%) compared with alendronate (1.9%)
  • Drugs for treatment and prevention of osteoporosis.*Bazedoxifene is used in a combination pill with estradiol.Data from Compston JE et al: Osteoporosis. Lancet. 393(10169):364-76, 2019; and Black DM et al: Postmenopausal osteoporosis. N Engl J Med. 374(3):254-62, 2016.
    Drug class and agentRoute of administration and frequencyProven site of fracture risk reductionRemarks
    Bisphosphonates
    AlendronateOral, once daily or weeklyVertebral, nonvertebral, hipFor oral route, all bisphosphonates must be taken with a full glass of water and the patient must refrain from ingesting any other medications or food for 30 minutes and remain upright for 30-60 minutes
    RisedronateOral, once daily, weekly, or monthlyVertebral, nonvertebral, hipSame precautions as for oral alendronate
    IbandronateOral once weekly or IV every 3 monthsVertebralSame precautions as for oral alendronate
    Zoledronic acidIV once yearlyVertebral, nonvertebral, hipAcute phase response possible after first dose in about one-third of patients
    Monoclonal antibodies (biologics)
    DenosumabSubcutaneous every 6 monthsVertebral, nonvertebral, hipMultiple vertebral fracture risk upon discontinuation
    RomosozumabSubcutaneous every month for up to 1 yearVertebral, nonvertebral, hipBoxed warning for cardiovascular events
    Parathyroid hormone receptor agonists
    TeriparatideSubcutaneous daily, up to 2 yearsVertebral, nonvertebralBlack box warning about risk of osteosarcoma (seen in rodents)
    AbaloparatideSubcutaneous daily, up to 2 yearsVertebral, nonvertebral
    Selective estrogen receptor modulators
    RaloxifeneOral once dailyVertebralRisk of venous thromboembolism
    Bazedoxifene*Oral once daily
    Estrogens/menopausal hormone therapy
    Conjugated equine estrogenOral once dailyVertebral, nonvertebral, hipRisk of breast cancer and venous thromboembolism
    EstradiolOral once daily or transdermal once weeklyNo dataRisk of breast cancer and venous thromboembolism
    Other
    CalcitoninIntranasal once dailyVertebralMay be useful for ameliorating pain of fractures

Sequence of therapy

  • Some experts advise that the optimal treatment sequence for patients with severe osteoporosis is initiation with an anabolic agent followed by an antiresorptive agent r62
    • Reason for this preference is that when anabolic drugs are used before antiresorptive drugs, bone mineral density will increase much faster and will attain a greater level, particularly in spine r63r64r65r66

Risks of therapy

  • Osteonecrosis of jaw and atypical femoral fractures have been reported with treatment but are rare
  • Benefit-risk ratio for osteoporosis treatment is strongly positive for most females with osteoporosis

Duration of therapy

  • Duration depends on which drug is used, and sequential therapy with another drug class is often advisable
    • Bisphosphonates
      • Duration of therapy is ideally 5 to 10 years; if bone loss progresses or there are recurrent fractures, consider switching to a parathyroid hormone analogue or romosozumab r4
    • Parathyroid hormone analogues or parathyroid hormone–related protein analogues
      • Duration of therapy is 2 years maximum, usually followed by transition to an oral or injectable antiresorptive agent r4
    • Monoclonal antibody therapies
      • Denosumab: can be indefinite and ideally is used until the patient is no longer at high risk. If denosumab is discontinued, ensure that it is followed by another antiresorptive drug to prevent high risk for rapid loss of bone mineral density and risk of multiple vertebral fractures r12r67
      • Romosozumab: duration of therapy is 1 year maximum, followed by transition to bisphosphonate or denosumab r4

Drug holidays

  • Drug holidays may be considered for bisphosphonates, under certain circumstances
    • Benefits are retained for years after discontinuation of alendronate or zoledronic acid, which serves as the justification for suspending drug therapy for osteoporosis
      • For oral bisphosphonates, consider a bisphosphonate holiday after 5 years of treatment if fracture risk is no longer high; treatment should continue for up to 10 years (total) if fracture risk remains high r4
      • For zoledronate, consider a bisphosphonate holiday after 3 years in high-risk patients if fracture risk is no longer high (ie, achieving a t score of −1.5 or better/higher), and continue for up to 6 years (total) in very-high-risk patients r4
    • In some circumstances of very high risk, the drug holiday can be interrupted by using teriparatide instead r4
    • Ending a drug holiday is determined on an individualized basis
      • Some factors to consider are development of a fragility fracture, loss of bone mineral density beyond the least significant change of the machine, or bone turnover marker levels rising to pretreatment levels
  • Generally, drug holiday is not appropriate for denosumab

Drug discontinuations

  • Upon discontinuation of an anabolic osteoporosis drug, start therapy with an antiresorptive agent to prevent decline in bone mineral density
    • Bone accrued during treatment with monoclonal antibody therapies (biologics) and parathyroid hormone analogues is lost rapidly after their withdrawal owing to rebound increase in bone resorption r68
    • Limit treatment with abaloparatide and teriparatide to 2 years, usually followed by bisphosphonate or denosumab therapy
    • Limit treatment with romosozumab to 1 year, followed by a drug intended for long-term use (eg, bisphosphonate, denosumab)
  • Denosumab can be given indefinitely, but discontinuations are reasonable if acceptable targets are reached or by patient preference for another form of therapy
    • After stopping denosumab, the treatment effect rapidly diminishes if an antiresorptive agent is not started, and the risk of fractures returns to baseline, and possibly higher for vertebral fractures r67
    • Several options are available to prescribe after a course of denosumab
      • One option is a single IV infusion of zoledronate given 6 months after denosumab. It has potent antifracture benefits, prevents bone loss for at least 2 years, and has a convenient dosing schedule r69r70
      • Another option is to transition to alendronate after denosumab, which is effective in maintaining the bone mineral density that has accrued r71
      • Switching to an anabolic agent (eg, teriparatide) after denosumab is not recommended because it is associated with loss of hip bone mineral density r72
    • Generally, drug holiday is not appropriate for denosumab; however, if a patient treated with denosumab reaches an acceptable target bone mineral density, changing the type of drug therapy can be considered
      • Improvement in hip t score on denosumab to a level of about −2 to −1.5 is associated with maximum reduction of fracture risk r73

Other circumstances under which to consider switching therapy

  • Switching therapy from one agent to another may be considered to address practical issues such as costs, adherence, patient preference for mode of administration, or therapy failure
    • Examples of circumstances that would warrant changing drug therapy include:
      • Loss of bone mineral density greater than the least significant change (usually 3% in lumbar spine, 4% in total hip, 5% in femoral neck) over 2 years r3
      • Bone turnover marker decrease on antiresorptive therapy less than the least significant change r3
      • Having 1 or more fractures while on antiresorptive therapy, especially vertebral r3
      • Development of osteonecrosis of jaw or an atypical femoral fracture on antiresorptive therapy r3

Surgical intervention

  • Kyphoplasty may be considered for painful vertebral fractures, but this intervention is controversial
  • A task force for the American Society for Bone and Mineral Research advocated against routine use of vertebral augmentation for vertebral fractures based on a review of several trials that showed no differences in pain and disability after 1 year r74
  • Some data have shown that vertebroplasty is superior to placebo for lessening pain in patients with fractures of less than 6 weeks duration and may be particularly beneficial for patients with extremely painful fractures requiring hospitalization or high doses of analgesics r75
  • However, other concerns have been raised regarding a possible increased risk of additional vertebral fractures at adjacent levels; whether this is a true effect remains unclear r74

Safety concerns of antiresorptive therapy

  • Atypical femoral fractures
    • Insufficiency stress fractures of the femoral shaft that present with pain in the thigh or groin after weight bearing r76
    • Absolute risk is very low, with incidence ranging between 1 in 100,000 and 5 in 10,000 r77
    • Risk appears to increase with more than 5 years of bisphosphonate use r78
    • Meta-analyses suggest a highly favorable benefit-risk ratio associated with treatment lasting up to 5 years in postmenopausal patients with osteoporosis r78r79
    • Risk may be reduced by taking a holiday from oral bisphosphonates after 5 years and from IV bisphosphonates after 3 years, as appropriate for patients who are at low or moderate risk of future fractures r80
  • Osteonecrosis of jaw
    • Nonhealing wound in the oral mucosa with exposed bone, lasting at least 2 months, that usually occurs in association with an invasive dental procedure r76
    • Absolute risk in patients with more than 4 years of antiresorptive therapy is low, with an estimate of 1 event in 10,000 to 100,000 patient-years r81
    • Incidence is greatest in patients with cancer, where high doses of these medications are used at frequent intervals; other risk factors include concomitant glucocorticoid use, diabetes, and poor oral hygiene r82
    • Routine dental care is important for preventing osteonecrosis of jaw in all patients treated with antiresorptive therapy r83
    • This condition may be treated with antibacterial mouth rinses for mild cases, but it requires surgical debridement and resection for advanced cases r83

Drug therapy

  • Vitamin D r2r84c95
    • Cholecalciferol c96
      • Vitamin D (Cholecalciferol) Oral tablet; Adults: 1000 to 2000 International Units PO daily. Maintain 25-hydroxyvitamin D levels of 30 to 50 nanograms/mL. r4
  • Calcium r2r84c97
    • Calcium Oral tablet; Adult females 50 years and older: 1000 to 1200 mg PO daily of elemental calcium. r4
  • Antiresorptive agents
    • Bisphosphonates r85
      • Alendronate r4r86c98
        • Alendronate Sodium Oral solution, weekly; Adult men and postmenopausal females: 70 mg PO once weekly. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. Continue for up to 10 years in postmenopausal women with very high risk of fracture. Consider discontinuation after 5 years of stability in high risk postmenopausal women and after 3 to 5 years in low or moderate risk patients.
      • Risedronate r87c99
        • Risedronate also has a coated formulation which may be taken after breakfast (Atelvia)
        • Weekly dosing
          • Risedronate Sodium Oral tablet, weekly; Adult postmenopausal females: 35 mg PO once weekly. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. For those patients at low risk for fracture, consider stopping risedronate after 3 to 5 years.
        • Monthly dosing
          • Risedronate Sodium Oral tablet; Adult postmenopausal females: 150 mg PO once monthly. An alternative once-monthly regimen is 75 mg PO on 2 consecutive days each month (for a total of 150 mg each month). Supplement calcium and vitamin D if dietary intake is inadequate. Continue for up to 10 years in postmenopausal women with very high risk of fracture. Consider discontinuation after 5 years of stability in high risk postmenopausal women and after 3 to 5 years in low or moderate risk patients.
      • Ibandronate c100
        • Monthly oral dosing
          • Ibandronate Sodium Oral tablet, monthly; Adult postmenopausal females: 150 mg PO once monthly on the same date each month. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. Continue for up to 10 years in postmenopausal women with very high risk of fracture. Consider discontinuation after 5 years of stability in high risk postmenopausal women and after 3 to 5 years in low or moderate risk patients.
        • Every 3 months IV dosing
          • Ibandronate Sodium Solution for injection; Adult postmenopausal females : 3 mg IV (over 15 to 30 seconds) every 3 months. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. Continue for up to 10 years in postmenopausal women with very high risk of fracture. Consider discontinuation after 5 years of stability in high risk postmenopausal women and after 3 to 5 years in low or moderate risk patients.
      • Zoledronic acid c101
        • Zoledronic Acid Solution for injection [Reclast]; Postmenopausal females: 5 mg IV infused once yearly. Supplement calcium and vitamin D daily if dietary intake is inadequate. Periodically reevaluate the need for continued therapy. For those patients determined to be at low risk of fracture, consider stopping treatment after 3 to 5 years. After discontinuation of therapy, periodically reevaluate the fracture risk.
    • Denosumab c102
      • Rapid loss of bone mineral density and increase in fracture risk (including risk of multiple vertebral fractures) occurs upon discontinuation of denosumab; transitioning to antiresorptive therapy 6 months after denosumab discontinuation is advisable to maintain gains in bone mineral density at the lumbar spine r11r12r70r88
      • Denosumab Solution for injection; Adults: 60 mg subcutaneously once every 6 months. All patients should receive a minimum of 1,000 mg of calcium and at least 10 mcg (400 international units) of vitamin D daily. If a dose is missed, administer as soon as possible and schedule future injections every 6 months from that date.
  • Selective estrogen receptor modulator c103
    • Raloxifene
      • Raloxifene Hydrochloride Oral tablet; Adult postmenopausal females: 60 mg PO once daily. Supplement calcium and vitamin D if dietary intake inadequate. Other agents are usually preferred as first-line treatments. Raloxifene may be appropriate in patients requiring spine-specific efficacy.
    • Bazedoxifene (with estrogen) c104
      • Approved by the FDA for prevention, but not treatment, of osteoporosis
      • Conjugated Estrogens, Bazedoxifene Oral tablet; Adult postmenopausal females: 1 tablet (conjugated estrogens 0.45 mg; bazedoxifene 20 mg) PO once daily. Only for women at significant risk of osteoporosis; carefully consider non-estrogen medication before using estrogen-based treatment. Supplement calcium and vitamin D if dietary intake inadequate. Reassess use periodically.
  • Anabolic agents
    • Parathyroid hormone analogues and parathyroid hormone–related protein analogues
      • Teriparatide c105c106
        • Teriparatide Solution for injection; Adults: 20 mcg subcutaneously once daily. Supplement calcium and vitamin D if dietary intake is inadequate. Usually reserved for those with known history of osteoporotic fracture or at higher risk for such fractures.
      • Abaloparatide c107c108
        • Abaloparatide Solution for injection; Adult postmenopausal females: 80 mcg subcutaneously once daily. Cumulative use of abaloparatide for more than 2 years during a patient's lifetime is not recommended. Supplement calcium and vitamin D if dietary intake is inadequate. Usually reserved for those with known history of osteoporotic fracture or those with higher risk for such fractures.
  • Combined anabolic/antiresorptive therapy
    • Romosozumab c109
      • Romosozumab Solution for injection; Adult postmenopausal females: 210 mg subcutaneously once monthly. Limit duration to 12 months. Supplement calcium and vitamin D if dietary intake is inadequate.

Nondrug and supportive care

Nonpharmacologic interventions are important to improve bone health for postmenopausal people with osteoporosis. Do the following: r89

  • Ensure adequate intake of dietary calcium and vitamin D
    • Efficacy of calcium and vitamin D supplements for preventing osteoporotic fractures is controversial owing to conflicting results from clinical trials, leading to some uncertainty about optimal doses and regimens
      • One randomized trial in older females who were nursing home residents found a large (about 33%) risk reduction in hip fractures for those treated with both calcium and vitamin D r90
      • A recent systematic review and meta-analysis found that using vitamin D supplements alone does not reduce risk of fractures, but daily supplementation with both vitamin D and calcium does reduce fractures r91
        • This systematic review found that use of both vitamin D (daily doses of 400-800 international units) and calcium (daily doses of 1000-1200 mg) resulted in a 6% reduced risk of any fracture (relative risk, 0.94; 95% confidence interval, 0.89-0.99) and a 16% reduced risk of hip fracture (relative risk, 0.84; 95% confidence interval, 0.72-0.97) r91
        • Other systematic reviews have found reductions in hip fractures with vitamin D and calcium supplementation, but use of these supplements has not been found to reduce other types of fractures (eg, vertebral or nonhip fractures) r92r93r94
      • Very-high-dose intermittent vitamin D is not recommended because it has been found to increase risk of falls and fractures in 2 separate trials r95r96
    • Recommended intakes:
      • Calcium: 1200 mg/day for females older than 50 years, obtained through diet, supplements, or both (preferably through diet) r3r18
      • Vitamin D: 1000 to 2000 international units/day for adults older than 50 years to maintain serum 25-hydroxyvitamin D level of 30 nanograms/mL or more
        • There is some debate about the preferable range for 25-hydroxyvitamin D level, but most experts suggest levels between 30 and 50 nanograms/mL
  • Advise participation in weight-bearing, resistance, and balance exercises r97c110
    • Aim for 30 to 40 minutes of walking (or other weight-bearing exercise) per session 3 to 4 days per week r4
    • Postmenopausal females who engage in strength training can be expected to have a 2% improvement in lumbar spine bone mineral density r98
    • One meta-analysis determined that improvements in lumbar spine and femoral neck bone mineral density after exercise interventions could reduce the 20-year osteoporosis fracture risk at any site by about 10% r98
  • Advise measures to reduce risk of falls r2r25c111
    • Balance programs such as tai chi and yoga may be helpful to improve balance, increase muscle tone, and reduce fall risk in older adults (eg, those aged 65 years or older)
    • Identify hazards in home and remove them (eg, loose rugs, objects on floor)
  • Advise optimized nutritional status with balanced diet of macronutrients r2r6c112c113
    • For patients who have experienced hip fractures, adequate protein intake is especially important to minimize bone loss; advise patients who have a history of hip fracture to consume the US recommended daily allowance of protein (0.8 g/kg) r99
  • Encourage cessation of cigarette smoking r2r25r100c114d2
  • Advise limitation of alcohol intake to 2 units (standard drinks) per day or less r2r25r101c115
Procedures c116

Comorbidities

  • Several comorbidities may increase osteoporosis severity:
    • Type 1 diabetes mellitus r102c117
    • Inflammatory bowel and joint diseases with or without glucocorticoid therapy r102c118c119
    • Celiac disease r102c120
    • Breast and prostate cancer treated with chemotherapy or hormone therapy r102c121c122

Special populations

  • Patients taking long-term glucocorticoid therapy are at increased risk of bone loss and osteoporotic fractures r103
    • Start bone-protective treatment at onset of glucocorticoid therapy in patients at high risk for fracture r2
      • Alendronate and risedronate are first line treatment options; if these are contraindicated or not tolerated, zoledronic acid and teriparatide are alternatives
  • Patients with breast cancer (or history thereof) d3
    • Postmenopausal females and those who are treated with adjuvant aromatase inhibitors or who experience ovarian failure owing to treatment are evaluated for osteoporosis, with bone mineral density measurement at baseline and at regular intervals thereafter r104
    • Provide bone protection to all patients with t score of −2 or less; to those with t score of less than −1.5 who have 1 additional clinical risk factor; and to those with 2 or more clinical risk factors for fracture r105
      • Bisphosphonates are the preferred pharmacologic agents to prevent bone loss induced by adjuvant endocrine therapy and to increase bone density in females with breast cancer (or history thereof) who have osteopenia or osteoporosis r106
        • In postmenopausal females, either oral bisphosphonate or IV zoledronic acid may be used; both have been shown to be effective in reducing bone loss due to aromatase inhibitor therapy r106
          • In premenopausal females, zoledronic acid is preferred r107
        • Continue treatment with bisphosphonates at least until adjuvant therapy is complete. Optimal duration beyond this point is not established r106
        • Factors to consider for duration of antiosteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture r104
        • Bisphosphonates also have potential anticancer effects that appear to improve long-term outcomes (ie, reduce distant recurrence, bone recurrence, and breast cancer mortality) in postmenopausal females or those receiving ovarian suppression therapy r108
      • Alternative agent is denosumab; evidence base is less extensive than for bisphosphonates, but 1 randomized controlled trial showed reduction in fractures when postmenopausal females with hormone receptor–positive breast cancer who were treated with aromatase inhibitors used denosumab r107
    • Avoid estrogen, progesterone, and selective estrogen receptor modulators in females with breast cancer r104

Monitoring

  • Monitoring treatment responses
    • For postmenopausal patients who are being treated for osteoporosis, obtain bone mineral density by DXA at spine and hip approximately every 1 to 3 years r5
      • Specific interval for repeating DXA varies by professional organization; most societies recommending the repeat DXA after 1 to 3 years and if findings are stable, then continued follow-up with DXA every 1 to 2 years or at a less frequent interval r4r18
      • Both UK and American College of Physicians guidelines suggest less frequent treatment reviews
        • UK guideline recommends reevaluation of treatment after 3 years of zoledronic acid therapy and 5 years of oral bisphosphonate therapy r2c123c124
          • If treatment is discontinued, reassess fracture risk after a new fracture, regardless of when it occurs; if no new fracture occurs, reassess fracture risk after 18 months to 3 years r2c125
        • American College of Physicians guideline recommends against bone density monitoring in females during the 5-year pharmacologic treatment period for osteoporosis r57c126
      • An alternative way of identifying suboptimal response or poor adherence to therapy is to measure bone turnover marker levels
        • Use serum C-terminal cross-linking telopeptide for antiresorptive therapy or procollagen type N-terminal propeptide for bone anabolic therapy
    • Repeated vertebral imaging is advisable if there is documented height loss, new back pain, or postural change
    • For patients on long-term bisphosphonate therapy who present with thigh or groin pain, it is advisable to obtain bilateral hip radiographs, followed by MRI, to rule out an atypical femoral fracture r47c127c128c129c130
  • Monitoring after withdrawal of bisphosphonates
    • Measurement of bone turnover marker levels after withdrawal of bisphosphonates is a potentially helpful method to evaluate patients who are taking a pause from treatment at a point before measurement of bone mineral density becomes useful r109
      • An increase in bone turnover marker levels more than the least significant change or reference mean reflects loss of treatment effect and identifies patients who are likely to have a decrease in bone mineral density
    • For patients who have begun a bisphosphonate holiday, reassess fracture risk at 2- to 4-year intervals with DXA
      • Consider resuming osteoporosis drug therapy earlier than the 5-year suggested holiday duration if there is a significant decline in bone mineral density, an intervening fracture, or other factors that alter risk (eg, glucocorticoid use)

Complications and Prognosis

Complications

  • Fragility fractures c131
    • 60% of females with osteoporosis will experience 1 or more fragility fractures r6
      • Current pharmacotherapies reduce risk of fracture roughly by half r93
  • Hip fractures (femoral neck fractures) are the most serious complication of osteoporosis r110c132d4
    • Associated with 12% to 20% reduction in expected survival
    • Can result in poor quality of life and dependent living situation r33
  • Vertebral fractures r6c133
    • Common complications of vertebral deformities are chronic back pain, back disability, height loss, limitations in activity, and emotional difficulties stemming from physical appearance
    • Associated with increased mortality at 5 years
  • Wrist fractures (ie, distal forearm fractures such as Colles fractures) r6c134
    • Important predictor of subsequent vertebral and hip fractures
    • Occurrence of wrist fracture after low-energy trauma in a patient in early postmenopause suggests bone fragility; this fracture should trigger investigation, including bone mineral density measurement
    • Not associated with an increase in mortality
  • Other fractures (eg, proximal humerus, pelvis, proximal tibia, rib) r6c135c136c137c138d5
    • Also associated with increased subsequent mortality

Prognosis

  • Osteoporosis is associated with mortality; for each standard deviation decrease in bone mineral density, mortality risk increases 1.17-fold r7
  • Evidence suggests an independent increase in mortality after an osteoporotic fracture r110
  • Burden of illness for osteoporotic fractures is comparable to that of other serious diseases
    • A retrospective analysis of hospitalizations for osteoporotic fractures found that in US females aged 55 years and older, hospitalization burden is greater than that of myocardial infarction, stroke, or breast cancer r111

Screening and Prevention

Screening

At-risk populations

  • All postmenopausal females aged 50 years or older should undergo comprehensive assessment for osteoporosis and fracture risk, using detailed history, examination, and (for most) FRAX tool assessment r20c139
  • All females aged 65 years or older should undergo bone mineral density testing regardless of other risk factors for osteoporosis r38
    • For postmenopausal females younger than 65 years, consider factors associated with increased risk of osteoporotic fractures to determine whether to proceed to bone mineral density testing r8r9
      • Although risk of osteoporosis and osteoporotic fractures generally increases with age, presence of multiple risk factors at a younger age may indicate that the risk-benefit profile is favorable for screening with bone measurement testing
        • These risk factors include parental history of hip fracture, smoking, excessive alcohol consumption, and low body weight
  • Suggested screening populations are similar among guidance documents from International Society for Clinical Densitometry, American College of Obstetricians and Gynecologists, and American College of Preventive Medicine r43r112

Screening tests

  • Screening tests for bone health and morphology include central DXA, peripheral DXA, and quantitative ultrasonography c140c141
  • Central DXA is the most commonly used bone measurement test used to screen for osteoporosis
    • Central DXA measures bone mineral density at hip and lumbar spine
  • Peripheral DXA measures bone mineral density at distal forearm and heel
  • Quantitative ultrasonography also evaluates peripheral sites and does not involve radiation exposure; however, it does not measure bone mineral density
  • FRAX tool also can be used as an adjunct to determine whether to obtain bone mineral density measurement for postmenopausal females younger than 65 years. This tool includes questions about previous DXA results but does not require this information to estimate fracture risk r16
  • Screening tests for osteoporosis.BMD, bone mineral density; DXA, dual energy x-ray absorptiometry; QUS, quantitative ultrasonography.
    Screening testDescription of techniqueConsiderations
    Central DXAMost commonly studied and used bone measurement test to screen for osteoporosis; reference with which other tests are compared; uses radiation to measure BMD at hip and at lumbar spineMost treatment guidelines recommend using BMD, as measured by central DXA, to define osteoporosis and the treatment threshold to prevent osteoporotic fractures
    Peripheral DXAUses radiation to measure BMD at peripheral sites, such as distal forearm and heel; accuracy is similar to that of central DXAMeasured with portable devices; no treatment studies have used BMD measured by peripheral DXA to define treatment thresholds
    QUSUses ultrasonography to evaluate peripheral bone sites (most commonly, the calcaneus)No exposure to radiation; measured with portable devices; does not measure BMD. Importantly, there are no data from studies using QUS measurements to define treatment thresholds. QUS should not be routinely used to initiate treatment without further DXA measurement

Prevention

  • Lifestyle measures to maximize peak bone mass and improve bone health are important to prevent osteoporosis: r2c142c143c144c145c146c147
    • Participating in lifelong regular physical activity, particularly weight-bearing, resistance, and balance exercises r97
    • Maintaining healthy body weight r38
    • Optimizing nutritional status throughout childhood and adolescence, in particular r38
    • Ensuring adequate intake of calcium and vitamin D, preferably through diet rather than supplements
      • In community-dwelling, postmenopausal females, US Preventive Services Task Force recommends against daily supplementation with vitamin D and calcium for primary prevention of fractures r113
      • To reduce fractures, institutionalized older adults should be encouraged to increase their intake of dairy products or calcium rich foods if dietary calcium intake is estimated to be less than 1200 mg per day r114
    • Reducing risk of falls r15
    • Avoiding tobacco use r100d2
    • Avoiding excessive alcohol consumption r101
      • Postmenopausal females should limit alcohol to no more than 2 drinks daily; 1 drink is equivalent to 120 mL of wine, 30 mL of liquor, or 260 mL of beer
  • Pharmacotherapy r35
    • Can consider bisphosphonates to prevent bone loss in postmenopausal females with low bone mineral density (t score lower than 1) and other risk factors for fracture who do not meet criteria for osteoporosis treatment
Black DM et al: Postmenopausal osteoporosis. N Engl J Med. 374(3):254-62, 201626789873Compston J et al: UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos. 12(1):43, 201728425085Eastell R et al: Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 104(5):1595-622, 201930907953Camacho PM et al: American Association of Clinical Endocrinologists/American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis--2020 update. Endocr Pract. 26(suppl 1):1-46, 202032427503Shoback D et al: Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab. 105(3):e255-64, 202032068863Chapurlat RD et al: Osteoporosis. In: Jameson JL et al, eds: Endocrinology: Adult and Pediatric. 7th ed. Saunders; 2016:1184-213.e6https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032318907100069X3-s2.0-B978032318907100069XQu X et al: Bone mineral density and all-cause, cardiovascular and stroke mortality: a meta-analysis of prospective cohort studies. Int J Cardiol. 166(2):385-93, 201322112679US Preventive Services Task Force et al: Screening for osteoporosis to prevent fractures: US Preventive Services Task Force recommendation statement. JAMA. 319(24):2521-31, 201829946735Viswanathan M et al: Screening to prevent osteoporotic fractures: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 319(24):2532-51, 201829946734Lewiecki EM et al: Best practices for dual-energy x-ray absorptiometry measurement and reporting: International Society for Clinical Densitometry guidance. J Clin Densitom. 19(2):127-40, 201627020004Cummings SR et al: Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. 33(2):190-8, 201829105841Lamy O et al: Stopping denosumab. Curr Osteoporos Rep. 17(1):8-15, 201930659428Compston JE et al: Osteoporosis. Lancet. 393(10169):364-76, 201930696576NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy: Osteoporosis prevention, diagnosis, and therapy. JAMA. 285(6):785-95, 200111176917Anam AK et al: Update on Osteoporosis Screening and Management. Med Clin North Am. 105(6):1117-1134, 202134688418Centre for Metabolic Bone Diseases, University of Sheffield: FRAX Fracture Risk Assessment Tool. University of Sheffield website. Accessed December 13, 2021. https://www.sheffield.ac.uk/FRAX/tool.jsphttps://www.sheffield.ac.uk/FRAX/tool.jspBliuc D et al: Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA. 301(5):513-21, 200919190316Cosman F et al: Clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 25(10):2359-81, 201425182228Johnell O et al: Predictive value of BMD for hip and other fractures. J Bone Miner Res. 20(7):1185-94, 200515940371Kanis JA; on behalf of the World Health Organization Scientific Group: Assessment of Osteoporosis at the Primary Health Care Level. Technical Report. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield. University of Sheffield website. Published 2007. Accessed December 13, 2021. https://www.sheffield.ac.uk/FRAX/pdfs/WHO_Technical_Report.pdfhttps://www.sheffield.ac.uk/FRAX/pdfs/WHO_Technical_Report.pdfLeslie WD et al: High fracture probability with FRAX usually indicates densitometric osteoporosis: implications for clinical practice. Osteoporos Int. 23(1):391-7, 201221365460Siris ES et al: What's in a name? What constitutes the clinical diagnosis of osteoporosis? Osteoporos Int. 23(8):2093-7, 201222543575Wainwright SA et al: Hip fracture in women without osteoporosis. J Clin Endocrinol Metab. 90(5):2787-93, 200515728213Siris ES et al: The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int. 25(5):1439-43, 201424577348Weber TJ: Osteoporosis. In: Goldman L et al, eds: Goldman-Cecil Medicine. 26th ed. Elsevier; 2020:1599-607.e3https://www.clinicalkey.com/#!/content/book/3-s2.0-B97803235326620023073-s2.0-B9780323532662002307Tannenbaum C et al: Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women. J Clin Endocrinol Metab. 87(10):4431-7, 200212364413Alejandro P et al: A review of osteoporosis in the older adult. Clin Geriatr Med. 33(1):27-40, 201727886696Manolagas SC: The quest for osteoporosis mechanisms and rational therapies: how far we've come, how much further we need to go. J Bone Miner Res. 33(3):371-85, 201829405383Golob AL et al: Osteoporosis: screening, prevention, and management. Med Clin North Am. 99(3):587-606, 201525841602Whittier X et al: Glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am. 42(1):177-89, x, 201626611558O'Sullivan SM et al: Bisphosphonates in pregnancy and lactation-associated osteoporosis. Osteoporos Int. 17(7):1008-12, 200616758139Wright NC et al: The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res. 29(11):2520-6, 201424771492Cummings SR et al: Epidemiology and outcomes of osteoporotic fractures. Lancet. 359(9319):1761-7, 200212049882Hannan MT et al: Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study. J Bone Miner Res. 15(4):710-20, 200010780863The North American Menopause Society (NAMS): Management of osteoporosis in postmenopausal women: the 2021 position statement of the North American Menopause Society. Menopause. 28(9):973-97, 202134448749Stone KL et al: BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res. 18(11):1947-54, 200314606506Cummings SR et al: Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group. Lancet. 341(8837):72-5, 19938093403Ensrud KE et al: Osteoporosis. Ann Intern Med. 167(3):ITC17-32, 201728761958Giangregorio LM et al: FRAX underestimates fracture risk in patients with diabetes. J Bone Miner Res. 27(2):301-8, 201222052532Silverman SL et al: The utility and limitations of FRAX: a US perspective. Curr Osteoporos Rep. 8(4):192-7, 201020811963Schacter GI et al: DXA-based measurements in diabetes: can they predict fracture risk? Calcif Tissue Int. 100(2):150-64, 201727591864Zeytinoglu M et al: Vertebral fracture assessment: enhancing the diagnosis, prevention, and treatment of osteoporosis. Bone. 104:54-65, 201728285014International Society for Clinical Densitometry: 2019 ISCD Official Positions--Adult. ISCD website. Updated January 9, 2020. Accessed December 13, 2021. https://iscd.org/learn/official-positions/adult-positions/https://iscd.org/learn/official-positions/adult-positions/Statham L et al: Can bone turnover markers help to define the suitability and duration of bisphosphonate drug holidays? Drugs Context. 9:2020-1-3, 202032426015Nishizawa Y et al: Executive summary of the Japan Osteoporosis Society guide for the use of bone turnover markers in the diagnosis and treatment of osteoporosis (2018 edition). Clin Chim Acta. 498:101-7, 201931425674Black DM et al: Axial and appendicular bone density predict fractures in older women. J Bone Miner Res. 7(6):633-8, 19921414481Expert Panel on Musculoskeletal Imaging et al: ACR Appropriateness Criteria: osteoporosis and bone mineral density. J Am Coll Radiol. 14(5S):S189-202, 201728473075Shevroja E et al: Use of trabecular bone score (TBS) as a complementary approach to dual-energy x-ray absorptiometry (DXA) for fracture risk assessment in clinical practice. J Clin Densitom. 20(3):334-45, 201728734710Royal Osteoporosis Society: Vitamin D and Bone Health: A Practical Clinical Guideline for Patient Management. Royal Osteoporosis Society website. Updated December 2018. Reviewed February 2020. Accessed December 13, 2021. https://strwebprdmedia.blob.core.windows.net/media/ef2ideu2/ros-vitamin-d-and-bone-health-in-adults-february-2020.pdfhttps://strwebprdmedia.blob.core.windows.net/media/ef2ideu2/ros-vitamin-d-and-bone-health-in-adults-february-2020.pdfDemay MB et al: Disorders of mineralization. In: Jameson JL et al, eds: Endocrinology: Adult and Pediatric. 7th ed. Saunders; 2016:1230-43.e4https://www.clinicalkey.com/#!/content/book/3-s2.0-B97803231890710007183-s2.0-B9780323189071000718Rosen CJ: Clinical practice: vitamin D insufficiency. N Engl J Med. 364(3):248-54, 201121247315Mauch JT et al: Review of the imaging features of benign osteoporotic and malignant vertebral compression fractures. AJNR Am J Neuroradiol. 39(9):1584-92, 201829348133Yamato M et al: MR appearance at different ages of osteoporotic compression fractures of the vertebrae. Radiat Med. 16(5):329-34, 19989862153Jung HS et al: Discrimination of metastatic from acute osteoporotic compression spinal fractures with MR imaging. Radiographics. 23(1):179-87, 200312533652Conley RB et al: Secondary fracture prevention: consensus clinical recommendations from a multistakeholder coalition. J Bone Miner Res. 35(1):36-52, 202031538675Bell K et al: Effect of a dedicated osteoporosis health professional on screening and treatment in outpatients presenting with acute low trauma non-hip fracture: a systematic review. Arch Osteoporos. 9:167, 201424452511Qaseem A et al: Treatment of low bone density or osteoporosis to prevent fractures in men and women: a clinical practice guideline update from the American College of Physicians. Ann Intern Med. 166(11):818-39, 201728492856NAMS 2017 Hormone Therapy Position Statement Advisory Panel: The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 24(7):728-53, 201728650869Pun KK et al: Analgesic effect of intranasal salmon calcitonin in the treatment of osteoporotic vertebral fractures. Clin Ther. 11(2):205-9, 19892660996Lyritis GP et al: Pain relief from nasal salmon calcitonin in osteoporotic vertebral crush fractures. A double blind, placebo-controlled clinical study. Acta Orthop Scand Suppl. 275:112-4, 19979385283Saag KG et al: Romosozumab versus alendronate and fracture risk in women with osteoporosis. N Engl J Med. 378(2):195-6, 201829320649Anastasilakis AD et al: Combination and sequential treatment in women with postmenopausal osteoporosis. Expert Opin Pharmacother. 21(4):477-90, 202031990595Black DM et al: One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med. 353(6):555-65, 200516093464Grey A et al: Maintaining order in osteoporosis treatments. J Bone Miner Res. 32(5):1147, 201728294409Rittmaster RS et al: Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab. 85(6):2129-34, 200010852440Cosman F et al: Treatment sequence matters: anabolic and antiresorptive therapy for osteoporosis. J Bone Miner Res. 32(2):198-202, 201727925287Anastasilakis AD et al: Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res. 32(6):1291-6, 201728240371Lukert BP: Which drug next? Sequential therapy for osteoporosis. J Clin Endocrinol Metab. 105(3):dgaa007, 202031922566Anastasilakis AD et al: Zoledronate for the prevention of bone loss in women discontinuing denosumab treatment. a prospective 2-year clinical trial. J Bone Miner Res. 34(12):2220-8, 201931433518Makras P et al: The Duration of Denosumab Treatment and the Efficacy of Zoledronate to Preserve Bone Mineral Density After Its Discontinuation. J Clin Endocrinol Metab. 106(10):e4155-e4162, 202133978745Kendler D et al: Bone mineral density after transitioning from denosumab to alendronate. J Clin Endocrinol Metab. 105(3):e255-64, 202031665314Leder BZ et al: Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial. Lancet. 386(9999):1147-55, 201526144908Ferrari S et al: Relationship between bone mineral density T-score and nonvertebral fracture risk over 10 years of denosumab treatment. J Bone Miner Res. 34(6):1033-40, 201930919997Ebeling PR et al: The efficacy and safety of vertebral augmentation: a second ASBMR task force report. J Bone Miner Res. 34(1):3-21, 201930677181Clark W et al: Safety and efficacy of vertebroplasty for acute painful osteoporotic fractures (VAPOUR): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 388(10052):1408-16, 201627544377Black DM et al: Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med. 362(19):1761-71, 201020335571Schilcher J et al: Risk of atypical femoral fracture during and after bisphosphonate use. N Engl J Med. 371(10):974-6, 201425184886Gedmintas L et al: Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res. 28(8):1729-37, 201323408697Crandall CJ et al: Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review. Ann Intern Med. 161(10):711-23, 201425199883Adler RA et al: Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res. 31(1):16-35, 201626350171Watts NB et al: Invasive oral procedures and events in postmenopausal women with osteoporosis treated with denosumab for up to 10 years. J Clin Endocrinol Metab. 104(6):2443-52, 201930759221Lo JC et al: Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. J Oral Maxillofac Surg. 68(2):243-53, 201019772941Ruggiero SL et al: American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw--2014 update. J Oral Maxillofac Surg. 72(10):1938-56, 201425234529Homik J et al: Calcium and vitamin D for corticosteroid-induced osteoporosis. Cochrane Database Syst Rev. 2:CD000952, 200010796394Allen CS et al: Bisphosphonates for steroid-induced osteoporosis. Cochrane Database Syst Rev. 10:CD001347, 201627706804Wells GA et al: Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 1:CD001155, 200818253985Wells G et al: Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 1:CD004523, 200818254053Makras P et al: The three-year effect of a single zoledronate infusion on bone mineral density and bone turnover markers following denosumab discontinuation in women with postmenopausal osteoporosis. Bone. 138:115478, 202032534221Chen LR et al: Nutritional support and physical modalities for people with osteoporosis: current opinion. Nutrients. 11(12):2848, 201931757101Chapuy MC et al: Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med. 327(23):1637-42, 19921331788Yao P et al: Vitamin D and calcium for the prevention of fracture: a systematic review and meta-analysis. JAMA Netw Open. 2(12):e1917789, 201931860103Tang BM et al: Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet. 370(9588):657-66, 200717720017Barrionuevo P et al: Efficacy of pharmacological therapies for the prevention of fractures in postmenopausal women: a network meta-analysis. J Clin Endocrinol Metab. 104(5):1623-30, 201930907957Zhao JG et al: Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults: a systematic review and meta-analysis. JAMA. 318(24):2466-82, 201729279934Sanders KM et al: Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 303(18):1815-22, 201020460620Bischoff-Ferrari HA et al: Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med. 176(2):175-83, 201626747333Howe TE et al: Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev. 7:CD000333, 201121735380Kelley GA et al: Effects of ground and joint reaction force exercise on lumbar spine and femoral neck bone mineral density in postmenopausal women: a meta-analysis of randomized controlled trials. BMC Musculoskelet Disord. 13:177, 201222992273Rizzoli R et al: Protein intake and bone disorders in the elderly. Joint Bone Spine. 68(5):383-92, 200111707004Giampietro PF et al: The role of cigarette smoking and statins in the development of postmenopausal osteoporosis: a pilot study utilizing the Marshfield Clinic Personalized Medicine Cohort. Osteoporos Int. 21(3):467-77, 201019506792Kanis JA et al: Alcohol intake as a risk factor for fracture. Osteoporos Int. 16(7):737-42, 200515455194David C et al: Severity of osteoporosis: what is the impact of co-morbidities? Joint Bone Spine. 77(suppl 2):S103-6, 201021211745Buckley L et al: 2017 American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 69(8):1095-110, 201728585410National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2022. NCCN website. Updated December 20, 2021. Accessed January 4, 2022. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdfhttps://www.nccn.org/professionals/physician_gls/pdf/breast.pdfHadji P et al: Management of aromatase inhibitor-associated bone loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol. 7:1-12, 201728413771Trémollieres FA et al: Osteoporosis management in patients with breast cancer: EMAS position statement. Maturitas. 95:65-71, 201727802892Gnant M et al: Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 386(9992):433-43, 201526040499Early Breast Cancer Trialists' Collaborative Group (EBCTCG) et al: Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 386(10001):1353-61, 201526211824Naylor KE et al: Clinical utility of bone turnover markers in monitoring the withdrawal of treatment with oral bisphosphonates in postmenopausal osteoporosis. Osteoporos Int. 30(4):917-22, 201930613868Center JR et al: Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet. 353(9156):878-82, 199910093980Singer A et al: Burden of illness for osteoporotic fractures compared with other serious diseases among postmenopausal women in the United States. Mayo Clin Proc. 90(1):53-62, 201525481833Lim LS et al: Screening for osteoporosis in the adult U.S. population: ACPM position statement on preventive practice. Am J Prev Med. 36(4):366-75, 200919285200US Preventive Services Task Force: Final Recommendation Statement: Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: Preventive Medication. USPSTF website. Published April 17, 2018. Accessed December 13, 2021. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/vitamin-d-calcium-or-combined-supplementation-for-the-primary-prevention-of-fractures-in-adults-preventive-medicationhttps://www.uspreventiveservicestaskforce.org/uspstf/recommendation/vitamin-d-calcium-or-combined-supplementation-for-the-primary-prevention-of-fractures-in-adults-preventive-medicationIuliano S et al: Effect of dietary sources of calcium and protein on hip fractures and falls in older adults in residential care: cluster randomised controlled trial. BMJ. 375:n2364, 202134670754
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