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Postmenopausal Osteoporosis

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Feb.12.2024

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 r2r3
  • Preferred initial pharmacologic agents for most patients with postmenopausal osteoporosis at high risk of fracture are bisphosphonates or denosumab r2r3r4r5
  • Preferred initial pharmacologic agents for most patients with postmenopausal osteoporosis at very high risk of fracture are anabolic agents r2r3r4r5
  • 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 (Fracture Risk Assessment) 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
  • Failure to obtain bilateral radiographs in a patient on long-term bisphosphonates presenting with thigh or groin pain may result in missed diagnosis of atypical femur fracture (often bilateral) r3r5

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
  • Menopause is the permanent cessation of menses d1
    • Defined retrospectively after menses has stopped for 12 months in a previously cycling patient r16
    • Natural or physiologic menopause occurs spontaneously, after the age of 45, due to loss of ovarian follicular activity r16
    • Premature menopause is defined as menopause before age 40 years, and early menopause occurs between age 40 and 45 years r17
    • Primary ovarian insufficiency refers to loss of ovarian function before age 40 years but with the potential for intermittent, transient return of hormone production and menstrual cycles r17
    • Surgical menopause occurs after bilateral oophorectomy r16
    • Pharmacologic menopause may be induced by gonadotropin suppression and may be temporary r16
    • Regardless of cause of menopause or age it occurs, postmenopausal hormonal changes (primarily decreased estrogen) increase the risk for osteoporosis r16r17
  • 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 FRAXr18 (Fracture Risk Assessment) 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 r19
      • 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 r20

Classification

  • Osteoporosis is commonly classified operationally on the level of bone mass, measured as bone mineral density r3
    • Risk of fracture increases approximately 2-fold for each 1 standard deviation decrease in bone mineral density r21
  • WHO definitions of osteopenia and osteoporosis are traditionally used for making decisions about health policy r22
    • Normal bone health: bone mineral density value within 1 standard deviation of young adult female reference mean (T-score −1 or higher)
    • Osteopenia: bone mineral density value 1 to 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 adult female 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: r22
        • Severe osteoporosis: bone mineral density value 2.5 standard deviations or more below that of young adult female 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 adopted in some guidelines. These include: r2r4r14r23r24r25r26
    • Fragility fracture of spine or hip, 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 any of the following:
      • History of fracture of proximal humerus, pelvis, or distal forearm
      • History of multiple fractures at other sites, excluding face, feet, and hands
      • High FRAX (Fracture Risk Assessment) score based on country-specific thresholds
  • Some classifications use clinical predictors to further stratify the level of risk of fracture in patients
    • 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 (Fracture Risk Assessment) probabilities greater than 30% for a major osteoporosis fracture or greater than 4.5% for hip fracture
      • High-risk category meets definition for osteoporosis but does not have indicators of very high risk r4
    • Adjustments to FRAX (Fracture Risk Assessment) scoring also permits classification into low, high, and very high risk to help determine appropriate treatment r3r27
      • Factors include high, moderate, and low exposure to glucocorticoids; concurrent data on lumbar spine bone mineral density; trabecular bone score of the lumbar spine; hip axis length; history of falls; country of birth; type 2 diabetes; chronic kidney disease; and how recently a fracture occurred
    • 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 greater or hip fracture risk of 3% or greaterRecent 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
  • Other calculators for predicting fracture risk exist (eg, US-based Fracture Index withr28/without known BMDr29, UK-based Qfracture-2016 risk calculatorr30, Australia-based Garvan Institute of Medical Research fracture risk calculatorr31) but these are not as widely used or as well validated, especially in diverse populations, as FRAX (Fracture Risk Assessment) tool

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 r32c2
    • 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 r32
  • 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 r32c5c6c7c8c9c10
    • Patients may also present with back "tiredness," which improves when they sit or lie down r32c11
      • 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 r32c12c13

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 r32c14
  • 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) r32
    • 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 r33

Causes and Risk Factors

Causes

  • Postmenopausal osteoporosis is a complex disease with a multifactorial origin r34
    • 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 r35
    • Abrupt decline of estrogen levels at menopause causes loss of bone and contributes to development of osteoporosis r35c19c20
      • 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 r15r36
    • 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 r37
      • 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 r37
      • Increased fracture risk partially offsets on cessation of therapy but not back to baseline r37
    • Other medications
      • Medications that may cause or contribute to osteoporosis include anticonvulsants, aromatase inhibitors, methotrexate and other chemotherapeutic agents, heparin, and cyclosporine r36c27c28c29c30c31c32
    • Autoimmune diseases
      • Rheumatoid arthritis c33
      • Ankylosing spondylarthritis c34
      • Systemic lupus erythematosus c35
      • Inflammatory bowel disease c36
    • Causes of 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
    • Connective tissue disorders
      • 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 r38c60c61

Risk factors and/or associations

Age
  • In the United States, it is estimated that more than 10 million Americans aged older than 50 years have osteoporosis r39c62
    • 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 approximately a 50% risk of any osteoporotic fracture r40
    • By age 80 years, 27% of females have low bone mass (osteopenia) alone, and 70% have osteoporosis at hip, spine, or forearm c66c67c68c69
Sex
  • Transgender patients may experience menopause depending on which gender-affirming treatments they undergo; more research is needed on fracture risk r41
    • Use of estrogen as gender-affirming hormonal treatment tends to improve bone density in trans women; use of testosterone does not change bone density in trans men r41
    • Limited data indicate that trans women aged 50 years and older had similar fracture risk as age-matched reference women, and trans women aged younger than 50 years had a higher fracture risk than age-matched reference women; trans men had a lower fracture risk than age-matched men r41r42
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 r32
    • 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 r3c71
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 r43
  • 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 (Fracture Risk Assessment) tool of the University of Sheffield r3r15c79
  • Diagnostic criteria
    • A diagnosis of osteoporosis in postmenopausal patients may be met in several ways, with slight variation in guidelines r2r4
      • 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 history of multiple fractures at other sites, excluding face, feet, and hands r2
      • Bone mineral density T-score between −1 and −2.5 and increased 10-year risk of fracture using FRAX (Fracture Risk Assessment) toolr18
  • 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 r2
    • DXA of lumbar spine, total hip, and proximal femur is the preferred method for diagnosis r21r44r45
      • Be aware that 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
    • The International Society for Clinical Densitometry recommends use of T-score, which compares patients to a young adult Caucasian female reference, for all individuals (cisgender, transgender, and gender non-conforming, of all ethnic groups) r46r47
  • Fragility fracture history (present or earlier)
    • 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 (Fracture Risk Assessment) tool computes an estimate of 10-year probability of hip fracture or a major osteoporotic fracture r3
      • 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 r48
      • FRAX (Fracture Risk Assessment) 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 (Fracture Risk Assessment) score, recommendations can be made about whether pharmacologic intervention is appropriate
    • FRAX (Fracture Risk Assessment) tool shortcomings
      • FRAX (Fracture Risk Assessment) score underestimates risk of all future fractures, given that it estimates only for hip and major fractures, which comprise approximately half of all fragility fractures r49
      • FRAX (Fracture Risk Assessment) 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 r50
        • For patients with diabetes, rheumatoid arthritis may be entered into the FRAX (Fracture Risk Assessment) algorithm as a surrogate to adjust for the elevated risk r51
      • An adjustment may be applied for certain known factors (eg, exposure to glucocorticoids, bone mineral density or trabecular bone score of the lumbar spine, hip axis length, falls history, country of birth, type 2 diabetes, chronic kidney disease, how recently a fracture occurred) to refine the risk estimation r3r27
  • Evaluation for causes of secondary osteoporosis
    • An evaluation is indicated for all patients 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 approximately one-third of females with osteoporosis r33
      • Common secondary causes include hyperparathyroidism, hypercalciuria, calcium malabsorption, vitamin D deficiency, and hyperthyroidism r33
    • 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
      • C-reactive protein or erythrocyte sedimentation rate can also be evaluated r3
    • 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: r3r4
      • Serum intact parathyroid hormone level, for possible hyperparathyroidism
      • Magnesium, if calcium is low
      • Additional tests for hyperthyroidism, if screening thyroid function tests are abnormal
      • 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
      • Serum testosterone, sex hormone binding globulin, follicle stimulating hormone, and luteinizing hormone, for suspected hypogonadism
      • Serum prolactin, for suspected hyperprolactinemia
  • 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 r52
      • 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 (Fracture Risk Assessment) 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 r47
  • 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 to investigate for secondary causes of osteoporosis and to identify conditions in the differential diagnosis r3r6
  • 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; may also include C-reactive protein or erythrocyte sedimentation rate r3r4c80c81c82c83
  • Bone turnover markers r53c84
    • 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
      • Not FDA approved for diagnosis of osteoporosis, but may have a role in assessing fracture risk and extent of fracture risk reduction in selected patients r54
    • 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) r54
      • Bone formation markers include proteins that are rather specific to bone (eg, osteocalcin) and those that are less specific to bone, such as serum P1NP (N-propeptide of type I collagen, fragments of type I procollagen released during formation of type I collagen), bone-specific ALP (the bone isoform of alkaline phosphatase), and osteocalcin
      • Bone resorption markers include fragments released from the telopeptide region of type I collagen after its enzymatic degradation, including urinary NTX (N-telopeptide of type I collagen) and serum 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 r55
      • 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 r21r44r45
      • 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 r56
      • Femoral neck is the site with the highest predictive value for fracture risk r3
      • 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; if so, hip may then be used r3
      • Be aware of misinterpretation of DXA in cases of fractured vertebrae with severe osteoporosis or extraskeletal calcifications r10
    • DXA is also the preferred method by which to monitor bone mineral density over time r57
      • Ideally, patients should be measured on the same DXA machine because different vendor technologies don't allow for comparisons unless cross-calibration has occurred r57
    • DXA results are categorized by WHO diagnostic criteria for osteopenia and osteoporosis r22
      • Normal: bone mineral density value 1 standard deviation below young adult female reference mean or higher (T-score −1 or higher)
      • 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 adult female reference mean (T-score −2.5 or less)
  • Quantitative CT r3c87c88
    • Quantitative CT femoral neck areal bone mineral density is equivalent to DXA bone mineral density, and predicts fractures
    • Femoral neck results may be used in FRAX (Fracture Risk Assessment)
    • Only use axial bone density measurements (lumbar spine, femoral neck, total hip, and distal 1/3 of the radius) in diagnostic evaluations; peripheral bone density measurements may only be used to assess fracture risk r4
  • Quantitative ultrasonography
    • Measurements are commonly made at the calcaneus, which is composed primarily of cancellous bone similar to the spine
    • Consider to identify patients at increased risk for fracture; DXA still required to make formal diagnosis of osteoporosis r4
    • Avoids radiation exposure
    • Not well validated compared to absorptiometric techniques r3
  • Vertebral fracture assessment r6r47
    • Test utilizing DXA with additional software to evaluate vertebral morphology from thoracic (T5) to lower lumbar spine (L5), where most vertebral fractures occur r57c89c90
    • Significant loss in vertebral height may be indicative of vertebral fracture, which can be missed using DXA alone r6
    • Vertebral fracture assessment is not indicated for screening, diagnosis, or routine monitoring; it is most useful in reclassifying patients who would otherwise not meet criteria for treatment on the basis of bone mineral density alone r57
      • Up to 2/3 of radiographically detected vertebral fractures are not recognized clinically
      • Finding unknown vertebral fractures has been shown to influence treatment initiation in asymptomatic patients and to help direct treatment for patients on therapy whose bone mineral density is stable or improved on DXA
    • Densitometric vertebral fracture assessment is indicated when T-score is less than −1 and one or more of the following factors are present: r57
      • 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
  • Skeletal radiography r6c91
    • Anteroposterior and lateral views are required for both the thoracic and lumbar spine to evaluate potential vertebral fractures
      • Radiographs of the spine may be considered when vertebral fracture assessment is not diagnostic or when images cannot be adequately derived, or as an alternative to vertebral fracture assessment in patients who have low BMD and risk factors for developing vertebral fractures r57
    • Vertebral fractures include wedge deformities, end-plate (biconcave) deformities, and compression (or crush) fractures
    • Vertebrae from T4 to L4 are graded on visual inspection of radiographs as follows:
      • Normal appearance (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 r58r59c92
    • 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 (Fracture Risk Assessment) tool to predict fracture r58
    • High scores indicate homogeneous, normal bone and reduce the FRAX (Fracture Risk Assessment) estimated risk, whereas low scores correlate with weaker bone texture and increase the FRAX (Fracture Risk Assessment) risk
    • Adjusting FRAX (Fracture Risk Assessment) 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 d2
    • Patients with osteomalacia may present with musculoskeletal pain, bony tenderness, hyperalgesia or paresthesia, proximal muscle weakness, waddling gait, history of fracture, and coexisting hypocalcemia r60
    • 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 r61
    • Differentiated from osteoporosis by clinical presentation in the setting of a low serum level of 25-hydroxyvitamin D, calcium, or phosphorus r62
  • Pathologic fractures due to other causes
    • Malignant vertebral compression fractures can be caused by metastatic cancers or primary tumors of bone r63c94
      • 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 [Single-photon emission computed tomography]) can provide additional information, as guided by radiologist evaluations r63
    • 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 r64
    • 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 r64
    • 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 r65
    • 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 r65

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: r66r67
    • 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

Numerous guidelines exist for management of postmenopausal osteoporosis, with considerable overlap but subtle differences; guidelines summarized here include the following:

  • American College of Physicians: Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass to Prevent Fractures in Adults: A Living Clinical Guideline (2023) r68
  • American College of Obstetricians and Gynecologists: Management of Postmenopausal Osteoporosis (2022) r5
  • The North American Menopause Society: Management of Osteoporosis in Postmenopausal Women (2021) r2
  • American Association of Clinical Endocrinologists/American College of Endocrinology: Clinical Practice Guidelines for the Diagnosis and Treatment of Postmenopausal Osteoporosis (2020) r4
  • Endocrine Society: Pharmacological management of osteoporosis in postmenopausal women (2019) r69
  • Osteoporosis Canada: Practice guideline for management of osteoporosis and fracture prevention in Canada (2023 update) r70
  • Bone Health and Osteoporosis Foundation (formerly the National Osteoporosis Foundation): Clinician's guide to prevention and treatment of osteoporosis (2022) r54
  • National Osteoporosis Guideline Group: Clinical Guideline for the Prevention and Treatment of Osteoporosis (2021) r3
  • Healthy Bones Australia (formerly Osteoporosis Australia): Position Statement on the Management of Osteoporosis (2023) r71

Bone health–preserving nonpharmacologic measures are indicated for everyone with, or at risk for, osteoporosis or osteopenia r3r5r54r68

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

Pharmacotherapy

  • Pharmacotherapy to reduce fracture risk (primary prevention) is indicated in patients with any of the following: r3r4r5r17r54r69r71
    • Formal diagnosis of osteoporosis (T-score −2.5 or less)
    • Osteopenia (T-score between −2.5 and −1.0) and high 10-year risk of fracture (risk of hip fracture greater than 3% or any fracture greater than 20%)
  • Pharmacotherapy for secondary fracture prevention is indicated for patients with any of the following: r54
    • Hip or vertebra fracture, regardless of bone mineral density
    • Proximal humerus, pelvis, or distal forearm fracture and osteopenia
      • Individualize decisions regarding treatment in patients with these fractures who do not have osteopenia or low bone mineral density
  • Major classes of drugs are antiresorptive agents, which primarily inhibit osteoclastic bone resorption, and anabolic agents, which primarily stimulate osteoblastic bone formation r3
    • Antiresorptive agents include bisphosphonates, RANK (receptor activator of nuclear factor kappa beta) ligand inhibitors, selective estrogen receptor modulators, hormone therapy, and calcitonin r5
      • Bisphosphonates
        • Oral alendronate, ibandronate, risedronate, and IV zoledronic acid
        • Effective antiresorptive agents composed of two phosphate groups; contraindicated in patients with estimated glomerular filtration rate less than 30 to 35 mL/min r54
        • Alendronate, risedronate, and zoledronic acid have been shown to reduce risk of vertebral, nonvertebral, and hip fractures, while ibandronate has demonstrated efficacy only for vertebral fractures
      • Denosumab r54r72
        • Human monoclonal antibody that inhibits RANK ligand, interfering with osteoclast production and activity
        • Effectiveness is similar to that of bisphosphates and has been shown to reduce risk of both vertebral and non-vertebral fractures r70
      • SERMs (selective estrogen receptor modulator)
        • Raloxifene has efficacy in prevention and treatment of postmenopausal osteoporosis and prevention of invasive breast cancer
          • Reduces incidence of vertebral fractures but does not reduce risk of non-vertebral fractures r54
        • Bazedoxifene is used in combination with conjugated estrogens for treatment of vasomotor symptoms and prevention of bone loss r54
          • No evidence regarding fracture prevention
      • Menopausal hormone therapy r16r17r54
        • Variety of oral and transdermal preparations containing either estrogen or a combination estrogen-progestin and a range of regimens (cyclic, sequential, or continuous)
        • Combined estrogen and progestin required for females with intact uterus; estrogen alone for those who had a hysterectomy
        • No longer recommended solely to treat osteoporosis
        • May be beneficial to prescribe 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 or for prevention of osteoporosis in patients at low to moderate risk of fracture for whom osteoporosis medications are not indicated
      • Calcitonin r4r54
        • Hormone found in salmon and other fish, prevents bone breakdown
        • Reduces vertebral fracture occurrence but does not reduce the risk of non-vertebral fractures
        • Rarely used because other therapies are more effective; is largely used to ameliorate pain of vertebral fractures
    • Anabolic agents include parathyroid hormone analogs and sclerostin-binding inhibitors r5
      • These agents are more effective than bisphosphonates in preventing fractures, including vertebral fractures r73
      • Parathyroid hormone analogs
        • Teriparatide (synthetic fragment of human PTH) and abaloparatide (synthetic peptide analog of human PTH-related protein)
        • Stimulate bone formation to restore bone structure, unlike antiresorptive medications
        • Both require daily subcutaneous injection; a transdermal formulation of abaloparatide has also been shown to increase bone mineral density but effect on fracture risk has not been determined r74
      • Romosozumab
        • Human monoclonal antibody that inhibits sclerostin; it both increases bone formation and decreases bone breakdown
    • Drugs differ in amount of risk reduction, but head-to-head data is somewhat limited
      • Overall, teriparatide, abaloparatide, denosumab, and romosozumab appear more effective compared with other agents; ibandronate has lower efficacy than other bisphosphonates, and selective estrogen receptor modulators have lower efficacy than other agents r75
  • An estimate of the 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
    • Those at very high risk include those with a recent fracture, multiple fractures, any fractures during treatment, long-term glucocorticoid therapy, high risk of falls, or very high fracture probability by FRAX (Fracture Risk Assessment) tool; defined as 30% or more for major osteoporotic fracture or 4.5% or more for hip fracture) r3r4
    • All others diagnosed with osteoporosis are considered high risk r3r4
    • 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 r69
      • Individual considerations for drug therapy.Based on ACOG Committee on Clinical Practice Guidelines–Gynecology: Management of postmenopausal osteoporosis: ACOG Clinical Practice Guideline No. 2. Obstet Gynecol. 139(4):698-717, 2022; Eastell R et al: Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 104(5):1595-622, 2019
        Patient circumstanceReasonable choice of drug
        Patient with history of breast cancerBisphosphonate or denosumab
        Patient at increased risk of breast cancer and vertebral fractureRaloxifene
        Patient with recent vertebral fracturesAn anabolic agent, such as teriparatide or abaloparatide
        Patient with severe gastroesophageal reflux disease or other esophageal conditionsAn injectable therapy, such as denosumab or zoledronic acid
        Patient with chronic kidney diseaseDenosumab, carefully monitoring calcium, magnesium, and phosphorous levels
        Patient with painful vertebral fracture(s)Consider calcitonin for analgesic effects; generally prescribed only when alternatives are not suitable
  • Initial treatment
    • Initial treatment for high-risk postmenopausal patients with osteoporosis
      • Antiresorptive agents are recommended first line in all guidelines; preferred medications differ slightly among guidelines r2r3r4r5r54r68
        • Bisphosphonates and denosumab have similar efficacy r72
        • Alendronate, risedronate, zoledronic acid, and denosumab have been shown to reduce risk of both vertebral and non-vertebral fractures and are preferred over ibandronate, which lacks evidence for efficacy in prevention of hip or nonvertebral fractures r54
        • Oral bisphosphonates are often first choice agents owing to cost and ease of access r70
      • Menopausal hormone therapy is an alternative for patients aged less than 60 years or within 10 years of menopause who prioritize alleviation of menopausal symptoms r70
    • Initial treatment for very-high-risk postmenopausal patients with osteoporosis r2r3r4r5r68
      • Guidelines suggest considering anabolic agents (eg, teriparatide or romosozumab) first line for those at very high risk; preferred medications differ slightly among guidelines r71
      • American Association of Clinical Endocrinology guidelines suggest consideration of denosumab or zoledronic acid (in addition to anabolic agent) for those at very high risk of fracture
    • Initial treatment in special circumstances
      • Consider raloxifene for someone at high risk for breast cancer, with low risk of stroke or venous thromboembolic disease, particularly if spinal protection is more important than hip (eg, discordant low vertebral bone mineral density with normal hip bone mineral density) r2r3r4r5
  • Sequential treatment and treatment duration
    • Bisphosphonates are recommended for 5 years (oral) or 3 years (IV) for patients not at very high risk, with consideration of a drug holiday afterwards r2r3r4r5
      • Drug holiday refers to stopping bisphosphonate with resumption of treatment if needed later
        • Consider because longer duration of treatment is associated with increased risk of side effects and uncertain benefits; also, treatment benefits are retained for years after discontinuation of alendronate or zoledronic acid
      • Reevaluate patients after bisphosphonates are stopped (2 to 4 years in American College of Obstetricians and Gynecologists guideline; UK guideline specifies after 18 months for risedronate and ibandronate, 2 years for alendronate, and 3 years for zoledronate) or immediately if fracture occurs
        • Resume treatment for patients with new fractures, additional risk factors for fractures, significant decreases in bone mineral density, or bone turnover marker levels rising to pretreatment levels
      • Continue treatment for 10 years (oral) or 6 years (IV) before considering a drug holiday for certain very high risk patients, such as:
        • Aged 70 years or older at the time of treatment initiation
        • History of hip or vertebral fracture(s)
        • Treated with oral glucocorticoids 7.5 mg or more prednisolone/day or equivalent
        • One or more fragility fractures during the first 5 years of bisphosphonate treatment or the first 3 years of zoledronate treatment (if treatment is not changed)
    • After treatment with an anabolic agent, an antiresorptive agent is recommended r3r4r5r68r71
      • Reason for this recommendation 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, and antiresorptive medications will maintain the increase r76r77r78r79r80r81
      • After teriparatide or abaloparatide use for up to 2 years, initiate a bisphosphonate or denosumab without delay r3r5
        • Teriparatide labeling now allows for use beyond 2 years but guidelines generally recommend limiting use of parathyroid analogs to 2 years
      • After romosozumab use for up to 1 year, initiate a bisphosphonate or denosumab without delay r3r5
    • Denosumab does not have a lifetime limit for use r3r5
      • If denosumab therapy is discontinued for any reason, initiate a different antiresorptive drug to prevent rapid bone loss and vertebral fractures r11r82r83r84
        • UK guideline recommends zoledronic acid 6 months after the last injection of denosumab, with an additional dose based on CTX (C-terminal telopeptide type-I collagen) monitoring of bone turnover, or if CTX is unavailable r3
        • Another option is to transition to alendronate after denosumab, which is effective in maintaining the bone mineral density that has accrued r85
        • Switching to an anabolic agent (eg, teriparatide) after denosumab is not recommended because it is associated with loss of hip bone mineral density r86
      • 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 r87
        • Improvement in hip T-score on denosumab to a level of approximately −2 to −1.5 is associated with maximum reduction of fracture risk r87
    • If hormone therapy is used (eg, in a patient younger than 60 years, within 10 years of menopause, with vasomotor symptoms of menopause), rapid bone loss after discontinuation may be prevented by switching to an antiresorptive drug r5
  • Second line treatment r3r4r5
    • Switching from one agent to another may be considered to address practical issues such as side effects, costs, adherence, or patient preference for mode of administration
    • Patients may be switched for therapy failure, often from antiresorptive medications to anabolic agents; common criteria 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 r69
      • Having 1 or more fractures while on antiresorptive therapy, especially vertebral r69
      • Development of osteonecrosis of jaw or an atypical femoral fracture on antiresorptive therapy r69
      • Bone turnover marker decrease on antiresorptive therapy less than the least significant change r69
    • Owing to limited efficacy and risk of side effects, agents such as strontium ranelate (not available in the US) and calcitonin are only suggested in guidelines for patients who cannot tolerate other therapies
  • Risks of therapy
    • Benefit-risk ratio for osteoporosis treatment is strongly positive for most patients with osteoporosis r3r5
    • Safety concerns of antiresorptive agents
      • Atypical femoral fractures
        • Insufficiency stress fractures of the femoral shaft that present with pain in the thigh or groin after weight bearing, and are often bilateral r88
          • American College of Radiology recommends bilateral radiographs for patients on long-term bisphosphonates who develop thigh or groin pain, followed by MRI if needed r5
        • Absolute risk is very low, with incidence ranging between 1 in 100,000 and 5 in 10,000 r89
        • Risk appears to increase with more than 5 years of bisphosphonate use r90
        • Meta-analyses suggest a highly favorable benefit-risk ratio associated with treatment lasting up to 5 years in postmenopausal patients with osteoporosis r90r91
        • 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 r92
      • 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 r88
        • 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 r93
        • 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 r94
        • Routine dental care is important for preventing osteonecrosis of jaw in all patients treated with antiresorptive therapy r95
        • This condition may be treated with antibacterial mouth rinses for mild cases, but it requires surgical debridement and resection for advanced cases r95
      • Oral bisphosphonates are not well absorbed and may cause esophageal irritation; offer patients with esophageal disorders intravenous formulations r3r5
      • Avoid bisphosphonates in patients with reduced kidney function (estimated glomerular filtration rate less than 30-35 ml/min); denosumab may be used r3r5
    • Estrogen-based therapies (selective estrogen receptor modulators and hormone therapy) increase risk for venous thromboembolism and stroke r3r5
    • Safety concerns of parathyroid hormone analogs r3r5
      • Do not use these agents in patients with hypercalcemia, hypercalciuria or urolithiasis, unexplained elevated alkaline phosphatase, or Paget disease of bone
      • Research in rats found an increased risk of osteosarcoma; it is unknown whether this may be observed in humans
      • Most experts recommend limiting use of these agents to 2 years and avoiding use in those who may be at risk for osteosarcoma (eg, young patients, history of skeletal malignancy or metastasis, prior skeletal radiation, hereditary risk, metabolic bone disease such as Paget disease of bone)
    • Safety concerns of romosozumab r3r5
      • Romosozumab may increase the risk of myocardial infarction, stroke, and cardiovascular death, and has a black box warning
      • Osteonecrosis of the jaw and atypical femur fractures have also been rarely reported
  • Medications for Postmenopausal OsteoporosisAbbreviations: RANK, receptor activator of nuclear factor kappa beta; PO, orally; IV, intravenously; SC, subcutaneously; MI, myocardial infarction
    Estimated pooled relative risk reduction data from network meta-analysis is provided only for agents achieving statistical significance at a given fracture location (vertebral, hip, or nonvertebral).
    From Management of postmenopausal osteoporosis: ACOG clinical practice guideline no. 2. Obstet Gynecol. 139(4):698-717, 2022; 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; Gregson CL et al: UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos. 17(1):58, 2022.
    Drug ClassAgentIndicationEstimated Fracture Risk ReductionAdministrationRemarks
    Antiresorptive Agents
    BisphosphonateAlendronatePrevention and treatmentVertebral: 0.57
    Hip: 0.61
    Nonvertebral: 0.84
    PO, daily or weeklyShould be taken after overnight fast, with plain water, with no other food or medicine for 30 minutes afterwards, and patient must remain upright for at least 30 minutes after taking
    RisedronatePrevention and treatmentVertebral: 0.61
    Hip: 0.73
    Nonvertebral: 0.78
    PO, daily, weekly, or monthlySame instructions as for alendronate
    Zoledronic acidPrevention and treatmentVertebral: 0.38
    Hip: 0.60
    Nonvertebral: 0.79
    IV, yearlyAcute phase reaction after first dose in about one-third of patients; co-administration of acetaminophen may help
    IbandronatePrevention (PO) and treatment (PO or IV)Vertebral: 0.67PO, monthly; or IV, every 3 monthsSame instructions as for alendronate when taken orally
    Monoclonal antibody RANK ligand inhibitorDenosumabPrevention and treatmentVertebral: 0.32
    Hip: 0.56
    Nonvertebral: 0.80
    SC, every 6 monthsMultiple vertebral fracture risk upon discontinuation; transition to alternative treatment
    Selective estrogen receptor modulatorRaloxifenePrevention and treatment for patients at increased risk of breast cancerVertebral: 0.59PO, dailyRisk of venous thromboembolism
    Bazedoxifene plus conjugated estrogensPreventionVertebral: 0.61PO, dailyConsider in patients with vasomotor symptoms of menopause
    Hormone therapyEstrogen with or without progesteronePreventionVertebral: 0.65
    Hip: 0.72
    Non vertebral: 0.78
    PO, dailyConsider for patients within 10 years of menopause with vasomotor symptoms; rapid bone loss upon discontinuation; transition to alternative treatment
    CalcitoninSalmon calcitoninTreatmentVertebral: 0.65
    Hip: 0.48
    Intranasal, dailyReserved for those who cannot tolerate other therapies; used primarily for pain reduction after vertebral fracture
    Anabolic Agents
    Parathyroid hormone analogAbaloparatideTreatment of patients at very high risk of fractureVertebral: 0.14
    Nonvertebral: 0.51
    SC, dailyMaximum treatment 2 years; transition to antiresorptive therapy upon discontinuation
    TeriparatideTreatment of patients at very high risk of fractureVertebral: 0.27
    Nonvertebral: 0.62
    SC, dailyMaximum treatment 2 years; transition to antiresorptive therapy upon discontinuation
    Sclerostin-binding inhibitorRomosozumabTreatment of patients at very high risk of fractureVertebral: 0.33
    Hip: 0.44
    Nonvertebral: 0.67
    SC, monthlyMaximum treatment 1 year; transition to antiresorptive therapy upon discontinuation; black box warning for potential increased risk of MI, stroke and cardiovascular death

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 r96
  • 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 r97
  • 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 r96

Drug therapy

  • Bisphosphonates r98
    • Alendronate r4r99c95
      • 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 r100c96
      • 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 c97
      • 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 c98
      • Zoledronic Acid Solution for injection [Osteoporosis/Bone Disorders]; Adults: 5 mg IV infusion over at least 15 minutes, given once yearly. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. Continue of zolendronic acid for up to 6 years in postmenopausal women at very high risk of fracture. Consider discontinuation after 3 years of stability in high risk postmenopausal patients and after 3 to 5 years in low or moderate risk patients.
  • Monoclonal antibody RANK ligand inhibitor
    • Denosumab c99
      • 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 r11r12r82r101
      • Denosumab Solution for injection [Osteoporosis/Bone Disorders]; 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.
  • Parathyroid hormone analogues and parathyroid hormone–related protein analogues
    • Teriparatide c100c101
      • 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 c102c103
      • 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.
  • Monoclonal antibody and sclerostin inhibitor
    • Romosozumab c104
      • 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.
  • Selective estrogen receptor modulator c105
    • 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) c106
      • 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.
  • Vitamin D (cholecalciferol preferred over ergocalciferol) r2r3r4c107
    • Dietary sources preferred over routine supplementation
    • Intermittent bolus dosing not recommended (eg, high monthly or annual dose) r4
    • Maintenance, when dietary sources are insufficient or for patients with malabsorption c108
      • Vitamin D (Cholecalciferol) Oral tablet; Adults 50 years and older: 17.5 to 50 mcg (600 to 2000 International Units) PO daily. Maintain 25-hydroxyvitamin D levels of ≥20 or 30 nanograms/mL (upper limit 50 ng/mL). r4
    • Vitamin D deficiency
      • Vitamin D (Cholecalciferol) Oral tablet; Adults: 7,000 to 10,000 mcg (280,000 to 400,000 International Units) PO loading dose divided in daily or weekly doses over 6 to 10 weeks to achieve a serum vitamin D concentration more than 30 ng/mL, then 20 to 100 mcg (800 to 4,000 International Units) PO once daily or given intermittently at higher equivalent dose starting 1 month after loading. Example loading dose regimens include: 100 mcg (4,000 International Units) PO once daily for 10 weeks; 150 mcg (6,000 International Units) PO once daily for 8 weeks; 1,000 mcg (40,000 International Units) once weekly for 7 weeks; or 1,250 mcg (50,000 International Units) PO once weekly for 6 to 8 weeks.
  • Calcium r2r3r4c109
    • Calcium Oral tablet; Adult females 50 years and older: 700 to 1200 mg PO daily of elemental calcium.

Nondrug and supportive care

Nonpharmacologic interventions are important to improve bone health for postmenopausal people with osteoporosis. Do the following: r102

  • 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 (approximately 33%) risk reduction in hip fractures for those treated with both calcium and vitamin D r103
      • 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 r104
        • 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) r104
        • 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) r75r105r106
      • 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 r107r108
    • Nearly all pharmacotherapy trials included calcium and vitamin D in both intervention and control groups; therefore, all guidelines recommend intake of at least the reference level (eg, US recommended daily allowance or UK reference nutrient intake) including supplementation if not met through dietary sources r2r3r4r5
    • Recommended intakes:
      • Calcium: 700 to 200 mg/day for females older than 50 years, obtained through diet, supplements, or both (preferably through diet) r2r3r4r5r20r69
      • Vitamin D: guidelines vary from 17.5 to 50 mcg (600 to 2000 International Units)/day for adults older than 50 years, preferably through diet r2r3r4r5
        • Supplementation may be needed for those with malabsorption or living in facilities
        • Maintain serum 25-hydroxyvitamin D level of 20 nanograms/mL or more; the optimal range for 25-hydroxyvitamin D level is unknown but most experts suggest levels between 30 and 50 nanograms/mL r4
  • Advise participation in weight-bearing, resistance, and balance exercises r109c110
    • Aim for 30 to 40 minutes of walking (or other weight-bearing exercise) per session 3 to 4 days per week r4
      • For people with osteoporosis who do not have history of vertebral fractures or multiple low-trauma fractures, moderate impact exercise (eg, stamping, jogging, low-level jumping, hopping) is recommended on most days r110
      • For people with osteoporosis who have vertebral fractures or have had multiple low-trauma fractures, encouraging exercise on most days at level of intensity equivalent to brisk walking is recommended owing to theoretical risks of further vertebral fracture r110
    • Recommend 2 to 3 sessions of muscle-strengthening exercise or activities per week to maintain bone strength r110
      • Progressive muscle resistance training has greatest benefit; start at lower intensity and ensure good technique before increasing intensity level to maximum weight that can be lifted 8 to 12 times (building up to three sets for each exercise)
    • Postmenopausal females who engage in strength training can be expected to have a 2% improvement in lumbar spine bone mineral density r111
    • 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 approximately 10% r111
  • Advise measures to reduce risk of falls r2r3r4r32c111
    • Activities such as tai chi, dance, pilates, 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); recommended at least twice a week r110
    • For patients who are already having falls, professionally supervised, specific and highly challenging balance and muscle strengthening exercises are recommended (eg, Otago or Falls Management Exercise [FaME] programs) r110
    • Identify hazards in home and remove them (eg, loose rugs, objects on floor); may be more effective when performed by occupational therapist
  • Advise optimized nutritional status with balanced diet of macronutrients r3r6c112c113
    • 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) r112
  • Encourage cessation of cigarette smoking r2r3r32r113c114d3
  • Advise limitation of alcohol intake to 2 units (standard drinks) per day or less r2r3r32r114c115
Procedures c116

Comorbidities

  • Several comorbidities may increase osteoporosis severity:
    • Type 1 diabetes mellitus r115c117
    • Inflammatory bowel and joint diseases with or without glucocorticoid therapy r115c118c119
    • Celiac disease r115c120
    • Breast and prostate cancer treated with chemotherapy or hormone therapy r115c121c122

Special populations

  • Patients taking long-term glucocorticoid therapy r116
    • Increased risk of bone loss and osteoporotic fractures; fracture risk is highest for patients treated with very high doses (30 mg/day or greater) or large cumulative doses (5 g/year or greater) r116
    • Undertake clinical fracture risk assessment including symptomatic and asymptomatic fracture history, FRAX (Fracture Risk Assessment) (aged 40 years or older), and bone mineral density screening in patients who are commencing or continuing on glucocorticoid therapy 2.5 mg/day or greater for longer than 3 months r116
      • FRAX (Fracture Risk Assessment) glucocorticoid correction (multiply risk of major osteoporotic fracture by 1.15 and risk of hip fractures by 1.2) is recommended for patients taking prednisone-equivalent doses greater than 7.5 mg/day
      • Reassess fracture risk every 1 to 2 years
    • Begin bone-protective treatment at onset of glucocorticoid therapy in patients at moderate, high, or very high risk for fracture r3r116
      • This includes anyone with a prior fragility fracture, patients aged 70 years or older, postmenopausal patients aged 50 years or older prescribed 7.5 mg/day or more of prednisolone or equivalent for over 3 months, and postmenopausal patients aged 50 years or older with a FRAX (Fracture Risk Assessment) probability of major osteoporotic fracture or of hip fracture exceeding the intervention threshold
      • Bone protective treatment is not recommended for patients receiving low doses of glucocorticoids and assessed as low fracture risk r116
    • Treatment options include oral or IV bisphosphonates, denosumab, or anabolic agents r116
      • Any of these agents may be used in patients with moderate risk of fracture (no order of preference)
      • Anabolic agents or denosumab are preferred over bisphosphonates for patients at high risk of fracture
      • Consider anabolic agents, rather than antiresorptive agents, as initial therapy for patients at very high risk of fracture
      • Raloxifene and romosozumab are not generally recommended except in patients who are intolerant of other agents
  • Patients with breast cancer (or history thereof) d4
    • Evaluate any patients with breast cancer who are treated with adjuvant aromatase inhibitors, or who experience ovarian failure owing to treatment, with bone mineral density measurement at baseline and at regular intervals thereafter r117
      • History, physical examination, and biochemical testing at baseline are recommended to establish risk factors and rule out secondary causes of osteoporosis r118
      • Avoid use of the FRAX (Fracture Risk Assessment) tool to estimate fracture risk, as this tool performs poorly in patients on endocrine therapy r118
    • Use an oral or IV bisphosphonate or denosumab to maintain or improve bone mineral density and reduce fracture risk in postmenopausal (natural or induced) patients receiving adjuvant aromatase inhibitor therapy
      • Evidence for IV zoledronic acid is more robust but ibandronate and clodronate have not been shown to be inferior r118
      • Bisphosphonates provide breast cancer survival benefits along with bone protection; recommended for risk reduction of distant metastasis for 3 to 5 years in postmenopausal patients with high-risk node-negative or node-positive tumors r117r119r120
      • Denosumab is superior for fracture prevention, but evidence for anti-cancer effects is lacking; preferred when fracture prevention is foremost in patient with low risk of cancer recurrence r118r121
      • Continue treatment with bisphosphonates at least until adjuvant therapy is complete. Benefit of duration of use beyond 3 years or optimal duration beyond 3 years have not been established r117r119
        • Factors to consider for duration of antiosteoporosis therapy include bone mineral density, response to therapy, and risk factors for continued bone loss or fracture r117
    • Avoid estrogen, progesterone, and selective estrogen receptor modulators in patients with breast cancer r117

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 r122
      • Specific interval for repeating DXA varies by professional organization; most societies recommend repeating DXA after 1 to 3 years and if findings are stable, continuing follow-up with DXA every 1 to 2 years or at a less frequent interval r2r4r20
      • UK guideline recommends reassessment of fracture risk after 3 years of zoledronic acid therapy and 5 years of oral bisphosphonate therapy for most patients r3
    • 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
    • Repeat 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 if needed, to rule out an atypical femoral fracture r5c123c124c125c126
  • 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 r123
      • 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 c127
    • 60% of females with osteoporosis will experience 1 or more fragility fractures r6
      • Current pharmacotherapies reduce risk of fracture roughly by half r75
  • Hip fractures (femoral neck fractures) are the most serious complication of osteoporosis r124c128d5
    • Associated with 12% to 20% reduction in expected survival
    • Can result in poor quality of life and dependent living situation r40
  • Vertebral fractures r6c129
    • 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) r6c130
    • 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) r6c131c132c133c134d6
    • 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 r124
  • 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 r125
  • Black women diagnosed with osteoporosis are significantly less likely to receive treatment compared with White women and have higher rates of death, debility, and destitution after a major fragility fracture than White women r5

Screening and Prevention

Screening

At-risk populations

  • Cisgender females
    • 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 (Fracture Risk Assessment) tool assessment r22c135
    • Proceed with bone mineral density testing in postmenopausal females younger than 65 years based on risk profile (eg, risk factors for fracture, history of fracture after age 50 years, medical condition or use of medication associated with lowered bone mass) r8r9r54
      • 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
      • For example, one guideline recommends bone mineral density testing in patients aged 50 to 64 years who have an osteoporosis-related fracture or 2 or more clinical risk factors and in those aged 65 years and older with 1 clinical risk factor for fracture r70
    • All females aged 65 years or older should undergo bone mineral density testing regardless of other risk factors for osteoporosis r8r9r48r54r126
    • Variations
      • Osteoporosis Canada guidelines recommend bone mineral density testing in all postmenopausal females aged 70 years or older r70
      • Canadian Task Force on Preventive Health Care recommend initial application of the Canadian Clinical Fracture Risk Assessment Tool r127(FRAX) without bone mineral density in females aged 65 years or older r126
        • Proceed to bone mineral density testing and re-estimation of fracture risk based on the 10 year absolute risk of major osteoporotic fractures and patient preference for pharmacologic therapy
        • Screening postmenopausal females younger than 65 years is not recommended owing to uncertain evidence of benefit and small increased risks of treatment-related adverse events r126r128
      • Australian guidelines recommend bone mineral density testing in all patients aged 70 years or older, and in patients aged 50 years and older with a minimal trauma fracture or major risk factors or diseases associated with bone loss r71
      • An International Osteoporosis Foundation position paper proposes universal screening of postmenopausal women aged 70 years or older via a centrally-coordinated, self-administered FRAX (Fracture Risk Assessment) risk assessment questionnaire, which would trigger referral for bone mineral density testing of those identified as moderate or greater risk of fracture r129
  • Transgender patients
    • In the absence of additional data on transgender and gender non-conforming patients, screen with DXA when risk factors for low bone density are present r41r46
      • For patients on standard gender-affirming hormone treatment, there is no indication to monitor for bone loss or osteoporosis strictly on the basis of transgender or gender non-conforming status
      • For individuals with prolonged hypogonadism, baseline and follow-up bone mineral density should occur as for cisgender individuals
  • 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 r47r130r131

Screening tests

  • Screening tests for bone health and morphology include central DXA, peripheral DXA, and quantitative ultrasonography c136c137
  • 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 (Fracture Risk Assessment) tool also can be used as an adjunct to determine whether to obtain bone mineral density measurement for postmenopausal individuals aged younger than 65 years. This tool includes questions about previous DXA results but does not require this information to estimate fracture risk r18
  • 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: r2r3c138c139c140c141c142c143
    • Participating in lifelong regular physical activity, particularly weight-bearing, resistance, and balance exercises r109
    • Maintaining healthy body weight r48
    • Optimizing nutritional status throughout childhood and adolescence, in particular r48
    • 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 r132
      • To reduce fractures, encourage institutionalized older adults 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 r133
      • Metaanalysis does not support calcium or vitamin D supplementation alone, or in combination, in healthy premenopausal women to improve bone mineral density in the total hip or lumbar spine r134
    • Reducing risk of falls r15
    • Avoiding tobacco use r113d3
    • Avoiding excessive alcohol consumption r114
      • 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 r2
    • Can consider bisphosphonates to prevent bone loss in postmenopausal females with low bone mineral density (T-score less than 1) and other risk factors for fracture who do not meet criteria for osteoporosis treatment
    • Consider hormone therapy in patients within 10 years of menopause, or aged younger than 60 years, with low to moderate risk of fracture (for whom specific osteoporosis medications are not indicated) r16r17d1
      • Base hormone therapy decisions on all clinical factors (eg, vasomotor symptoms, not skeletal considerations) r17
Black DM et al: Postmenopausal osteoporosis. N Engl J Med. 374(3):254-62, 201626789873The 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, 202134448749Gregson CL et al: UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos. 17(1):58, 202235378630Camacho 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, 202032427503ACOG Committee on Clinical Practice Guidelines–Gynecology: Management of postmenopausal osteoporosis: ACOG Clinical Practice Guideline No. 2. Obstet Gynecol. 139(4):698-717, 202235594133Chapurlat RD et al: Osteoporosis. In: Jameson JL et al, eds: Endocrinology: Adult and Pediatric. 7th ed. Saunders; 2016:1184-213.e6Qu 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, 201627020004Lamy O et al: Stopping denosumab. Curr Osteoporos Rep. 17(1):8-15, 201930659428Cummings 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, 201829105841Compston 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):1117-34, 202134688418Trémollieres FA et al: Management of postmenopausal women: Collège National des Gynécologues et Obstétriciens Français (CNGOF) and Groupe d'Etude sur la Ménopause et le Vieillissement (GEMVi) clinical practice guidelines. Maturitas. 163:62-81, 202235717745"The 2022 Hormone Therapy Position Statement of The North American Menopause Society" Advisory Panel: The 2022 hormone therapy position statement of the North American Menopause Society. Menopause. 29(7):767-94, 202235797481Centre for Metabolic Bone Diseases, University of Sheffield: FRAX Fracture Risk Assessment Tool. University of Sheffield website. Accessed January 23, 2024. 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; 2007Leslie 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: The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int. 25(5):1439-43, 201424577348Siris 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, 200515728213Kanis JA et al: Algorithm for the management of patients at low, high and very high risk of osteoporotic fractures. Osteoporos Int. 31(1):1-12, 202031720707Clinical Calculators powered by ClinicalKey: Fracture Index WITH known Bone Mineral Density (BMD). ClinicalKey website. Accessed February 24, 2023. [DE: please check link -I could not open link to calculator] https://www.clinicalkey.com/#!/tools/calculators/calculator/77-s2.0-160https://www.clinicalkey.com/#!/tools/calculators/calculator/77-s2.0-160Clinical Calculators powered by ClinicalKey: Fracture Index WITHOUT known Bone Mineral Density (BMD). ClinicalKey website. Accessed February 24, 2023. [DE: please check link -I could not open link to calculator] https://www.clinicalkey.com/#!/tools/calculators/calculator/77-s2.0-161https://www.clinicalkey.com/#!/tools/calculators/calculator/77-s2.0-161ClinRisk, Ltd.: Welcome to the QFracture®-2016 risk calculator: http://qfracture.org. ClinRisk website. Accessed January 23, 2024. https://qfracture.org/https://qfracture.org/Garvan Institute of Medical Research: Fracture Risk Calculator. Garvan Institute website. Accessed January 23, 2024.https://www.garvan.org.au/promotions/bone-fracture-risk/calculator/Weber TJ: Osteoporosis. In: Goldman L et al, eds: Goldman-Cecil Medicine. 26th ed. Elsevier; 2020:1599-607.e3Tannenbaum 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, 200212049882Stevenson MO et al: Osteoporosis and bone health in transgender persons. Endocrinol Metab Clin North Am. 48(2):421-7, 201931027549Wiepjes CM et al: Fracture risk in trans women and trans men using long-term gender-affirming hormonal treatment: a nationwide cohort study. J Bone Miner Res. 35(1):64-70, 202031487065Hannan 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, 200010780863Cummings 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, 19938093403Stone 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, 200314606506Rosen HN et al: Bone densitometry in transgender and gender non-conforming (TGNC) individuals: 2019 ISCD official position. J Clin Densitom. 22(4):544-53, 201931327665International Society for Clinical Densitometry: 2023 ISCD Official Positions--Adult. ISCD website. Published August 24, 2023. Accessed January 23, 2024. https://iscd.org/learn/official-positions/adult-positions/https://iscd.org/learn/official-positions/adult-positions/Ensrud 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, 201728285014Statham L et al: Can bone turnover markers help to define the suitability and duration of bisphosphonate drug holidays? Drugs Context. 9:2020-1-3, 202032426015LeBoff MS et al: The clinician's guide to prevention and treatment of osteoporosis. Osteoporos Int. 33(10):2049-2102, 202235478046Nishizawa 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: 2022 update. J Am Coll Radiol. 19(11S):S417-32, 202236436967Shevroja E et al: Update on the clinical use of trabecular bone score (TBS) in the management of osteoporosis: results of an expert group meeting organized by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), and the International Osteoporosis Foundation (IOF) under the auspices of WHO Collaborating Center for Epidemiology of Musculoskeletal Health and Aging. Osteoporos Int. 34(9):1501-1529, 202337393412Shevroja 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. Published December 2018. Reviewed February 2020. Accessed January 23, 2024. 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.e4Rosen 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, 200312533652Bell 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, 201424452511Conley RB et al: Secondary fracture prevention: consensus clinical recommendations from a multistakeholder coalition. J Bone Miner Res. 35(1):36-52, 202031538675Qaseem A et al: Pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults: a Living clinical guideline from the American College of Physicians. Ann Intern Med. 176(2):224-38, 202336592456Eastell R et al: Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 104(5):1595-622, 201930907953Morin SN et al: Clinical practice guideline for management of osteoporosis and fracture prevention in Canada: 2023 update. CMAJ. 195(39):E1333-E1348, 202337816527Position Statement on the Management of Osteoporosis. Healthy Bones Australia. Published February 2023. Accessed January 23, 2024. https://healthybonesaustralia.org.au/wp-content/uploads/2023/02/position-statement-on-osteoporosis-february-2023.pdfhttps://healthybonesaustralia.org.au/wp-content/uploads/2023/02/position-statement-on-osteoporosis-february-2023.pdfMoe S et al: Osteoporosis in postmenopausal women. Can Fam Physician. 67(5):346, 202133980628Händel MN et al: Fracture risk reduction and safety by osteoporosis treatment compared with placebo or active comparator in postmenopausal women: systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials. BMJ. 381:e068033, 202337130601Lewiecki EM et al: Efficacy and Safety of Transdermal Abaloparatide in Postmenopausal Women with Osteoporosis: A Randomized Study. J Bone Miner Res. 38(10):1404-1414, 202337417725Barrionuevo 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, 201930907957Black 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, 200516093464Cosman F et al: Treatment sequence matters: anabolic and antiresorptive therapy for osteoporosis. J Bone Miner Res. 32(2):198-202, 201727925287Rittmaster RS et al: Enhancement of bone mass in osteoporotic women with parathyroid hormone followed by alendronate. J Clin Endocrinol Metab. 85(6):2129-34, 200010852440Grey A et al: Maintaining order in osteoporosis treatments. J Bone Miner Res. 32(5):1147, 201728294409Anastasilakis AD et al: Combination and sequential treatment in women with postmenopausal osteoporosis. Expert Opin Pharmacother. 21(4):477-90, 202031990595Lukert BP: Which drug next? Sequential therapy for osteoporosis. J Clin Endocrinol Metab. 105(3):dgaa007, 202031922566Makras 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):e4155-62, 202133978745Anastasilakis 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, 201931433518Anastasilakis 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, 201728240371Kendler 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, 201930919997Black 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, 201425234529Ebeling 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, 201627544377Allen 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 GA et al: Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev. 5:CD004523, 202235502787Makras 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, 201931860103Zhao 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, 201729279934Tang 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, 200717720017Bischoff-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, 201626747333Sanders 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, 201020460620Howe TE et al: Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev. 7:CD000333, 201121735380Brooke-Wavell K et al: Strong, steady and straight: UK consensus statement on physical activity and exercise for osteoporosis. Br J Sports Med. 56(15):837-46, 202235577538Kelley 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, 201021211745Humphrey MB et al: 2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol. 75(12):2088-2102, 202337845798National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 5.2023. NCCN website. Updated December 5, 2023. Accessed January 23, 2024. https://www.nccn.orghttps://www.nccn.orgWaqas K et al: Updated guidance on the management of cancer treatment-induced bone loss (CTIBL) in pre- and postmenopausal women with early-stage breast cancer. J Bone Oncol. 28:100355, 202133948427Trémollieres FA et al: Osteoporosis management in patients with breast cancer: EMAS position statement. Maturitas. 95:65-71, 201727802892Early 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, 201526211824Gnant M et al: Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 386(9992):433-43, 201526040499Shoback D et al: Pharmacological management of osteoporosis in postmenopausal women: an Endocrine Society guideline update. J Clin Endocrinol Metab. 105(3):e255-64, 202032068863Naylor 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, 201525481833Thériault G et al: Recommendations on screening for primary prevention of fragility fractures. CMAJ. 195(18):E639-E649, 202337156553Canadian Clinical FRAX risk assessment toolhttps://frax.shef.ac.uk/FRAX/tool.aspx?country=19Gates M et al: Screening for the primary prevention of fragility fractures among adults aged 40 years and older in primary care: systematic reviews of the effects and acceptability of screening and treatment, and the accuracy of risk prediction tools. Syst Rev. 12(1):51, 202336945065Chotiyarnwong P et al: Is it time to consider population screening for fracture risk in postmenopausal women? A position paper from the International Osteoporosis Foundation Epidemiology/Quality of Life Working Group. Arch Osteoporos. 17(1):87, 202235763133Lim 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, 200919285200Osteoporosis Prevention, Screening, and Diagnosis: ACOG Clinical Practice Guideline No. 1. Obstet Gynecol. 138(3):494-506, 202134412075US 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 January 23, 2024. 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, 202134670754Méndez-Sánchez L et al: Calcium and vitamin D for increasing bone mineral density in premenopausal women. 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