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Postmenopausal Osteoporosis

Synopsis
Terminology
Diagnosis
Treatment
Complications and Prognosis
Screening and Prevention

Aug.07.2024

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 ^r2^r3
Preferred initial pharmacologic agents for most patients with postmenopausal osteoporosis at high risk of fracture are bisphosphonates or denosumab ^r2^r3^r4^r5
Preferred initial pharmacologic agents for most patients with postmenopausal osteoporosis at very high risk of fracture are anabolic agents ^r2^r3^r4^r5
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-fold^r7
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 ^r8^r9

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 ^r11^r12
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) ^r3^r5

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 ^r16^r17
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 FRAX^r18 (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: ^r2^r4^r14^r23^r24^r25^r26
- 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 ^r3^r27
- 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.
High risk	Very 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 greater	Recent fracture, within past 12 months
T-score between -1 and -2.5 and history of fragility fracture of hip or spine	Fractures during approved osteoporosis therapy
Any patient with an osteoporosis diagnosis who does not meet criteria for very high risk as defined in this table	Multiple 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 with^r28/without known BMD^r29, UK-based Qfracture-2016 risk calculator^r30, Australia-based Garvan Institute of Medical Research fracture risk calculator^r31) 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 ^r32^c2
- 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 ^r6^c3^c4
- 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 ^r32^c5^c6^c7^c8^c9^c10
- Patients may also present with back "tiredness," which improves when they sit or lie down ^r32^c11
  - 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 ^r32^c12^c13

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 ^r32^c14
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) ^c15^c16^c17
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 ^r35^c19^c20
  - 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 ^r15^r36
- 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 ^r36^c27^c28^c29^c30^c31^c32
- 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 ^c44^c45^c46^c47
- 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 ^r38^c60^c61

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 ^r39^c62
- 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 ^c63^c64^c65
- 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 ^c66^c67^c68^c69

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 ^r41^r42

Genetics

Peak bone mass, which is reached in early adult life, primarily depends on genetic factors ^r6^c70
- 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 ^r3^c71

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 ^r6^c72^c73^c74

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 ^r3^r15^c79
Diagnostic criteria
- A diagnosis of osteoporosis in postmenopausal patients may be met in several ways, with slight variation in guidelines ^r2^r4
  - 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) tool^r18
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 ^r21^r44^r45
  - 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) ^r46^r47
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 ^r3^r27
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: ^r3^r4
  - 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 ^r46
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 ^r3^r6
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 ^r3^r4^c80^c81^c82^c83
Bone turnover markers ^r53^c84
- 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 ^c85^c86
- DXA of lumbar spine, total hip, and proximal femur is the preferred method for diagnosis ^r21^r44^r45
  - 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 ^r3^c87^c88
- 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 ^r6^r46
- Test utilizing DXA with additional software to evaluate vertebral morphology from thoracic (T5) to lower lumbar spine (L5), where most vertebral fractures occur ^r57^c89^c90
- 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 ^r6^c91
- 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 ^r58^r59^c92
- 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 ^r59
- 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 ^r63^c94
  - 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: ^r66^r67
- 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 ^r3^r5^r54^r68

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: ^r3^r4^r5^r17^r54^r69^r71
- 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 ^r54^r72
    - 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 ^r16^r17^r54
    - 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 ^r4^r54
    - 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) ^r3^r4
All others diagnosed with osteoporosis are considered high risk ^r3^r4

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.
Patient circumstance	Reasonable choice of drug
Patient with history of breast cancer	Bisphosphonate or denosumab
Patient at increased risk of breast cancer and vertebral fracture	Raloxifene
Patient with recent vertebral fractures	An anabolic agent, such as teriparatide or abaloparatide
Patient with severe gastroesophageal reflux disease or other esophageal conditions	An injectable therapy, such as denosumab or zoledronic acid
Patient with chronic kidney disease	Denosumab, 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 ^r2^r3^r4^r5^r54^r68
    - 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 ^r2^r3^r4^r5^r68
  - 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) ^r2^r3^r4^r5
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 ^r2^r3^r4^r5
  - 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 ^r3^r4^r5^r68^r71
  - 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 ^r76^r77^r78^r79^r80^r81
  - After teriparatide or abaloparatide use for up to 2 years, initiate a bisphosphonate or denosumab without delay ^r3^r5
    - 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 ^r3^r5
- Denosumab does not have a lifetime limit for use ^r3^r5
  - If denosumab therapy is discontinued for any reason, initiate a different antiresorptive drug to prevent rapid bone loss and vertebral fractures ^r11^r82^r83^r84
    - 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 ^r3^r4^r5
- 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 ^r3^r5
- 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 ^r90^r91
    - 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 ^r3^r5
  - Avoid bisphosphonates in patients with reduced kidney function (estimated glomerular filtration rate less than 30-35 ml/min); denosumab may be used ^r3^r5
- Estrogen-based therapies (selective estrogen receptor modulators and hormone therapy) increase risk for venous thromboembolism and stroke ^r3^r5
- Safety concerns of parathyroid hormone analogs ^r3^r5
  - 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 ^r3^r5
  - 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 Osteoporosis
Drug Class	Agent	Indication	Estimated Fracture Risk Reduction	Administration	Remarks
Antiresorptive Agents
Bisphosphonate	Alendronate	Prevention and treatment	Vertebral: 0.57 Hip: 0.61 Nonvertebral: 0.84	PO, daily or weekly	Should 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
	Risedronate	Prevention and treatment	Vertebral: 0.61 Hip: 0.73 Nonvertebral: 0.78	PO, daily, weekly, or monthly	Same instructions as for alendronate
	Zoledronic acid	Prevention and treatment	Vertebral: 0.38 Hip: 0.60 Nonvertebral: 0.79	IV, yearly	Acute phase reaction after first dose in about one-third of patients; co-administration of acetaminophen may help
	Ibandronate	Prevention (PO) and treatment (PO or IV)	Vertebral: 0.67	PO, monthly; or IV, every 3 months	Same instructions as for alendronate when taken orally
Monoclonal antibody RANK ligand inhibitor	Denosumab	Prevention and treatment	Vertebral: 0.32 Hip: 0.56 Nonvertebral: 0.80	SC, every 6 months	Multiple vertebral fracture risk upon discontinuation; transition to alternative treatment
Selective estrogen receptor modulator	Raloxifene	Prevention and treatment for patients at increased risk of breast cancer	Vertebral: 0.59	PO, daily	Risk of venous thromboembolism
	Bazedoxifene plus conjugated estrogens	Prevention	Vertebral: 0.61	PO, daily	Consider in patients with vasomotor symptoms of menopause
Hormone therapy	Estrogen with or without progesterone	Prevention	Vertebral: 0.65 Hip: 0.72 Non vertebral: 0.78	PO, daily	Consider for patients within 10 years of menopause with vasomotor symptoms; rapid bone loss upon discontinuation; transition to alternative treatment
Calcitonin	Salmon calcitonin	Treatment	Vertebral: 0.65 Hip: 0.48	Intranasal, daily	Reserved for those who cannot tolerate other therapies; used primarily for pain reduction after vertebral fracture

Anabolic Agents
Parathyroid hormone analog	Abaloparatide	Treatment of patients at very high risk of fracture	Vertebral: 0.14 Nonvertebral: 0.51	SC, daily	Maximum treatment 2 years; transition to antiresorptive therapy upon discontinuation
	Teriparatide	Treatment of patients at very high risk of fracture	Vertebral: 0.27 Nonvertebral: 0.62	SC, daily	Maximum treatment 2 years; transition to antiresorptive therapy upon discontinuation
Sclerostin-binding inhibitor	Romosozumab	Treatment of patients at very high risk of fracture	Vertebral: 0.33 Hip: 0.44 Nonvertebral: 0.67	SC, monthly	Maximum 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 ^r4^r99^c95
  - 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 ^r100^c96
  - 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 ^r11^r12^r83^r101
  - 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 ^c100^c101
  - Teriparatide Solution for injection; Adults: 20 mcg subcutaneously once daily. Supplement calcium and vitamin D if dietary intake is inadequate.
- Abaloparatide ^c102^c103
  - 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) ^r2^r3^r4^c107
- 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: 150 mcg (6,000 International Units) PO once daily or 1,250 mcg (50,000 International Units) PO once weekly for at least 8 weeks to achieve a serum vitamin D concentration more than 30 ng/mL, then 25 to 50 mcg (1,000 to 2,000 International Units) PO once daily or 1,250 mcg (50,000 International Units) PO once monthly.
Calcium ^r2^r3^r4^c109
- 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) ^r75^r105^r106
  - 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 ^r107^r108
- 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 ^r2^r3^r4^r5
- Recommended intakes:
  - Calcium: 700 to 200 mg/day for females older than 50 years, obtained through diet, supplements, or both (preferably through diet) ^r2^r3^r4^r5^r20^r69
  - 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 ^r2^r3^r4^r5
    - 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 ^r109^c110
- 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 ^r2^r3^r4^r32^c111
- 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 ^r3^r6^c112^c113
- 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 ^r2^r3^r32^r113^c114^d3
Advise limitation of alcohol intake to 2 units (standard drinks) per day or less ^r2^r3^r32^r114^c115

Procedures ^c116

Comorbidities

Several comorbidities may increase osteoporosis severity:
- Type 1 diabetes mellitus ^r115^c117
- Inflammatory bowel and joint diseases with or without glucocorticoid therapy ^r115^c118^c119
- Celiac disease ^r115^c120
- Breast and prostate cancer treated with chemotherapy or hormone therapy ^r115^c121^c122

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 ^r3^r116
  - 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 ^r117^r119^r120
  - 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 ^r118^r121
  - 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 ^r117^r119
    - 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 ^r2^r4^r20
  - 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 ^r5^c123^c124^c125^c126
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 ^r124^c128^d5
- Associated with 12% to 20% reduction in expected survival
- Can result in poor quality of life and dependent living situation ^r40
Vertebral fractures ^r6^c129
- 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) ^r6^c130
- 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) ^r6^c131^c132^c133^c134^d6
- 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 ^r22^c135
- 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) ^r8^r9^r54
  - 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 ^r8^r9^r48^r54^r126
- 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 ^r126^r128
  - 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 ^r41^r47
  - 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 ^r46^r130^r131

Screening tests

Screening tests for bone health and morphology include central DXA, peripheral DXA, and quantitative ultrasonography ^c136^c137
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.
Screening test	Description of technique	Considerations
Central DXA	Most 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 spine	Most treatment guidelines recommend using BMD, as measured by central DXA, to define osteoporosis and the treatment threshold to prevent osteoporotic fractures
Peripheral DXA	Uses radiation to measure BMD at peripheral sites, such as distal forearm and heel; accuracy is similar to that of central DXA	Measured with portable devices; no treatment studies have used BMD measured by peripheral DXA to define treatment thresholds
QUS	Uses 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: ^r2^r3^c138^c139^c140^c141^c142^c143
- 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 ^r113^d3
- 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) ^r16^r17^d1
  - Base hormone therapy decisions on all clinical factors (eg, vasomotor symptoms, not skeletal considerations) ^r17

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Postmenopausal Osteoporosis

Synopsis

Key Points

Pitfalls

Terminology

Clinical Clarification

Classification

Diagnosis

Clinical Presentation

History

Physical examination

Causes and Risk Factors

Causes

Risk factors and/or associations

Age

Sex

Genetics

Ethnicity/race

Other risk factors/associations r43

Diagnostic Procedures

Primary diagnostic tools

Laboratory

Imaging

Differential Diagnosis

Most common

Treatment

Goals

Disposition

Recommendations for specialist referral

Treatment Options

Drug therapy

Nondrug and supportive care

Procedures c116

Comorbidities

Special populations

Monitoring

Complications and Prognosis

Complications

Prognosis

Screening and Prevention

Screening

At-risk populations

Screening tests

Prevention

Other risk factors/associations ^r43

Procedures ^c116