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Synopsis
Terminology
Diagnosis
Treatment
Complications and Prognosis
Screening and Prevention

Feb.24.2022

Postmenopausal Osteoporosis

Synopsis

Key Points

Osteoporosis is a systemic skeletal disease involving low bone mass and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and consequent increased fracture risk ^r1
Diagnosis of postmenopausal osteoporosis may be met in 1 of 4 ways:
- Bone mineral density t score of −2.5 or less in the lumbar spine, femoral neck, total hip, and/or distal third of radius
- Presence of fragility fracture in absence of other metabolic bone disease, even with normal bone density
- Bone mineral density t score from −1 to −2.5 and a fragility fracture of proximal humerus, pelvis, or distal forearm
- Bone mineral density t score from −1 to −2.5 and elevated 10-year risk of hip or major osteoporotic fracture using FRAX (Fracture Risk Assessment Tool)
Bone mineral density test results determine whether a patient has normal bone density, osteopenia, osteoporosis, or severe osteoporosis
- Preferred method for diagnosis of osteoporosis is DXA applied to femoral neck
Lifestyle measures to improve bone health include increasing weight-bearing and resistance physical activity, reducing fall risk, ensuring proper nutritional status with adequate calcium and vitamin D intake, stopping smoking, and moderating alcohol intake ^r2
Preferred initial pharmacologic agents for most patients with postmenopausal osteoporosis at high risk of fracture include alendronate, denosumab, risedronate, and zoledronic acid (to reduce the risk for hip and vertebral fractures) ^r3^r4^r5
Preferred initial pharmacologic agents for most patients with postmenopausal osteoporosis at very high risk of fracture include abaloparatide, denosumab, teriparatide, and zoledronic acid
Complications of osteoporosis include fractures of hip (femoral neck), vertebrae, wrist, and pelvis ^r6
Osteoporosis is associated with elevated rates of mortality; for each standard deviation decrease in bone mineral density, mortality risk increases 1.17-fold^r7
Screening for osteoporosis is suggested for all postmenopausal patients aged 50 years or older using history, examination, and FRAX score; bone mineral density testing is suggested for those aged 65 years or older ^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

Terminology

Clinical Clarification

Osteoporosis is a systemic skeletal disease involving low bone mass and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and consequent increased fracture risk ^r13
- Compromised bone strength reflects the integration of bone density and bone quality ^r14
  - Bone density corresponds to the amount of mineral within a volume, and bone quality depends on architecture, bone turnover, bone matrix composition, damage accumulation, and mineralization ^r15
Osteoporosis develops silently over years before it becomes apparent through bone mineral density screening or fractures
- Fragility fractures are the main physical manifestation and occur at diverse sites such as the proximal femur, vertebral bodies, and distal radius
A formal diagnosis of osteoporosis is made in a postmenopausal patient when 1 or more of the following criteria are met:
- Bone mineral density t score of −2.5 or less in the lumbar spine, femoral neck, total hip, and/or distal third of radius
- Fragility fracture of the spine or hip, in the absence of metabolic bone disease, regardless of bone mineral density
- Bone mineral density t score between −1 and −2.5 and a fragility fracture of the proximal humerus, pelvis, or distal forearm
- Osteopenia or low bone mass (t score from −1 to −2.5) and high FRAX^r16 (Fracture Risk Assessment Tool) score, such as high probability of fracture
Fractures are associated with serious clinical consequences, including pain, disability, loss of independence, and death
- Most major fractures are associated with reduced relative survival, with an impact persisting more than 5 years after the event ^r17
  - Major osteoporotic fractures are fractures that occur at spine, proximal femur, distal forearm, and proximal humerus. Other skeletal sites are prone to fragility fractures, including pelvis, ribs, and proximal tibia ^r18

Classification

Osteoporosis is commonly classified operationally on the level of bone mass, measured as bone mineral density ^r2
- Risk of fracture increases approximately 2-fold for each 1 standard deviation decrease in bone mineral density ^r19
WHO definitions of osteopenia and osteoporosis are traditionally used for making decisions about health policy ^r20
- Normal bone health: bone mineral density value more than 1 standard deviation below young adult female reference mean (t score −1 or more)
- Osteopenia: bone mineral density value more than 1 but less than 2.5 standard deviations below that of young adult female reference mean (t score less than −1 and greater than −2.5)
- Osteoporosis: bone mineral density value 2.5 or more standard deviations below that of young female adult reference mean (t score −2.5 or less)
  - Within the category of osteoporosis, WHO identifies an additional subset of severe based on very high risk of fracture: ^r20
    - Severe osteoporosis: bone mineral density value 2.5 standard deviations or more below that of young female adult reference mean (t score of −2.5 or less) and 1 or more documented fragility fractures
Additional defining criteria for osteoporosis beyond bone mineral density measurements have been proposed and adopted. These include: ^r21^r22^r23^r24
- Low-trauma spine or hip fracture, regardless of bone mineral density
- Low bone mineral density that falls within the range for osteopenia (ie, t score between −1.1 and −2.5) and fragility fracture of proximal humerus, pelvis, or distal forearm
- Low bone mineral density that falls within the range for osteopenia (ie, t score between −1.1 and −2.5) and high FRAX score based on country-specific thresholds

Newly proposed classifications use a set of clinical predictors to further estimate the level of risk of fracture in patients with established (diagnosed) osteoporosis

Stratification of osteoporosis severity, according to high-risk and very-high-risk features, assists with selection of first line therapy and also suggests length of therapy ^r4
- Very-high-risk category meets definition for osteoporosis and 1 of the following: ^r4
  - Recent fracture (within past 12 months)
  - Fractures even while on approved osteoporosis therapy
  - Multiple fractures
  - Glucocorticoid use
  - t score less than −3
  - High risk of falls
  - History of injurious falls
  - FRAX probabilities of more than 30% for a major osteoporosis fracture or more than 4.5% for hip fracture
- High-risk category meets definition for osteoporosis but does not have indicators of very high risk ^r4

Risk stratification for selection and duration of therapy.
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 more or hip fracture risk of 3% or more	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

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 ^r25^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 ^r25
Vertebral fractures are the most common form of osteoporotic fracture
- New vertebral fractures, even those not recognized clinically, are associated with substantial increases in back pain and limited mobility ^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 ^r25^c5^c6^c7^c8^c9^c10
- Patients also may present with back "tiredness," which improves when they sit or lie down ^r25^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 ^r25^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 ^r25^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) ^r25
- 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 ^r26

Causes and Risk Factors

Causes

Postmenopausal osteoporosis is a complex disease with a multifactorial origin ^r27
- Adult bone mass is determined by 2 processes: acquisition of peak bone mass during adolescence and subsequent bone loss after maturity
- Changes in bone mass result from physiologic and pathophysiologic processes in the bone remodeling cycle, and ultimately this can lead to skeletal fragility ^r28
- Abrupt decline of estrogen levels at menopause causes loss of bone and contributes to development of osteoporosis ^r28^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^r29
- Endocrine disorders
  - Hypogonadism ^c21
  - Hyperthyroidism ^c22
  - Hyperparathyroidism ^c23
  - Diabetes mellitus ^c24
  - Hypopituitarism ^c25
- Glucocorticoid medications ^c26
  - Glucocorticoid-induced osteoporosis is the most common secondary form of the disease ^r30
  - Consistent evidence indicates that glucocorticoids impair bone formation ^r6
  - With oral corticosteroids (eg, prednisone), increased fracture risk starts with dosages as low as 2.5 mg/day ^r30
  - Increased fracture risk partially offsets on cessation of therapy but not back to baseline ^r30
- Other medications
  - Medications that may cause or contribute to osteoporosis include anticonvulsants, aromatase inhibitors, methotrexate and other chemotherapeutic agents, heparin, and cyclosporine ^r29^c27^c28^c29^c30^c31^c32
- Autoimmune diseases
  - Rheumatoid arthritis ^c33
  - Ankylosing spondylarthritis ^c34
  - Systemic lupus erythematosus ^c35
  - Inflammatory bowel disease ^c36
- Diseases resulting in malabsorption ^c37
  - Celiac disease ^c38
  - Gastrectomy ^c39
- Conditions associated with immobilization
  - Parkinson disease ^c40
  - Poliomyelitis ^c41
  - Cerebral palsy ^c42
  - Paraplegia ^c43
- Bone marrow disorders, including myeloproliferative disorders (eg, multiple myeloma, leukemia) and anemias ^c44^c45^c46^c47
- Disorders of connective tissues
  - Osteogenesis imperfecta ^c48
  - Marfan syndrome ^c49
- Other
  - Pompe disease ^c50
  - Gaucher disease ^c51
  - Total parenteral nutrition ^c52
  - Homocystinuria ^c53
  - Hypercalciuria ^c54
  - Mastocytosis ^c55
  - Hemochromatosis ^c56
  - Anorexia nervosa ^c57
  - Chronic liver diseases ^c58
  - Turner syndrome ^c59
Pregnancy and lactation are stressors of calcium homeostasis and can (uncommonly) contribute to osteopenia or osteoporosis ^r31^c60^c61

Risk factors and/or associations

Age

In the United States, it is estimated that more than 10 million Americans older than 50 years have osteoporosis ^r32^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 about a 50% risk of any osteoporotic fracture ^r33
- By age 80 years, 27% of females have low bone mass (osteopenia) alone, and 70% have osteoporosis at hip, spine, or forearm ^c66^c67^c68^c69

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 ^r25
- Bone mass at a given age is a function of the achieved peak bone mass and of the amount of bone lost later through menopause, aging, disease processes, or medications; therefore, the level that can be achieved at the end of bone growth is critical for future risk of fracture
Parental history of hip fracture is a significant risk factor for future fracture that is largely independent of bone mineral density ^r2^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 ^r34

Alcohol use ^c75
Tobacco use ^c76
Physical inactivity ^c77
High caffeine intake ^c78

Diagnostic Procedures

Primary diagnostic tools

Diagnosis of osteoporosis is assigned using a combination of history, measurement of bone mineral density by DXA, and estimation of fracture risk using the FRAX tool of the University of Sheffield ^r2^r15^c79
Diagnostic criteria
- A diagnosis of osteoporosis in postmenopausal patients may be met in 1 or more of 4 ways: ^r4^r14^r21^r24
  - Bone mineral density that is 2.5 standard deviations or more below the young adult mean for females (ie, t score of −2.5 or less) at the lumbar spine, femoral neck, total hip, or distal third of radius
  - Presence of fragility fracture at spine or hip, in the absence of other metabolic bone disease, even with normal bone density
  - Bone mineral density t score between −1 and −2.5 and a fragility fracture of proximal humerus, pelvis, or distal forearm
  - Bone mineral density t score between −1 and −2.5 and increased 10-year risk of fracture using FRAX tool^r16
Bone mineral density measurement
- Bone mineral density measurement can be used to determine categories of normal bone density, osteopenia, or osteoporosis
  - Bone mineral density measurements also are used in monitoring response to therapy
  - Bone mineral density testing is indicated for all postmenopausal patients with risk factors for low bone mineral density or fracture ^r35
- DXA of lumbar spine, total hip, and proximal femur is the preferred method for diagnosis ^r19^r36^r37
Fragility fracture history (present or earlier)
- Fragility fracture is one that is sustained from a force similar to a fall from a standing position or less that would not occur in healthy bone
- Documentation of a fragility fracture at any of certain sites (ie, spine, hip, proximal humerus, pelvis, distal forearm) meets criteria for osteoporosis regardless of bone mineral density measurements
  - Bone mineral density testing is still indicated for these patients, to be used for monitoring purposes
Fracture risk assessment
- Perform risk assessment on all patients at time of initial evaluation for osteoporosis; this assessment is warranted even for those that meet the diagnostic criteria by virtue of bone mineral density or fracture history
- FRAX tool computes an estimate of 10-year probability of hip fracture or a major osteoporotic fracture ^r2
  - It is an internet-accessible computerized algorithm that uses country-specific data on clinical risk factors and femoral neck bone mineral density to calculate fracture probability
    - Calculation also may be performed without data entered for the values obtained from bone mineral density testing
  - Risk score is based on the following parameters: age, sex, weight, height, previous fracture, parental history of hip fracture, smoking status, glucocorticoid use, rheumatoid arthritis, secondary osteoporosis, alcohol intake, and (where available) femoral neck bone mineral density ^r38
  - FRAX score predicts 10-year probability of hip fracture and major osteoporosis fracture (major fractures include hip, spine, humerus, and forearm)
  - From history and physical examination plus FRAX score, recommendations can be made about whether pharmacologic intervention is appropriate
- FRAX shortcomings
  - FRAX score underestimates risk of all future fractures, given that it estimates only for hip and major fractures, which comprise about half of all fragility fractures ^r39
  - FRAX score underestimates risk for patients with multiple prior fractures, those with recent fracture, those whose lumbar spine bone mineral density is much less than at femoral neck, those with secondary osteoporosis, those with diabetes, and those at high risk of falls ^r40
    - For patients with diabetes, rheumatoid arthritis may be entered into the FRAX algorithm as a surrogate to adjust for the elevated risk ^r41
Evaluation for causes of secondary osteoporosis
- An evaluation is indicated for all females diagnosed with postmenopausal osteoporosis to identify coexisting medical conditions that cause or contribute to bone loss
  - Undiagnosed metabolic bone and mineral diseases are present in about one-third of females with osteoporosis ^r26
  - Common secondary causes include hyperparathyroidism, hypercalciuria, calcium malabsorption, vitamin D deficiency, and hyperthyroidism ^r26
- Routine laboratory investigation of osteoporosis needs to include CBC, serum chemistry panel (with levels of calcium, albumin, total protein, creatinine, phosphate, alkaline phosphatase, and liver transaminases), thyroid function tests, and 25-hydroxyvitamin D level ^r4
- 24-hour urine collection for calcium, sodium, and creatinine levels is also recommended to assess for calcium malabsorption or hypercalciuria
- Additional tests beyond the aforementioned ones may be helpful, depending on initial results, and may be useful in considering unusual secondary causes or conditions in the differential diagnosis. They include: ^r2^r4
  - Serum intact parathyroid hormone level, for possible hyperparathyroidism
  - Thyroid function tests, for possible hyperthyroidism
  - Tissue transglutaminase antibodies test, for suspected celiac disease
  - Serum protein electrophoresis and free kappa and lambda light chains test, for suspected multiple myeloma
  - 24-hour urine free cortisol test or 1 mg overnight dexamethasone suppression test, for suspected endogenous hypercortisolemia
  - Serum tryptase or urine N-methylhistidine test, for mastocytosis
Evaluate for prevalent vertebral fractures
- Vertebral fracture assessment is densitometric spine imaging performed for the purpose of detecting vertebral fractures that might otherwise go unidentified ^r42
  - Detecting vertebral fractures requires specific imaging techniques that can be done at same time as DXA
  - Finding vertebral fractures, regardless of results of bone mineral density testing or FRAX score, meets a criterion for the diagnosis of osteoporosis
- Indications for vertebral fracture assessment include advanced age, history of height loss, use of systemic glucocorticoid therapy, and self-reported but undocumented prior vertebral fracture ^r43
Utility of bone turnover markers
- Bone turnover markers are not used for diagnosis, but baseline levels are sometimes obtained before start of therapy because they can be useful for initial evaluation and for monitoring response to therapy
  - Elevated levels can predict more rapid rates of bone loss
  - High bone turnover levels are associated with increased fracture risk independent of bone mineral density
- Bone turnover markers respond quickly to therapy, and comparing levels over time can allow for insights into drug adherence and absorption
- Most useful bone turnover markers are PINP (N-propeptides of type I collagen), which derive from bone formation osteoblast products, and CTX (C-terminal cross-linking telopeptides of type 1 collagen), which derive from bone resorption products of collagen degradation

Laboratory

Laboratory tests are most helpful when a secondary cause of osteoporosis is suspected or to identify conditions in the differential diagnosis ^r2^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 ^r4^c80^c81^c82^c83
Bone turnover markers ^r44^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
- Bone turnover markers can be measured in serum, plasma, and urine, and their levels relate to the activity of osteoblasts (bone formation markers) and osteoclasts (bone resorption markers)
  - Bone formation markers include proteins that are rather specific to bone (eg, osteocalcin) and those that are less specific to bone, such as PINP (N-propeptide of type I collagen, fragments of type I procollagen released during formation of type I collagen) and bone ALP (the bone isoform of alkaline phosphatase)
  - Bone resorption markers include fragments released from the telopeptide region of type I collagen after its enzymatic degradation, including NTX (N-telopeptide of type I collagen) and CTX (C-terminal cross-linking telopeptides of type 1 collagen), deoxypyridinoline, and tartrate-resistant acid phosphatase
  - In cohort studies of females, the higher the bone turnover marker levels, the more rapid the bone loss and the greater the risk of fracture
- Interpretation of results
  - Suppression of bone resorption markers is seen on initiation of bisphosphonate therapy, whereas with treatment cessation, bone resorption marker levels increase; the changes in bone mineral density lag far behind
    - An appropriate level of CTX (C-terminal cross-linking telopeptides of type 1 collagen) or bone resorption marker suppression is at or below a healthy premenopausal mean; the lower half of the premenopausal reference intervals have been used as a target for those on bisphosphonate therapy and gives an indication of appropriate suppression of bone turnover by bisphosphonate
    - Another criterion for response evaluation is whether the minimum significant changes are exceeded; minimum significant changes are twice the mean morning day-to-day variation seen in premenopausal people ^r45
  - Increased levels of bone formation markers in response to anabolic therapy are reassurance that the drug is effective
- Practical issues
  - Ideally, blood sample for bone turnover markers is collected in early morning in fasting state
  - Avoid collecting specimen during acute phase after a fracture
  - Some bone turnover markers are affected by renal impairment, whereas others are unaffected

Imaging

DXA ^c85^c86
- DXA of lumbar spine, total hip, and proximal femur is the preferred method for diagnosis ^r19^r36^r37
  - Central DXA, measuring axial sites, is preferred over peripheral DXA for diagnosis, although distal third of radius also may be used as an alternative diagnostic site if central sites are unavailable ^r46
  - Femoral neck is the site with the highest predictive value for fracture risk ^r2
  - Spine is ideal site for assessing treatment response, provided that lumbar spine does not have significant degenerative or artifactual changes that render it invalid for analysis ^r2
- DXA is also the preferred method by which to monitor bone mineral density over time ^r47
- DXA results are categorized by WHO diagnostic criteria for osteopenia and osteoporosis ^r20
  - Normal: bone mineral density value more than 1 standard deviation below young adult female reference mean (t score −1 or more)
  - Osteopenia: bone mineral density value more than 1 but less than 2.5 standard deviations below that of young adult female reference mean (t score less than −1 and greater than −2.5)
  - Osteoporosis: bone mineral density value 2.5 or more standard deviations below that of young female adult reference mean (t score −2.5 or less)
Quantitative CT and quantitative ultrasonography ^c87^c88
- Alternative techniques to assess bone mineral density
  - Ultrasonography (often of calcaneus) is portable and is sometimes used in nonclinical settings (eg, community health fairs)
  - Peripheral bone density measurement methods can identify patients at increased risk for fracture, but the DXA diagnostic criteria established by WHO and supported by multiple professional society guidelines apply only to axial measurements ^r2^r3^r4^r18
Vertebral fracture assessment ^r6^r43
- Test evaluating vertebral morphology that uses either lateral lumbar and thoracic spine radiographs or lateral spine DXA from upper thoracic to lower lumbar spine ^c89^c90
  - It is a useful study in some cases to identify patients at risk whose bone mineral density may be above treatment thresholds ^r47
- Significant loss in vertebral height may be indicative of vertebral fracture, which can be missed using DXA alone ^r6
- Lateral spine imaging with standard radiography or densitometric vertebral fracture assessment is indicated when t score is less than −1 and of 1 or more of the following factors are present: ^r42
  - Females aged 70 years or older; males aged 80 years or older
  - Historical height loss greater than 4 cm
  - Self-reported but undocumented prior vertebral fracture
  - Glucocorticoid therapy equivalent to 5 mg or more of prednisone or equivalent per day for 3 months or longer
  - Kyphosis
Skeletal radiography ^r6^c91
- Anteroposterior and lateral views are required for both the thoracic and lumbar spine to evaluate potential vertebral fractures
- Vertebral fractures include wedge deformities, end-plate (biconcave) deformities, and compression (or crush) fractures
- Vertebrae from T4 to L4 are graded on visual inspection as follows:
  - Normal (grade 0)
  - Mildly deformed (grade 1: 20%-25% loss in anterior, middle, and/or posterior height)
  - Moderately deformed (grade 2: 25%-40% loss in anterior, middle, and/or posterior height)
  - Severely deformed (grade 3: 40% or more loss in anterior, middle, and/or posterior height)
Trabecular bone score ^r48^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 to predict fracture
- High scores indicate homogeneous, normal bone and reduce the FRAX estimated risk, whereas low scores correlate with weaker bone texture and increase the FRAX risk
- Adjusting FRAX interpretation with trabecular bone score has the greatest clinical utility in people whose fracture risk is close to the therapeutic intervention threshold. For example:
  - A low trabecular bone score in a female with osteopenia might lead to favoring treatment with a pharmacologic agent
  - A high trabecular bone score in a female with diabetes might also favor pharmacologic intervention

Differential Diagnosis

Most common

Osteomalacia ^c93
- Condition defined by impaired skeletal mineralization, usually due to low calcium or phosphorus levels
- Vitamin D deficiency is one of the most common causes of osteomalacia; most patients with mild to moderate vitamin D deficiency are asymptomatic ^d1
- Patients with osteomalacia may present with musculoskeletal pain, bony tenderness, hyperalgesia or paresthesia, proximal muscle weakness, waddling gait, history of fracture, and coexisting hypocalcemia ^r49
- Classic findings of osteomalacia on plain radiographs are pseudofractures (radiolucent bands) ranging from a few millimeters to a few centimeters in length, most visible near the femoral neck or pelvis ^r50
- Differentiated from osteoporosis by clinical presentation in the setting of a low serum level of 25-hydroxyvitamin D, calcium, or phosphorus ^r51
Pathologic fractures due to other causes
- Malignant vertebral compression fractures can be caused by metastatic cancers or primary tumors of bone ^r52^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) can provide additional information, as guided by radiologist evaluations ^r52
- Acute (less than 2 weeks) and subacute (2 weeks to 3 months) benign vertebral compression fractures often have large areas of MRI signal alteration or increased metabolism on nuclear medicine scans; these areas can mimic malignancy ^r53
- Chronic (more than 3 months) benign vertebral compression fractures have small areas of usually linear signal alteration and show restoration of fatty marrow and normal metabolism ^r53
- MRI findings suggestive of metastatic vertebral compression fracture are as follows: expansion of fractured vertebral body, epidural and/or paraspinal soft tissue mass, abnormal signal intensity of pedicle or posterior element, epidural mass, encasing epidural mass, and other spinal metastasis ^r54
- MRI findings suggestive of acute osteoporotic vertebral compression fracture are as follows: a band of low signal intensity on T1- and T2-weighted images, preservation of normal bone marrow signal intensity, retropulsion of a posterior bone fragment, and multiple levels of compression fractures ^r54

Treatment

Goals

Prevent fragility fractures ^r14
Maintain quality of life ^r14

Disposition

Recommendations for specialist referral

Patients with any of the following factors may benefit from referral to endocrinologists or other physicians with expertise in osteoporosis: ^r55^r56
- Fracture or significant ongoing loss of bone mineral density despite adherence to first line therapy
- Complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease)
- Unusual features including young age or abnormal laboratory test results (eg, low phosphorus level)
- Artifacts on DXA that are unexplained

Treatment Options

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

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

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

Indications for pharmacologic therapy

Pharmacotherapy to reduce fracture risk is indicated in most patients with formal diagnosis of osteoporosis and/or in the following circumstances: ^r3^r4
- t score of −2.5 or less (ie, or worse) in spine, femoral neck, total hip, or distal third of radius
- t score from −1 down to −2.5 in spine, femoral neck, total hip, or distal third of radius and fragility fracture of spine or hip
- t score from −1 down to −2.5 in spine, femoral neck, total hip, or distal third of radius and FRAX score shows that 10-year probability of a major osteoporotic fracture is 20% or more or that 10-year probability of hip fracture is 3% or more

Pharmacotherapy

3 major classes of drugs are antiresorptive agents, parathyroid hormone analogues or parathyroid hormone–related protein analogues, and monoclonal antibodies

Choice of therapy is individualized according to patient's clinical situation and the trade-off between benefits and harms

Although there is general guidance on the selection of a drug according to risk of fracture (high or very high), it is important to weigh risks, benefits, and patient preferences and to consider individual patient circumstances when selecting a drug ^r3

Individual considerations for drug therapy.
Patient circumstance	Reasonable choice of drug
Female with history of breast cancer	Bisphosphonate or denosumab
Female with recent vertebral fractures	An anabolic agent, such as teriparatide or abaloparatide
Female with severe gastroesophageal reflux disease	An injectable therapy, such as denosumab or zoledronic acid
Any patient with chronic kidney disease stage 4	Denosumab, carefully monitoring for hypocalcemia
Female with painful vertebral fracture(s)	Calcitonin is optional for analgesic effects

Menopausal hormone therapy is no longer recommended to treat osteoporosis; however, it may be beneficial to prescribe on a short-term basis in specific circumstances, such as in people younger than 60 years or within 10 years of menopause who are in need of therapies to treat vasomotor symptoms of menopause ^r57^r58

Initial treatment for high-risk postmenopausal people with osteoporosis
- Preferred medications for initial treatment include alendronate, denosumab, risedronate, and zoledronate ^r4
- Alternative medications for initial treatment include ibandronate and raloxifene, which are appropriate when reduction of hip fracture risk is a lower priority ^r4
- Intranasal calcitonin has weak antifracture efficacy and is largely used to ameliorate pain of vertebral fractures ^r59^r60
Initial treatment for very-high-risk postmenopausal people with osteoporosis
- Females at very high risk include those with a recent fracture, multiple fractures, fractures during treatment, long-term glucocorticoid therapy, high risk of falls, or very high fracture probability by FRAX (defined as 30% or more for major osteoporotic fracture or 4.5% or more for hip fracture)
- Preferred medications for initial treatment include abaloparatide, denosumab, teriparatide, or zoledronate ^r4
  - Romosozumab is highly effective for preventing fractures, but some experts reserve it as a second line option in the near term because there is a black box warning regarding the possible association of an elevated risk for cardiovascular events found in initial clinical trials ^r61
- Alternative medications for initial treatment for very-high-risk category include alendronate and risedronate ^r4

The various drug classes yield differing amounts of risk reduction

Pharmacologic agents and expected fracture reduction.
Drug class	Drug	Reduction in vertebral fracture risk (%)	Reduction in hip fracture risk (%)	Reduction in nonvertebral fracture risk (%)
Bisphosphonates
	Alendronate	44	40	17
	Risedronate	36	26	20
	Ibandronate	31	—	—
	Zoledronate	56	42	18
Monoclonal antibodies
	Denosumab	68	39	19
	Romosozumab	73	—	—
Estrogens or selective estrogen receptor modulators
	Menopausal hormone therapy	34	29	21
	Raloxifene	40	—	—
	Bazedoxifene	39	—	—
Parathyroid hormone analogues or parathyroid hormone–related protein analogues
	Teriparatide	74	—	—
	Abaloparatide	87	—	—
Other
	Calcitonin	46*	—	—

Romosozumab for osteoporosis
- Romosozumab represents a new class of drug, a humanized monoclonal antibody directed against sclerostin, which is a protein secreted by osteocytes to reduce bone formation
  - It has an early anabolic effect along with some antiresorptive properties
- Romosozumab is indicated for females with history of osteoporotic fracture, those with multiple risk factors for fracture, those who cannot take other osteoporosis medications, and those for whom other osteoporosis therapies have failed
  - It is also useful for patients who were previously treated with a parathyroid hormone analogue for maximum duration but still need anabolic effect, as well as for patients who are receiving injectable antiresorptive therapy but have poor treatment response (as shown by worsening bone mineral density or by fracture that occurs during pharmacotherapy)
- In the FRAME trial, postmenopausal people with t score of −2.5 to −3.5 for total hip or femoral neck who were treated with romosozumab for 12 months showed a 73% lower risk of new vertebral fracture compared with placebo
- In the ARCH trial, postmenopausal people with osteoporosis and a fragility fracture who were treated with romosozumab for 12 months and then treated with alendronate showed a 48% lower risk of new vertebral fracture compared with alendronate alone
  - Females in the study arm assigned to romosozumab had a 19% lower risk of nonvertebral fracture and 38% lower risk of hip fracture
  - Risk of serious cardiovascular events was higher for females receiving romosozumab (2.5%) compared with alendronate (1.9%)

Drugs for treatment and prevention of osteoporosis.
Drug class and agent	Route of administration and frequency	Proven site of fracture risk reduction	Remarks
Bisphosphonates
Alendronate	Oral, once daily or weekly	Vertebral, nonvertebral, hip	For oral route, all bisphosphonates must be taken with a full glass of water and the patient must refrain from ingesting any other medications or food for 30 minutes and remain upright for 30-60 minutes
Risedronate	Oral, once daily, weekly, or monthly	Vertebral, nonvertebral, hip	Same precautions as for oral alendronate
Ibandronate	Oral once weekly or IV every 3 months	Vertebral	Same precautions as for oral alendronate
Zoledronic acid	IV once yearly	Vertebral, nonvertebral, hip	Acute phase response possible after first dose in about one-third of patients
Monoclonal antibodies (biologics)
Denosumab	Subcutaneous every 6 months	Vertebral, nonvertebral, hip	Multiple vertebral fracture risk upon discontinuation
Romosozumab	Subcutaneous every month for up to 1 year	Vertebral, nonvertebral, hip	Boxed warning for cardiovascular events
Parathyroid hormone receptor agonists
Teriparatide	Subcutaneous daily, up to 2 years	Vertebral, nonvertebral	Black box warning about risk of osteosarcoma (seen in rodents)
Abaloparatide	Subcutaneous daily, up to 2 years	Vertebral, nonvertebral
Selective estrogen receptor modulators
Raloxifene	Oral once daily	Vertebral	Risk of venous thromboembolism
Bazedoxifene*	Oral once daily
Estrogens/menopausal hormone therapy
Conjugated equine estrogen	Oral once daily	Vertebral, nonvertebral, hip	Risk of breast cancer and venous thromboembolism
Estradiol	Oral once daily or transdermal once weekly	No data	Risk of breast cancer and venous thromboembolism
Other
Calcitonin	Intranasal once daily	Vertebral	May be useful for ameliorating pain of fractures

Sequence of therapy

Some experts advise that the optimal treatment sequence for patients with severe osteoporosis is initiation with an anabolic agent followed by an antiresorptive agent ^r62
- Reason for this preference is that when anabolic drugs are used before antiresorptive drugs, bone mineral density will increase much faster and will attain a greater level, particularly in spine ^r63^r64^r65^r66

Risks of therapy

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

Duration of therapy

Duration depends on which drug is used, and sequential therapy with another drug class is often advisable
- Bisphosphonates
  - Duration of therapy is ideally 5 to 10 years; if bone loss progresses or there are recurrent fractures, consider switching to a parathyroid hormone analogue or romosozumab ^r4
- Parathyroid hormone analogues or parathyroid hormone–related protein analogues
  - Duration of therapy is 2 years maximum, usually followed by transition to an oral or injectable antiresorptive agent ^r4
- Monoclonal antibody therapies
  - Denosumab: can be indefinite and ideally is used until the patient is no longer at high risk. If denosumab is discontinued, ensure that it is followed by another antiresorptive drug to prevent high risk for rapid loss of bone mineral density and risk of multiple vertebral fractures ^r12^r67
  - Romosozumab: duration of therapy is 1 year maximum, followed by transition to bisphosphonate or denosumab ^r4

Drug holidays

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

Drug discontinuations

Upon discontinuation of an anabolic osteoporosis drug, start therapy with an antiresorptive agent to prevent decline in bone mineral density
- Bone accrued during treatment with monoclonal antibody therapies (biologics) and parathyroid hormone analogues is lost rapidly after their withdrawal owing to rebound increase in bone resorption ^r68
- Limit treatment with abaloparatide and teriparatide to 2 years, usually followed by bisphosphonate or denosumab therapy
- Limit treatment with romosozumab to 1 year, followed by a drug intended for long-term use (eg, bisphosphonate, denosumab)
Denosumab can be given indefinitely, but discontinuations are reasonable if acceptable targets are reached or by patient preference for another form of therapy
- After stopping denosumab, the treatment effect rapidly diminishes if an antiresorptive agent is not started, and the risk of fractures returns to baseline, and possibly higher for vertebral fractures ^r67
- Several options are available to prescribe after a course of denosumab
  - One option is a single IV infusion of zoledronate given 6 months after denosumab. It has potent antifracture benefits, prevents bone loss for at least 2 years, and has a convenient dosing schedule ^r69^r70
  - Another option is to transition to alendronate after denosumab, which is effective in maintaining the bone mineral density that has accrued ^r71
  - Switching to an anabolic agent (eg, teriparatide) after denosumab is not recommended because it is associated with loss of hip bone mineral density ^r72
- Generally, drug holiday is not appropriate for denosumab; however, if a patient treated with denosumab reaches an acceptable target bone mineral density, changing the type of drug therapy can be considered
  - Improvement in hip t score on denosumab to a level of about −2 to −1.5 is associated with maximum reduction of fracture risk ^r73

Other circumstances under which to consider switching therapy

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

Surgical intervention

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

Safety concerns of antiresorptive therapy

Atypical femoral fractures
- Insufficiency stress fractures of the femoral shaft that present with pain in the thigh or groin after weight bearing ^r76
- Absolute risk is very low, with incidence ranging between 1 in 100,000 and 5 in 10,000 ^r77
- Risk appears to increase with more than 5 years of bisphosphonate use ^r78
- Meta-analyses suggest a highly favorable benefit-risk ratio associated with treatment lasting up to 5 years in postmenopausal patients with osteoporosis ^r78^r79
- Risk may be reduced by taking a holiday from oral bisphosphonates after 5 years and from IV bisphosphonates after 3 years, as appropriate for patients who are at low or moderate risk of future fractures ^r80
Osteonecrosis of jaw
- Nonhealing wound in the oral mucosa with exposed bone, lasting at least 2 months, that usually occurs in association with an invasive dental procedure ^r76
- Absolute risk in patients with more than 4 years of antiresorptive therapy is low, with an estimate of 1 event in 10,000 to 100,000 patient-years ^r81
- Incidence is greatest in patients with cancer, where high doses of these medications are used at frequent intervals; other risk factors include concomitant glucocorticoid use, diabetes, and poor oral hygiene ^r82
- Routine dental care is important for preventing osteonecrosis of jaw in all patients treated with antiresorptive therapy ^r83
- This condition may be treated with antibacterial mouth rinses for mild cases, but it requires surgical debridement and resection for advanced cases ^r83

Drug therapy

Vitamin D ^r2^r84^c95
- Cholecalciferol ^c96
  - Vitamin D (Cholecalciferol) Oral tablet; Adults: 1000 to 2000 International Units PO daily. Maintain 25-hydroxyvitamin D levels of 30 to 50 nanograms/mL. ^r4
Calcium ^r2^r84^c97
- Calcium Oral tablet; Adult females 50 years and older: 1000 to 1200 mg PO daily of elemental calcium. ^r4
Antiresorptive agents
- Bisphosphonates ^r85
  - Alendronate ^r4^r86^c98
    - 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 ^r87^c99
    - Risedronate also has a coated formulation which may be taken after breakfast (Atelvia)
    - Weekly dosing
      - Risedronate Sodium Oral tablet, weekly; Adult postmenopausal females: 35 mg PO once weekly. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. For those patients at low risk for fracture, consider stopping risedronate after 3 to 5 years.
    - Monthly dosing
      - Risedronate Sodium Oral tablet; Adult postmenopausal females: 150 mg PO once monthly. An alternative once-monthly regimen is 75 mg PO on 2 consecutive days each month (for a total of 150 mg each month). Supplement calcium and vitamin D if dietary intake is inadequate. Continue for up to 10 years in postmenopausal women with very high risk of fracture. Consider discontinuation after 5 years of stability in high risk postmenopausal women and after 3 to 5 years in low or moderate risk patients.
  - Ibandronate ^c100
    - Monthly oral dosing
      - Ibandronate Sodium Oral tablet, monthly; Adult postmenopausal females: 150 mg PO once monthly on the same date each month. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. Continue for up to 10 years in postmenopausal women with very high risk of fracture. Consider discontinuation after 5 years of stability in high risk postmenopausal women and after 3 to 5 years in low or moderate risk patients.
    - Every 3 months IV dosing
      - Ibandronate Sodium Solution for injection; Adult postmenopausal females : 3 mg IV (over 15 to 30 seconds) every 3 months. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. Continue for up to 10 years in postmenopausal women with very high risk of fracture. Consider discontinuation after 5 years of stability in high risk postmenopausal women and after 3 to 5 years in low or moderate risk patients.
  - Zoledronic acid ^c101
    - Zoledronic Acid Solution for injection [Reclast]; Postmenopausal females: 5 mg IV infused once yearly. Supplement calcium and vitamin D daily if dietary intake is inadequate. Periodically reevaluate the need for continued therapy. For those patients determined to be at low risk of fracture, consider stopping treatment after 3 to 5 years. After discontinuation of therapy, periodically reevaluate the fracture risk.
- Denosumab ^c102
  - Rapid loss of bone mineral density and increase in fracture risk (including risk of multiple vertebral fractures) occurs upon discontinuation of denosumab; transitioning to antiresorptive therapy 6 months after denosumab discontinuation is advisable to maintain gains in bone mineral density at the lumbar spine ^r11^r12^r70^r88
  - Denosumab Solution for injection; Adults: 60 mg subcutaneously once every 6 months. All patients should receive a minimum of 1,000 mg of calcium and at least 10 mcg (400 international units) of vitamin D daily. If a dose is missed, administer as soon as possible and schedule future injections every 6 months from that date.
Selective estrogen receptor modulator ^c103
- Raloxifene
  - Raloxifene Hydrochloride Oral tablet; Adult postmenopausal females: 60 mg PO once daily. Supplement calcium and vitamin D if dietary intake inadequate. Other agents are usually preferred as first-line treatments. Raloxifene may be appropriate in patients requiring spine-specific efficacy.
- Bazedoxifene (with estrogen) ^c104
  - Approved by the FDA for prevention, but not treatment, of osteoporosis
  - Conjugated Estrogens, Bazedoxifene Oral tablet; Adult postmenopausal females: 1 tablet (conjugated estrogens 0.45 mg; bazedoxifene 20 mg) PO once daily. Only for women at significant risk of osteoporosis; carefully consider non-estrogen medication before using estrogen-based treatment. Supplement calcium and vitamin D if dietary intake inadequate. Reassess use periodically.
Anabolic agents
- Parathyroid hormone analogues and parathyroid hormone–related protein analogues
  - Teriparatide ^c105^c106
    - 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 ^c107^c108
    - Abaloparatide Solution for injection; Adult postmenopausal females: 80 mcg subcutaneously once daily. Cumulative use of abaloparatide for more than 2 years during a patient's lifetime is not recommended. Supplement calcium and vitamin D if dietary intake is inadequate. Usually reserved for those with known history of osteoporotic fracture or those with higher risk for such fractures.
Combined anabolic/antiresorptive therapy
- Romosozumab ^c109
  - Romosozumab Solution for injection; Adult postmenopausal females: 210 mg subcutaneously once monthly. Limit duration to 12 months. Supplement calcium and vitamin D if dietary intake is inadequate.

Nondrug and supportive care

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

Ensure adequate intake of dietary calcium and vitamin D
- Efficacy of calcium and vitamin D supplements for preventing osteoporotic fractures is controversial owing to conflicting results from clinical trials, leading to some uncertainty about optimal doses and regimens
  - One randomized trial in older females who were nursing home residents found a large (about 33%) risk reduction in hip fractures for those treated with both calcium and vitamin D ^r90
  - A recent systematic review and meta-analysis found that using vitamin D supplements alone does not reduce risk of fractures, but daily supplementation with both vitamin D and calcium does reduce fractures ^r91
    - This systematic review found that use of both vitamin D (daily doses of 400-800 international units) and calcium (daily doses of 1000-1200 mg) resulted in a 6% reduced risk of any fracture (relative risk, 0.94; 95% confidence interval, 0.89-0.99) and a 16% reduced risk of hip fracture (relative risk, 0.84; 95% confidence interval, 0.72-0.97) ^r91
    - Other systematic reviews have found reductions in hip fractures with vitamin D and calcium supplementation, but use of these supplements has not been found to reduce other types of fractures (eg, vertebral or nonhip fractures) ^r92^r93^r94
  - 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 ^r95^r96
- Recommended intakes:
  - Calcium: 1200 mg/day for females older than 50 years, obtained through diet, supplements, or both (preferably through diet) ^r3^r18
  - Vitamin D: 1000 to 2000 international units/day for adults older than 50 years to maintain serum 25-hydroxyvitamin D level of 30 nanograms/mL or more
    - There is some debate about the preferable range for 25-hydroxyvitamin D level, but most experts suggest levels between 30 and 50 nanograms/mL
Advise participation in weight-bearing, resistance, and balance exercises ^r97^c110
- Aim for 30 to 40 minutes of walking (or other weight-bearing exercise) per session 3 to 4 days per week ^r4
- Postmenopausal females who engage in strength training can be expected to have a 2% improvement in lumbar spine bone mineral density ^r98
- One meta-analysis determined that improvements in lumbar spine and femoral neck bone mineral density after exercise interventions could reduce the 20-year osteoporosis fracture risk at any site by about 10% ^r98
Advise measures to reduce risk of falls ^r2^r25^c111
- Balance programs such as tai chi and yoga may be helpful to improve balance, increase muscle tone, and reduce fall risk in older adults (eg, those aged 65 years or older)
- Identify hazards in home and remove them (eg, loose rugs, objects on floor)
Advise optimized nutritional status with balanced diet of macronutrients ^r2^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) ^r99
Encourage cessation of cigarette smoking ^r2^r25^r100^c114^d2
Advise limitation of alcohol intake to 2 units (standard drinks) per day or less ^r2^r25^r101^c115

Procedures ^c116

Comorbidities

Several comorbidities may increase osteoporosis severity:
- Type 1 diabetes mellitus ^r102^c117
- Inflammatory bowel and joint diseases with or without glucocorticoid therapy ^r102^c118^c119
- Celiac disease ^r102^c120
- Breast and prostate cancer treated with chemotherapy or hormone therapy ^r102^c121^c122

Special populations

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

Monitoring

Monitoring treatment responses
- For postmenopausal patients who are being treated for osteoporosis, obtain bone mineral density by DXA at spine and hip approximately every 1 to 3 years ^r5
  - Specific interval for repeating DXA varies by professional organization; most societies recommending the repeat DXA after 1 to 3 years and if findings are stable, then continued follow-up with DXA every 1 to 2 years or at a less frequent interval ^r4^r18
  - Both UK and American College of Physicians guidelines suggest less frequent treatment reviews
    - UK guideline recommends reevaluation of treatment after 3 years of zoledronic acid therapy and 5 years of oral bisphosphonate therapy ^r2^c123^c124
      - If treatment is discontinued, reassess fracture risk after a new fracture, regardless of when it occurs; if no new fracture occurs, reassess fracture risk after 18 months to 3 years ^r2^c125
    - American College of Physicians guideline recommends against bone density monitoring in females during the 5-year pharmacologic treatment period for osteoporosis ^r57^c126
  - An alternative way of identifying suboptimal response or poor adherence to therapy is to measure bone turnover marker levels
    - Use serum C-terminal cross-linking telopeptide for antiresorptive therapy or procollagen type N-terminal propeptide for bone anabolic therapy
- Repeated vertebral imaging is advisable if there is documented height loss, new back pain, or postural change
- For patients on long-term bisphosphonate therapy who present with thigh or groin pain, it is advisable to obtain bilateral hip radiographs, followed by MRI, to rule out an atypical femoral fracture ^r47^c127^c128^c129^c130
Monitoring after withdrawal of bisphosphonates
- Measurement of bone turnover marker levels after withdrawal of bisphosphonates is a potentially helpful method to evaluate patients who are taking a pause from treatment at a point before measurement of bone mineral density becomes useful ^r109
  - An increase in bone turnover marker levels more than the least significant change or reference mean reflects loss of treatment effect and identifies patients who are likely to have a decrease in bone mineral density
- For patients who have begun a bisphosphonate holiday, reassess fracture risk at 2- to 4-year intervals with DXA
  - Consider resuming osteoporosis drug therapy earlier than the 5-year suggested holiday duration if there is a significant decline in bone mineral density, an intervening fracture, or other factors that alter risk (eg, glucocorticoid use)

Complications and Prognosis

Complications

Fragility fractures ^c131
- 60% of females with osteoporosis will experience 1 or more fragility fractures ^r6
  - Current pharmacotherapies reduce risk of fracture roughly by half ^r93
Hip fractures (femoral neck fractures) are the most serious complication of osteoporosis ^r110^c132^d4
- Associated with 12% to 20% reduction in expected survival
- Can result in poor quality of life and dependent living situation ^r33
Vertebral fractures ^r6^c133
- 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^c134
- 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^c135^c136^c137^c138^d5
- Also associated with increased subsequent mortality

Prognosis

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

Screening and Prevention

Screening

At-risk populations

All postmenopausal females aged 50 years or older should undergo comprehensive assessment for osteoporosis and fracture risk, using detailed history, examination, and (for most) FRAX tool assessment ^r20^c139
All females aged 65 years or older should undergo bone mineral density testing regardless of other risk factors for osteoporosis ^r38
- For postmenopausal females younger than 65 years, consider factors associated with increased risk of osteoporotic fractures to determine whether to proceed to bone mineral density testing ^r8^r9
  - Although risk of osteoporosis and osteoporotic fractures generally increases with age, presence of multiple risk factors at a younger age may indicate that the risk-benefit profile is favorable for screening with bone measurement testing
    - These risk factors include parental history of hip fracture, smoking, excessive alcohol consumption, and low body weight
Suggested screening populations are similar among guidance documents from International Society for Clinical Densitometry, American College of Obstetricians and Gynecologists, and American College of Preventive Medicine ^r43^r112

Screening tests

Screening tests for bone health and morphology include central DXA, peripheral DXA, and quantitative ultrasonography ^c140^c141
Central DXA is the most commonly used bone measurement test used to screen for osteoporosis
- Central DXA measures bone mineral density at hip and lumbar spine
Peripheral DXA measures bone mineral density at distal forearm and heel
Quantitative ultrasonography also evaluates peripheral sites and does not involve radiation exposure; however, it does not measure bone mineral density
FRAX tool also can be used as an adjunct to determine whether to obtain bone mineral density measurement for postmenopausal females younger than 65 years. This tool includes questions about previous DXA results but does not require this information to estimate fracture risk ^r16

Screening tests for osteoporosis.
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^c142^c143^c144^c145^c146^c147
- Participating in lifelong regular physical activity, particularly weight-bearing, resistance, and balance exercises ^r97
- Maintaining healthy body weight ^r38
- Optimizing nutritional status throughout childhood and adolescence, in particular ^r38
- Ensuring adequate intake of calcium and vitamin D, preferably through diet rather than supplements
  - In community-dwelling, postmenopausal females, US Preventive Services Task Force recommends against daily supplementation with vitamin D and calcium for primary prevention of fractures ^r113
  - To reduce fractures, institutionalized older adults should be encouraged to increase their intake of dairy products or calcium rich foods if dietary calcium intake is estimated to be less than 1200 mg per day ^r114
- Reducing risk of falls ^r15
- Avoiding tobacco use ^r100^d2
- Avoiding excessive alcohol consumption ^r101
  - Postmenopausal females should limit alcohol to no more than 2 drinks daily; 1 drink is equivalent to 120 mL of wine, 30 mL of liquor, or 260 mL of beer
Pharmacotherapy ^r35
- Can consider bisphosphonates to prevent bone loss in postmenopausal females with low bone mineral density (t score lower than 1) and other risk factors for fracture who do not meet criteria for osteoporosis treatment

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