Postmenopausal Osteoporosis

History

• Osteoporosis is asymptomatic in absence of a fracture; it is usually diagnosed on routine screening or after a fracture occurs ^c1
• History of fracture with minimal trauma (ie, fragility) is strongly suggestive of osteoporosis ^r32c2
  • Fragility fracture is defined as a fracture sustained from force similar to a fall from a standing position or less that would not have occurred in healthy bone ^r32
• Vertebral fractures are the most common form of osteoporotic fracture
  • New vertebral fractures, even those not recognized clinically, are associated with substantial increases in back pain and limited mobility ^r6c3c4
  • A vertebral fracture may occur after a fall or a spinal flexion-loading event; patients might report hearing a "pop" and complain of sharp midline back pain, possibly radiating to the flanks ^{r32c5c6c7c8c9c10}
  • Patients may also present with back "tiredness," which improves when they sit or lie down ^r32c11
    • This symptom is likely related to paraspinal weakness or spasm from abnormal spinal curvature that occurs with chronic vertebral compression
• Hip fractures also commonly occur with falls, although these fractures rarely may occur with limited force such as twisting ^r32c12c13

Physical examination

• Complete examination of the spine includes measuring height and assessing pain, paraspinal muscle contraction, thoracic kyphosis, lumbar lordosis, scoliosis, and the gap between the costal margin and iliac crest. Also evaluate for the abdominal protrusion that can occur with multiple vertebral fractures ^r15
• A kyphotic deformity of the upper thoracic spine may be present; it is important to distinguish it from accentuated cervical lordosis with associated prominence of T1 ^r32c14
• Measured height loss of more than 4 cm since young adult maximum height is suggestive of prior vertebral fractures; it is best measured with a calibrated device (eg, stadiometer) ^r32
  • Height loss also occurs with scoliosis and aging (approximately 0.8 cm of height is lost each decade after age 50 years) ^c15c16c17
• Acute vertebral compression fracture can cause spinal tenderness to palpation and percussion ^c18
• Physical examination also may find underlying processes contributing to secondary osteoporosis
  • Common secondary causes include hyperparathyroidism, hypercalciuria, calcium malabsorption, vitamin D deficiency, and hyperthyroidism ^r33

Causes

• Postmenopausal osteoporosis is a complex disease with a multifactorial origin ^r34
  • Adult bone mass is determined by 2 processes: acquisition of peak bone mass during adolescence and subsequent bone loss after maturity
  • Changes in bone mass result from physiologic and pathophysiologic processes in the bone remodeling cycle, and ultimately this can lead to skeletal fragility ^r35
  • Abrupt decline of estrogen levels at menopause causes loss of bone and contributes to development of osteoporosis ^r35c19c20
    • Menopause induces accelerated bone loss within 5 to 8 years, followed by a linear rate of bone loss that accelerates after age 75 years ^r6
• Numerous diseases and treatments may cause or contribute to osteoporosis, either as comorbid primary diseases or as causes of secondary osteoporosis ^r15r36
  • Endocrine disorders
    • Hypogonadism ^c21
    • Hyperthyroidism ^c22
    • Hyperparathyroidism ^c23
    • Diabetes mellitus ^c24
    • Hypopituitarism ^c25
  • Glucocorticoid medications ^c26
    • Glucocorticoid-induced osteoporosis is the most common secondary form of the disease ^r37
    • Consistent evidence indicates that glucocorticoids impair bone formation ^r6
    • With oral corticosteroids (eg, prednisone), increased fracture risk starts with dosages as low as 2.5 mg/day ^r37
    • Increased fracture risk partially offsets on cessation of therapy but not back to baseline ^r37
  • Other medications
    • Medications that may cause or contribute to osteoporosis include anticonvulsants, aromatase inhibitors, methotrexate and other chemotherapeutic agents, heparin, and cyclosporine ^{r36c27c28c29c30c31c32}
  • Autoimmune diseases
    • Rheumatoid arthritis ^c33
    • Ankylosing spondylarthritis ^c34
    • Systemic lupus erythematosus ^c35
    • Inflammatory bowel disease ^c36
  • Causes of malabsorption ^c37
    • Celiac disease ^c38
    • Gastrectomy ^c39
  • Conditions associated with immobilization
    • Parkinson disease ^c40
    • Poliomyelitis ^c41
    • Cerebral palsy ^c42
    • Paraplegia ^c43
  • Bone marrow disorders, including myeloproliferative disorders (eg, multiple myeloma, leukemia) and anemias ^c44c45c46c47
  • Connective tissue disorders
    • Osteogenesis imperfecta ^c48
    • Marfan syndrome ^c49
  • Other
    • Pompe disease ^c50
    • Gaucher disease ^c51
    • Total parenteral nutrition ^c52
    • Homocystinuria ^c53
    • Hypercalciuria ^c54
    • Mastocytosis ^c55
    • Hemochromatosis ^c56
    • Anorexia nervosa ^c57
    • Chronic liver diseases ^c58
    • Turner syndrome ^c59
• Pregnancy and lactation are stressors of calcium homeostasis and can (uncommonly) contribute to osteopenia or osteoporosis ^r38c60c61

Risk factors and/or associations

Primary diagnostic tools

• Diagnosis of osteoporosis is assigned using a combination of history, measurement of bone mineral density by DXA, and estimation of fracture risk using the FRAX (Fracture Risk Assessment) tool of the University of Sheffield ^r3r15c79
• Diagnostic criteria
  • A diagnosis of osteoporosis in postmenopausal patients may be met in several ways, with slight variation in guidelines ^r2r4
    • Bone mineral density that is 2.5 standard deviations or more below the young adult mean for females (ie, T-score of −2.5 or less) at the lumbar spine, femoral neck, total hip, or distal third of radius
    • Presence of fragility fracture at spine or hip in the absence of other metabolic bone disease, even with normal bone density
    • Bone mineral density T-score between −1 and −2.5 and a fragility fracture of proximal humerus, pelvis, or distal forearm
    • Bone mineral density T-score between −1 and −2.5 and history of multiple fractures at other sites, excluding face, feet, and hands ^r2
    • Bone mineral density T-score between −1 and −2.5 and increased 10-year risk of fracture using FRAX (Fracture Risk Assessment) 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 ^r21r44r45
    • Be aware that bone density reports can produce incorrect results if interpreted incorrectly; examples of circumstances that can yield misleading conclusions are inclusion of measurements from fractured vertebrae with severe osteoarthritis and measuring extraskeletal calcifications ^r10
  • The International Society for Clinical Densitometry recommends use of T-score, which compares patients to a young adult Caucasian female reference, for all individuals (cisgender, transgender, and gender non-conforming, of all ethnic groups) ^r46r47
• Fragility fracture history (present or earlier)
  • Documentation of a fragility fracture at any of certain sites (ie, spine, hip, proximal humerus, pelvis, distal forearm) meets criteria for osteoporosis regardless of bone mineral density measurements
    • Bone mineral density testing is still indicated for these patients, to be used for monitoring purposes
• Fracture risk assessment
  • Perform risk assessment on all patients at time of initial evaluation for osteoporosis; this assessment is warranted even for those that meet the diagnostic criteria by virtue of bone mineral density or fracture history
  • FRAX (Fracture Risk Assessment) tool computes an estimate of 10-year probability of hip fracture or a major osteoporotic fracture ^r3
    • It is an internet-accessible computerized algorithm that uses country-specific data on clinical risk factors and femoral neck bone mineral density to calculate fracture probability
      • Calculation also may be performed without data entered for the values obtained from bone mineral density testing
    • Risk score is based on the following parameters: age, sex, weight, height, previous fracture, parental history of hip fracture, smoking status, glucocorticoid use, rheumatoid arthritis, secondary osteoporosis, alcohol intake, and (where available) femoral neck bone mineral density ^r48
    • FRAX (Fracture Risk Assessment) score predicts 10-year probability of hip fracture and major osteoporosis fracture (major fractures include hip, spine, humerus, and forearm)
    • From history and physical examination plus FRAX (Fracture Risk Assessment) score, recommendations can be made about whether pharmacologic intervention is appropriate
  • FRAX (Fracture Risk Assessment) tool shortcomings
    • FRAX (Fracture Risk Assessment) score underestimates risk of all future fractures, given that it estimates only for hip and major fractures, which comprise approximately half of all fragility fractures ^r49
    • FRAX (Fracture Risk Assessment) score underestimates risk for patients with multiple prior fractures, those with recent fracture, those whose lumbar spine bone mineral density is much less than at femoral neck, those with secondary osteoporosis, those with diabetes, and those at high risk of falls ^r50
      • For patients with diabetes, rheumatoid arthritis may be entered into the FRAX (Fracture Risk Assessment) algorithm as a surrogate to adjust for the elevated risk ^r51
    • An adjustment may be applied for certain known factors (eg, exposure to glucocorticoids, bone mineral density or trabecular bone score of the lumbar spine, hip axis length, falls history, country of birth, type 2 diabetes, chronic kidney disease, how recently a fracture occurred) to refine the risk estimation ^r3r27
• Evaluation for causes of secondary osteoporosis
  • An evaluation is indicated for all patients diagnosed with postmenopausal osteoporosis to identify coexisting medical conditions that cause or contribute to bone loss
    • Undiagnosed metabolic bone and mineral diseases are present in approximately one-third of females with osteoporosis ^r33
    • Common secondary causes include hyperparathyroidism, hypercalciuria, calcium malabsorption, vitamin D deficiency, and hyperthyroidism ^r33
  • Routine laboratory investigation of osteoporosis needs to include CBC, serum chemistry panel (with levels of calcium, albumin, total protein, creatinine, phosphate, alkaline phosphatase, and liver transaminases), thyroid function tests, and 25-hydroxyvitamin D level ^r4
    • C-reactive protein or erythrocyte sedimentation rate can also be evaluated ^r3
  • 24-hour urine collection for calcium, sodium, and creatinine levels is also recommended to assess for calcium malabsorption or hypercalciuria
  • Additional tests beyond the aforementioned ones may be helpful, depending on initial results, and may be useful in considering unusual secondary causes or conditions in the differential diagnosis. They include: ^r3r4
    • Serum intact parathyroid hormone level, for possible hyperparathyroidism
    • Magnesium, if calcium is low
    • Additional tests for hyperthyroidism, if screening thyroid function tests are abnormal
    • Tissue transglutaminase antibodies test, for suspected celiac disease
    • Serum protein electrophoresis and free kappa and lambda light chains test, for suspected multiple myeloma
    • 24-hour urine free cortisol test or 1 mg overnight dexamethasone suppression test, for suspected endogenous hypercortisolemia
    • Serum tryptase or urine N-methylhistidine test, for mastocytosis
    • Serum testosterone, sex hormone binding globulin, follicle stimulating hormone, and luteinizing hormone, for suspected hypogonadism
    • Serum prolactin, for suspected hyperprolactinemia
• Evaluate for prevalent vertebral fractures
  • Vertebral fracture assessment is densitometric spine imaging performed for the purpose of detecting vertebral fractures that might otherwise go unidentified ^r52
    • Detecting vertebral fractures requires specific imaging techniques that can be done at same time as DXA
    • Finding vertebral fractures, regardless of results of bone mineral density testing or FRAX (Fracture Risk Assessment) score, meets a criterion for the diagnosis of osteoporosis
  • Indications for vertebral fracture assessment include advanced age, history of height loss, use of systemic glucocorticoid therapy, and self-reported but undocumented prior vertebral fracture ^r47
• Utility of bone turnover markers
  • Bone turnover markers are not used for diagnosis, but baseline levels are sometimes obtained before start of therapy because they can be useful for initial evaluation and for monitoring response to therapy
    • Elevated levels can predict more rapid rates of bone loss
    • High bone turnover levels are associated with increased fracture risk independent of bone mineral density
  • Bone turnover markers respond quickly to therapy, and comparing levels over time can allow for insights into drug adherence and absorption
  • Most useful bone turnover markers are PINP (N-propeptides of type I collagen), which derive from bone formation osteoblast products, and CTX (C-terminal cross-linking telopeptides of type 1 collagen), which derive from bone resorption products of collagen degradation

Laboratory

• Laboratory tests are most helpful to investigate for secondary causes of osteoporosis and to identify conditions in the differential diagnosis ^r3r6
• Routine laboratory investigation of osteoporosis includes CBC; serum chemistry panel (with levels of calcium, albumin, total protein, creatinine, phosphate, alkaline phosphatase, and liver transaminases); thyroid function tests; and 25-hydroxyvitamin D level; may also include C-reactive protein or erythrocyte sedimentation rate ^{r3r4c80c81c82c83}
• Bone turnover markers ^r53c84
  • Bone turnover markers, including CTX (C-terminal cross-linking telopeptides of type 1 collagen), are used primarily as a means to measure metabolic activity of bone in patients on osteoporosis therapies
    • These markers also have a role in monitoring patients on a drug holiday, to ensure persistence of antiresorptive effect
    • Not FDA approved for diagnosis of osteoporosis, but may have a role in assessing fracture risk and extent of fracture risk reduction in selected patients ^r54
  • Bone turnover markers can be measured in serum, plasma, and urine, and their levels relate to the activity of osteoblasts (bone formation markers) and osteoclasts (bone resorption markers) ^r54
    • Bone formation markers include proteins that are rather specific to bone (eg, osteocalcin) and those that are less specific to bone, such as serum P1NP (N-propeptide of type I collagen, fragments of type I procollagen released during formation of type I collagen), bone-specific ALP (the bone isoform of alkaline phosphatase), and osteocalcin
    • Bone resorption markers include fragments released from the telopeptide region of type I collagen after its enzymatic degradation, including urinary NTX (N-telopeptide of type I collagen) and serum CTX (C-terminal cross-linking telopeptides of type 1 collagen), deoxypyridinoline, and tartrate-resistant acid phosphatase
    • In cohort studies of females, the higher the bone turnover marker levels, the more rapid the bone loss and the greater the risk of fracture
  • Interpretation of results
    • Suppression of bone resorption markers is seen on initiation of bisphosphonate therapy, whereas with treatment cessation, bone resorption marker levels increase; the changes in bone mineral density lag far behind
      • An appropriate level of CTX (C-terminal cross-linking telopeptides of type 1 collagen) or bone resorption marker suppression is at or below a healthy premenopausal mean; the lower half of the premenopausal reference intervals have been used as a target for those on bisphosphonate therapy and gives an indication of appropriate suppression of bone turnover by bisphosphonate
      • Another criterion for response evaluation is whether the minimum significant changes are exceeded; minimum significant changes are twice the mean morning day-to-day variation seen in premenopausal people ^r55
    • Increased levels of bone formation markers in response to anabolic therapy are reassurance that the drug is effective
  • Practical issues
    • Ideally, blood sample for bone turnover markers is collected in early morning in fasting state
    • Avoid collecting specimen during acute phase after a fracture
    • Some bone turnover markers are affected by renal impairment, whereas others are unaffected

Imaging

• DXA ^c85c86
  • DXA of lumbar spine, total hip, and proximal femur is the preferred method for diagnosis ^r21r44r45
    • Central DXA, measuring axial sites, is preferred over peripheral DXA for diagnosis, although distal third of radius also may be used as an alternative diagnostic site if central sites are unavailable ^r56
    • Femoral neck is the site with the highest predictive value for fracture risk ^r3
    • Spine is ideal site for assessing treatment response, provided that lumbar spine does not have significant degenerative or artifactual changes that render it invalid for analysis; if so, hip may then be used ^r3
    • Be aware of misinterpretation of DXA in cases of fractured vertebrae with severe osteoporosis or extraskeletal calcifications ^r10
  • DXA is also the preferred method by which to monitor bone mineral density over time ^r57
    • Ideally, patients should be measured on the same DXA machine because different vendor technologies don't allow for comparisons unless cross-calibration has occurred ^r57
  • DXA results are categorized by WHO diagnostic criteria for osteopenia and osteoporosis ^r22
    • Normal: bone mineral density value 1 standard deviation below young adult female reference mean or higher (T-score −1 or higher)
    • Osteopenia: bone mineral density value more than 1 but less than 2.5 standard deviations below that of young adult female reference mean (T-score less than −1 and greater than −2.5)
    • Osteoporosis: bone mineral density value 2.5 or more standard deviations below that of young adult female reference mean (T-score −2.5 or less)
• Quantitative CT ^r3c87c88
  • Quantitative CT femoral neck areal bone mineral density is equivalent to DXA bone mineral density, and predicts fractures
  • Femoral neck results may be used in FRAX (Fracture Risk Assessment)
  • Only use axial bone density measurements (lumbar spine, femoral neck, total hip, and distal 1/3 of the radius) in diagnostic evaluations; peripheral bone density measurements may only be used to assess fracture risk ^r4
• Quantitative ultrasonography
  • Measurements are commonly made at the calcaneus, which is composed primarily of cancellous bone similar to the spine
  • Consider to identify patients at increased risk for fracture; DXA still required to make formal diagnosis of osteoporosis ^r4
  • Avoids radiation exposure
  • Not well validated compared to absorptiometric techniques ^r3
• Vertebral fracture assessment ^r6r47
  • Test utilizing DXA with additional software to evaluate vertebral morphology from thoracic (T5) to lower lumbar spine (L5), where most vertebral fractures occur ^r57c89c90
  • Significant loss in vertebral height may be indicative of vertebral fracture, which can be missed using DXA alone ^r6
  • Vertebral fracture assessment is not indicated for screening, diagnosis, or routine monitoring; it is most useful in reclassifying patients who would otherwise not meet criteria for treatment on the basis of bone mineral density alone ^r57
    • Up to 2/3 of radiographically detected vertebral fractures are not recognized clinically
    • Finding unknown vertebral fractures has been shown to influence treatment initiation in asymptomatic patients and to help direct treatment for patients on therapy whose bone mineral density is stable or improved on DXA
  • Densitometric vertebral fracture assessment is indicated when T-score is less than −1 and one or more of the following factors are present: ^r57
    • Females aged 70 years or older; males aged 80 years or older
    • Historical height loss greater than 4 cm
    • Self-reported but undocumented prior vertebral fracture
    • Glucocorticoid therapy equivalent to 5 mg or more of prednisone or equivalent per day for 3 months or longer
• Skeletal radiography ^r6c91
  • Anteroposterior and lateral views are required for both the thoracic and lumbar spine to evaluate potential vertebral fractures
    • Radiographs of the spine may be considered when vertebral fracture assessment is not diagnostic or when images cannot be adequately derived, or as an alternative to vertebral fracture assessment in patients who have low BMD and risk factors for developing vertebral fractures ^r57
  • Vertebral fractures include wedge deformities, end-plate (biconcave) deformities, and compression (or crush) fractures
  • Vertebrae from T4 to L4 are graded on visual inspection of radiographs as follows:
    • Normal appearance (grade 0)
    • Mildly deformed (grade 1: 20%-25% loss in anterior, middle, and/or posterior height)
    • Moderately deformed (grade 2: 25%-40% loss in anterior, middle, and/or posterior height)
    • Severely deformed (grade 3: 40% or more loss in anterior, middle, and/or posterior height)
• Trabecular bone score ^r58r59c92
  • Obtained using software compatible with DXA systems; provides information about bone microarchitecture
  • Can predict fracture risk independently of bone mineral density values and improves the ability of FRAX (Fracture Risk Assessment) tool to predict fracture ^r58
  • High scores indicate homogeneous, normal bone and reduce the FRAX (Fracture Risk Assessment) estimated risk, whereas low scores correlate with weaker bone texture and increase the FRAX (Fracture Risk Assessment) risk
  • Adjusting FRAX (Fracture Risk Assessment) interpretation with trabecular bone score has the greatest clinical utility in people whose fracture risk is close to the therapeutic intervention threshold. For example:
    • A low trabecular bone score in a female with osteopenia might lead to favoring treatment with a pharmacologic agent
    • A high trabecular bone score in a female with diabetes might also favor pharmacologic intervention

Most common

• Osteomalacia ^c93
  • Condition defined by impaired skeletal mineralization, usually due to low calcium or phosphorus levels
  • Vitamin D deficiency is one of the most common causes of osteomalacia; most patients with mild to moderate vitamin D deficiency are asymptomatic ^d2
  • Patients with osteomalacia may present with musculoskeletal pain, bony tenderness, hyperalgesia or paresthesia, proximal muscle weakness, waddling gait, history of fracture, and coexisting hypocalcemia ^r60
  • Classic findings of osteomalacia on plain radiographs are pseudofractures (radiolucent bands) ranging from a few millimeters to a few centimeters in length, most visible near the femoral neck or pelvis ^r61
  • Differentiated from osteoporosis by clinical presentation in the setting of a low serum level of 25-hydroxyvitamin D, calcium, or phosphorus ^r62
• Pathologic fractures due to other causes
  • Malignant vertebral compression fractures can be caused by metastatic cancers or primary tumors of bone ^r63c94
    • Cancers with a propensity to metastasize to bone (eg, breast, prostate, thyroid, lung) can lead to malignant vertebral compression fractures
    • Primary tumors of bone and lymphoproliferative or myeloproliferative diseases (eg, lymphomas, multiple myeloma) also can be the cause of malignant vertebral compression fractures
  • Consider possible malignant vertebral compression fractures after a vertebral fracture in a patient with known history of cancer or one whose laboratory test results point to possible malignancy (eg, abnormal serum protein electrophoresis results). In very unusual cases, a vertebral compression fracture can be the first manifestation of malignancy
    • Most often, these patients have back pain at site of tumor, often worse at night
  • Advanced imaging is often necessary to distinguish benign from malignant vertebral compression fractures
    • MRI is the technique of choice, but other modalities (eg, CT, PET, SPECT [Single-photon emission computed tomography]) can provide additional information, as guided by radiologist evaluations ^r63
  • Acute (less than 2 weeks) and subacute (2 weeks to 3 months) benign vertebral compression fractures often have large areas of MRI signal alteration or increased metabolism on nuclear medicine scans; these areas can mimic malignancy ^r64
  • Chronic (more than 3 months) benign vertebral compression fractures have small areas of usually linear signal alteration and show restoration of fatty marrow and normal metabolism ^r64
  • MRI findings suggestive of metastatic vertebral compression fracture are as follows: expansion of fractured vertebral body, epidural and/or paraspinal soft tissue mass, abnormal signal intensity of pedicle or posterior element, epidural mass, encasing epidural mass, and other spinal metastasis ^r65
  • MRI findings suggestive of acute osteoporotic vertebral compression fracture are as follows: a band of low signal intensity on T1- and T2-weighted images, preservation of normal bone marrow signal intensity, retropulsion of a posterior bone fragment, and multiple levels of compression fractures ^r65

Recommendations for specialist referral

• Patients with any of the following factors may benefit from referral to endocrinologists or other physicians with expertise in osteoporosis: ^r66r67
  • Fracture or significant ongoing loss of bone mineral density despite adherence to first line therapy
  • Complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease)
  • Unusual features including young age or abnormal laboratory test results (eg, low phosphorus level)
  • Artifacts on DXA that are unexplained

Drug therapy

• Bisphosphonates ^r98
  • Alendronate ^r4r99c95
    • Alendronate Sodium Oral solution, weekly; Adult men and postmenopausal females: 70 mg PO once weekly. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. Continue for up to 10 years in postmenopausal women with very high risk of fracture. Consider discontinuation after 5 years of stability in high risk postmenopausal women and after 3 to 5 years in low or moderate risk patients.
  • Risedronate ^r100c96
    • Risedronate also has a coated formulation, which may be taken after breakfast (Atelvia)
    • Weekly dosing
      • Risedronate Sodium Oral tablet, weekly; Adult postmenopausal females: 35 mg PO once weekly. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. For those patients at low risk for fracture, consider stopping risedronate after 3 to 5 years.
    • Monthly dosing
      • Risedronate Sodium Oral tablet; Adult postmenopausal females: 150 mg PO once monthly. An alternative once-monthly regimen is 75 mg PO on 2 consecutive days each month (for a total of 150 mg each month). Supplement calcium and vitamin D if dietary intake is inadequate. Continue for up to 10 years in postmenopausal women with very high risk of fracture. Consider discontinuation after 5 years of stability in high risk postmenopausal women and after 3 to 5 years in low or moderate risk patients.
  • Ibandronate ^c97
    • Monthly oral dosing
      • Ibandronate Sodium Oral tablet, monthly; Adult postmenopausal females: 150 mg PO once monthly on the same date each month. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. Continue for up to 10 years in postmenopausal women with very high risk of fracture. Consider discontinuation after 5 years of stability in high risk postmenopausal women and after 3 to 5 years in low or moderate risk patients.
    • Every 3 months IV dosing
      • Ibandronate Sodium Solution for injection; Adult postmenopausal females : 3 mg IV (over 15 to 30 seconds) every 3 months. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. Continue for up to 10 years in postmenopausal women with very high risk of fracture. Consider discontinuation after 5 years of stability in high risk postmenopausal women and after 3 to 5 years in low or moderate risk patients.
  • Zoledronic acid ^c98
    • Zoledronic Acid Solution for injection [Osteoporosis/Bone Disorders]; Adults: 5 mg IV infusion over at least 15 minutes, given once yearly. Supplement calcium and vitamin D if dietary intake is inadequate. Reevaluate periodically. Continue of zolendronic acid for up to 6 years in postmenopausal women at very high risk of fracture. Consider discontinuation after 3 years of stability in high risk postmenopausal patients and after 3 to 5 years in low or moderate risk patients.
• Monoclonal antibody RANK ligand inhibitor
  • Denosumab ^c99
    • Rapid loss of bone mineral density and increase in fracture risk (including risk of multiple vertebral fractures) occurs upon discontinuation of denosumab; transitioning to antiresorptive therapy 6 months after denosumab discontinuation is advisable to maintain gains in bone mineral density at the lumbar spine ^{r11r12r82r101}
    • Denosumab Solution for injection [Osteoporosis/Bone Disorders]; Adults: 60 mg subcutaneously once every 6 months. All patients should receive a minimum of 1,000 mg of calcium and at least 10 mcg (400 international units) of vitamin D daily. If a dose is missed, administer as soon as possible and schedule future injections every 6 months from that date.
• Parathyroid hormone analogues and parathyroid hormone–related protein analogues
  • Teriparatide ^c100c101
    • Teriparatide Solution for injection; Adults: 20 mcg subcutaneously once daily. Supplement calcium and vitamin D if dietary intake is inadequate. Usually reserved for those with known history of osteoporotic fracture or at higher risk for such fractures.
  • Abaloparatide ^c102c103
    • Abaloparatide Solution for injection; Adult postmenopausal females: 80 mcg subcutaneously once daily. Cumulative use of abaloparatide for more than 2 years during a patient's lifetime is not recommended. Supplement calcium and vitamin D if dietary intake is inadequate. Usually reserved for those with known history of osteoporotic fracture or those with higher risk for such fractures.
• Monoclonal antibody and sclerostin inhibitor
  • Romosozumab ^c104
    • Romosozumab Solution for injection; Adult postmenopausal females: 210 mg subcutaneously once monthly. Limit duration to 12 months. Supplement calcium and vitamin D if dietary intake is inadequate.
• Selective estrogen receptor modulator ^c105
  • Raloxifene
    • Raloxifene Hydrochloride Oral tablet; Adult postmenopausal females: 60 mg PO once daily. Supplement calcium and vitamin D if dietary intake inadequate. Other agents are usually preferred as first-line treatments. Raloxifene may be appropriate in patients requiring spine-specific efficacy.
  • Bazedoxifene (with estrogen) ^c106
    • Approved by the FDA for prevention, but not treatment, of osteoporosis
    • Conjugated Estrogens, Bazedoxifene Oral tablet; Adult postmenopausal females: 1 tablet (conjugated estrogens 0.45 mg; bazedoxifene 20 mg) PO once daily. Only for women at significant risk of osteoporosis; carefully consider non-estrogen medication before using estrogen-based treatment. Supplement calcium and vitamin D if dietary intake inadequate. Reassess use periodically.
• Vitamin D (cholecalciferol preferred over ergocalciferol) ^r2r3r4c107
  • Dietary sources preferred over routine supplementation
  • Intermittent bolus dosing not recommended (eg, high monthly or annual dose) ^r4
  • Maintenance, when dietary sources are insufficient or for patients with malabsorption ^c108
    • Vitamin D (Cholecalciferol) Oral tablet; Adults 50 years and older: 17.5 to 50 mcg (600 to 2000 International Units) PO daily. Maintain 25-hydroxyvitamin D levels of ≥20 or 30 nanograms/mL (upper limit 50 ng/mL). ^r4
  • Vitamin D deficiency
    • Vitamin D (Cholecalciferol) Oral tablet; Adults: 7,000 to 10,000 mcg (280,000 to 400,000 International Units) PO loading dose divided in daily or weekly doses over 6 to 10 weeks to achieve a serum vitamin D concentration more than 30 ng/mL, then 20 to 100 mcg (800 to 4,000 International Units) PO once daily or given intermittently at higher equivalent dose starting 1 month after loading. Example loading dose regimens include: 100 mcg (4,000 International Units) PO once daily for 10 weeks; 150 mcg (6,000 International Units) PO once daily for 8 weeks; 1,000 mcg (40,000 International Units) once weekly for 7 weeks; or 1,250 mcg (50,000 International Units) PO once weekly for 6 to 8 weeks.
• Calcium ^r2r3r4c109
  • Calcium Oral tablet; Adult females 50 years and older: 700 to 1200 mg PO daily of elemental calcium.

Nondrug and supportive care

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

• Ensure adequate intake of dietary calcium and vitamin D
  • Efficacy of calcium and vitamin D supplements for preventing osteoporotic fractures is controversial owing to conflicting results from clinical trials, leading to some uncertainty about optimal doses and regimens
    • One randomized trial in older females who were nursing home residents found a large (approximately 33%) risk reduction in hip fractures for those treated with both calcium and vitamin D ^r103
    • A recent systematic review and meta-analysis found that using vitamin D supplements alone does not reduce risk of fractures, but daily supplementation with both vitamin D and calcium does reduce fractures ^r104
      • This systematic review found that use of both vitamin D (daily doses of 400-800 international units) and calcium (daily doses of 1000-1200 mg) resulted in a 6% reduced risk of any fracture (relative risk, 0.94; 95% confidence interval, 0.89-0.99) and a 16% reduced risk of hip fracture (relative risk, 0.84; 95% confidence interval, 0.72-0.97) ^r104
      • Other systematic reviews have found reductions in hip fractures with vitamin D and calcium supplementation, but use of these supplements has not been found to reduce other types of fractures (eg, vertebral or nonhip fractures) ^r75r105r106
    • Very-high-dose intermittent vitamin D is not recommended because it has been found to increase risk of falls and fractures in 2 separate trials ^r107r108
  • Nearly all pharmacotherapy trials included calcium and vitamin D in both intervention and control groups; therefore, all guidelines recommend intake of at least the reference level (eg, US recommended daily allowance or UK reference nutrient intake) including supplementation if not met through dietary sources ^r2r3r4r5
  • Recommended intakes:
    • Calcium: 700 to 200 mg/day for females older than 50 years, obtained through diet, supplements, or both (preferably through diet) ^{r2r3r4r5r20r69}
    • Vitamin D: guidelines vary from 17.5 to 50 mcg (600 to 2000 International Units)/day for adults older than 50 years, preferably through diet ^r2r3r4r5
      • Supplementation may be needed for those with malabsorption or living in facilities
      • Maintain serum 25-hydroxyvitamin D level of 20 nanograms/mL or more; the optimal range for 25-hydroxyvitamin D level is unknown but most experts suggest levels between 30 and 50 nanograms/mL ^r4
• Advise participation in weight-bearing, resistance, and balance exercises ^r109c110
  • Aim for 30 to 40 minutes of walking (or other weight-bearing exercise) per session 3 to 4 days per week ^r4
    • For people with osteoporosis who do not have history of vertebral fractures or multiple low-trauma fractures, moderate impact exercise (eg, stamping, jogging, low-level jumping, hopping) is recommended on most days ^r110
    • For people with osteoporosis who have vertebral fractures or have had multiple low-trauma fractures, encouraging exercise on most days at level of intensity equivalent to brisk walking is recommended owing to theoretical risks of further vertebral fracture ^r110
  • Recommend 2 to 3 sessions of muscle-strengthening exercise or activities per week to maintain bone strength ^r110
    • Progressive muscle resistance training has greatest benefit; start at lower intensity and ensure good technique before increasing intensity level to maximum weight that can be lifted 8 to 12 times (building up to three sets for each exercise)
  • Postmenopausal females who engage in strength training can be expected to have a 2% improvement in lumbar spine bone mineral density ^r111
  • One meta-analysis determined that improvements in lumbar spine and femoral neck bone mineral density after exercise interventions could reduce the 20-year osteoporosis fracture risk at any site by approximately 10% ^r111
• Advise measures to reduce risk of falls ^{r2r3r4r32c111}
  • Activities such as tai chi, dance, pilates, and yoga may be helpful to improve balance, increase muscle tone, and reduce fall risk in older adults (eg, those aged 65 years or older); recommended at least twice a week ^r110
  • For patients who are already having falls, professionally supervised, specific and highly challenging balance and muscle strengthening exercises are recommended (eg, Otago or Falls Management Exercise [FaME] programs) ^r110
  • Identify hazards in home and remove them (eg, loose rugs, objects on floor); may be more effective when performed by occupational therapist
• Advise optimized nutritional status with balanced diet of macronutrients ^r3r6c112c113
  • For patients who have experienced hip fractures, adequate protein intake is especially important to minimize bone loss; advise patients who have a history of hip fracture to consume the US recommended daily allowance of protein (0.8 g/kg) ^r112
• Encourage cessation of cigarette smoking ^{r2r3r32r113c114d3}
• Advise limitation of alcohol intake to 2 units (standard drinks) per day or less ^{r2r3r32r114c115}

Comorbidities

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

Special populations

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

At-risk populations

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

Screening tests

• Screening tests for bone health and morphology include central DXA, peripheral DXA, and quantitative ultrasonography ^c136c137
• Central DXA is the most commonly used bone measurement test used to screen for osteoporosis
  • Central DXA measures bone mineral density at hip and lumbar spine
• Peripheral DXA measures bone mineral density at distal forearm and heel
• Quantitative ultrasonography also evaluates peripheral sites and does not involve radiation exposure; however, it does not measure bone mineral density
• FRAX (Fracture Risk Assessment) tool also can be used as an adjunct to determine whether to obtain bone mineral density measurement for postmenopausal individuals aged younger than 65 years. This tool includes questions about previous DXA results but does not require this information to estimate fracture risk ^r18

• Screening tests for osteoporosis.

  BMD, bone mineral density; DXA, dual energy x-ray absorptiometry; QUS, quantitative ultrasonography.

  Screening 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