INTRODUCTION — The treatment of osteoporosis consists of lifestyle measures and pharmacologic therapy [1]. An overview of the approach to therapy of osteoporosis in postmenopausal women will be presented here. The diagnosis and evaluation of osteoporosis in postmenopausal women, the prevention of osteoporosis, and the management of osteoporosis in males and premenopausal females are discussed separately.
●(See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women".)
●(See "Prevention of osteoporosis".)
●(See "Treatment of osteoporosis in men".)
●(See "Evaluation and treatment of premenopausal osteoporosis".)
LIFESTYLE MEASURES — Lifestyle measures should be adopted universally to reduce bone loss in postmenopausal women. Lifestyle measures include adequate calcium and vitamin D, exercise, smoking cessation, counseling on fall prevention, and avoidance of heavy alcohol use. In addition, affected patients should avoid, if possible, drugs that increase bone loss, such as glucocorticoids. (See "Falls: Prevention in community-dwelling older persons" and "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Drugs that affect bone metabolism".)
Calcium/vitamin D — An optimal diet for treatment (or prevention) of osteoporosis includes an adequate intake of calories (to avoid malnutrition), calcium, and vitamin D.
Postmenopausal women who are getting adequate calcium from dietary intake alone (approximately 1200 mg daily) (table 1) do not need to take calcium supplements. Women with inadequate dietary intake should take supplemental elemental calcium (generally 500 to 1000 mg/day), in divided doses at mealtime, such that their total calcium intake (diet plus supplements) approximates 1200 mg/day (table 2) [2]. There is considerable controversy around the effects of calcium supplements on the risk of cardiovascular disease. This is discussed in detail separately. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Side effects'.)
Women should also ingest a total of 800 international units of vitamin D daily. Higher doses are required if they have malabsorption or rapid metabolism of vitamin D due to concomitant antiseizure medication therapy. Most postmenopausal women with osteoporosis require vitamin D supplementation as it is difficult to achieve goals with diet alone (table 3). (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Defining vitamin D sufficiency'.)
Data on the efficacy of calcium and vitamin D replacement for osteoporosis are discussed in detail elsewhere. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Skeletal health outcomes'.)
Diet — When celiac disease is a major contributor to osteopenia, a gluten-free diet may result in improvement in bone mineral density (BMD) [3]. (See "Management of celiac disease in adults".)
Data on the impact of protein intake on bone density are conflicting. While some studies suggest that higher protein intake may be associated with a lower risk of hip fractures [4] and bone loss [5-8], others suggest that high protein intake may increase bone resorption and calcium excretion [9]. Thus, given the conflicting data, we do not recommend modifying protein intake as a strategy for preventing bone loss.
Exercise — Women with osteoporosis (or who are seeking to prevent it) should engage in weightbearing exercise for at least 30 minutes on most days of the week and incorporate muscle-strengthening and posture exercises two to three days a week [10]. Exercises that increase muscular strength and improve balance may confer the most benefit for fracture reduction by decreasing risk of falls [11-13]. For patients with frailty or history of vertebral fracture, brisk walking is sufficient and safe weightbearing exercise. (See "Physical activity and exercise in older adults", section on 'Overview of physical activity components'.)
In prospective cohort studies, exercise was associated with a reduced risk of hip fracture in older women [11,14]. In a meta-analysis of 10 trials, exercise reduced the occurrence of overall fractures in older adults (4.8 versus 10.9 percent in the control group; relative risk [RR] 0.49, 95% CI 0.31-0.76) [15]. The reduction in vertebral fractures was not statistically significant (three trials, 18 versus 30 percent; RR 0.56, 95% CI 0.30-1.04) [15]. This may be related to the small number of patients included in the vertebral fracture trials.
Exercise also has beneficial effects on BMD in premenopausal and postmenopausal women [16,17]. A meta-analysis of 43 randomized trials (4320 participants) of exercise and BMD in postmenopausal women showed a significant positive effect of exercise on BMD at the lumbar spine (LS; mean difference 0.85, 95% CI 0.62-1.07) and trochanter (mean difference 1.03, 95% CI 0.56-1.49) compared with controls [17]. A variety of exercise types, including resistance training, jogging, jumping, and walking, was effective. The most effective type of exercise for BMD of the femoral neck was non-weightbearing, high-force exercise (eg, progressive resistance strength training), whereas a combined program (mixture of more than one exercise type) was most effective for LS BMD [17]. The meta-analysis was limited by loss to follow-up and the poor quality of allocation concealment and blinding. Overall, the beneficial effect of exercise on bone density is small. However, these changes reflect areal BMD measurements. It is still uncertain how long-term exercise affects other measures of bone architecture.
Intensity of exercise — There is no convincing evidence that high-intensity exercise, such as running, is of greater benefit than lower intensity exercise, such as walking. Because enjoyment of the regimen is important (the benefits of exercise are quickly lost after the woman stops exercising [18]), we recommend that women pick a regular weightbearing exercise regimen that they enjoy to facilitate long-term compliance. Excessive exercise in premenopausal women may lead to weight loss and amenorrhea, thereby causing osteoporosis. (See "Functional hypothalamic amenorrhea: Pathophysiology and clinical manifestations".)
Cessation of smoking — We strongly recommend smoking cessation to all women concerned with their skeletal health, because smoking cigarettes accelerates bone loss. One study, as an example, evaluated female twins who were discordant for smoking [19]. Smoking one pack per day throughout adult life was associated with a 5 to 10 percent reduction in bone density. Smoking may also negate the beneficial effect of estrogen therapy in postmenopausal women [20,21]. This may be mediated in part by acceleration of the metabolism of estrogen, thereby lowering serum estrogen concentrations.
Other — There is a growing interest in other nonpharmacologic therapies for osteoporosis. In animal models, mechanical stimulation from vibration produced anabolic effects on cancellous and cortical bone [22,23]. Although whole-body vibration platforms have been proposed as a nonpharmacologic therapy for postmenopausal osteoporosis, the available data from randomized trials show minimal to no improvement in BMD with the use of whole body vibration platforms when compared with sham vibration, walking, or no treatment [24-26]. In most trials, data were evaluated per protocol, rather than intention to treat. None of the trials evaluated fracture outcomes. In addition, the safety of vibration therapy in older patients has not been carefully examined. Thus, there are insufficient data to recommend this therapy in postmenopausal women.
PHARMACOLOGIC THERAPY
Patient selection — Women with the highest risk of fracture are the ones most likely to benefit from osteoporosis drug therapy. Therefore, selection of patients based upon fracture risk, as determined by a combination of bone mineral density (BMD) and clinical risk factors, is desirable. Our approach for initiation of therapy is largely in agreement with the Bone Health and Osteoporosis Foundation (BHOF, formerly the National Osteoporosis Foundation [NOF]) recommendations (table 4) [27]. These recommendations are widely accepted, and clinical trial data support the use of bisphosphonates to prevent fracture in such individuals. (See 'Limitations' below and "Bisphosphonate therapy for the treatment of osteoporosis".) (Related Pathway(s): Osteoporosis and osteopenia: Initial management in postmenopausal patients.)
●We recommend pharmacologic therapy for postmenopausal women with a history of fragility fracture or with osteoporosis based upon bone mineral density (BMD) measurement (T-score ≤-2.5). Particular attention should be paid to treating women with a recent fracture, including hip fracture, because they are at high risk for a second fracture [28,29]. (See "Osteoporotic fracture risk assessment", section on 'Personal history of fracture as an adult'.)
●We also suggest pharmacologic therapy for the treatment of high-risk postmenopausal women with T-scores between -1.0 and -2.5. We calculate fracture risk using the Fracture Risk Assessment Tool (FRAX). A reasonable threshold to define high risk is a 10-year probability of hip fracture or combined major osteoporotic fracture of ≥3.0 or ≥20 percent, respectively.
The FRAX criteria for pharmacologic intervention were chosen on the basis of a United States-specific economic analysis, and they have not been assessed in clinical trials.
Intervention thresholds have been estimated for other countries based upon assessment of absolute fracture risk and country-specific analyses. As examples:
●The 2010 Osteoporosis Canada guidelines recommend pharmacologic therapy to patients at high absolute risk (>20 percent probability for major osteoporotic fracture over 10 years) and to individuals over age 50 years who have a fragility fracture [30]. For those at moderate risk (10 to 20 percent), the decision to treat should be based upon the presence of additional risk factors not considered in the risk assessment system and upon individual preference.
●The United Kingdom National Osteoporosis Guideline Group (NOGG) recommends an age-dependent intervention threshold that ranges from 7.5 to 30 percent for ages 50 to 80 years [31]. In one analysis, pharmacologic treatment was cost effective at all ages when the 10-year probability of major osteoporotic fracture exceeded 7 percent [32]. For clinicians in the United Kingdom, intervention thresholds may be accessed directly from the FRAX website (click on "Calculation Tool," select "UK," and then click on "View NOGG Guidance" after entering patient-specific information).
Although country-adapted fracture-prediction algorithms and national recommendations provide general clinical guidance, osteoporosis treatment should remain individualized through shared decision-making between patient and clinician.
Fracture risk assessment — In 2008, a World Health Organization (WHO) task force introduced FRAX, which estimates the 10-year probability of hip fracture or major osteoporotic fractures combined (hip, spine, shoulder, or wrist) for an untreated patient using femoral neck BMD and easily obtainable clinical risk factors for fracture (table 5). The technical aspects of FRAX are reviewed in detail separately. (See "Osteoporotic fracture risk assessment", section on 'Fracture risk assessment tool'.)
The 10-year probability of hip and major osteoporotic fracture can be calculated for individual patients using the FRAX website (click on "Calculation Tool" and select country). The FRAX algorithm uses femoral neck BMD (g/cm2) for calculation of fracture probability. BMD from non-hip sites has not been validated and is, therefore, not recommended for use.
Limitations — We largely agree with the BHOF recommendations (initiate therapy in postmenopausal women with a history of hip or vertebral fracture, osteoporosis based upon BMD measurement [T-score ≤-2.5], or osteopenia and high risk of fracture based on calculation of a 10-year probability of fracture) (table 4). However, the benefit of treatment based upon 10-year probability of fracture, rather than BMD criteria alone, has not been assessed in clinical trials.
The emphasis on absolute fracture risk increases the proportion of older women who are candidates for therapy. As an example, in a study using data from the Study of Osteoporotic Fracture (SOF), with a prospective cohort of community-dwelling White women ≥65 years of age, application of the revised 2008 NOF treatment guidelines that first incorporated FRAX resulted in recommendations for pharmacologic therapy for 72 percent of women over 65 years of age and 93 percent of women over 75 years [33]. Applying bone density criteria alone (BMD lower than -2.5 at lumbar spine [LS] or femoral neck) resulted in a treatment recommendation for 50 percent of women in both age groups.
Whether the selection of patients based upon clinical risk factors and BMD, rather than on BMD alone, improves benefit in older patients has not yet been established.
In addition, initial economic analyses estimated drug costs based upon use of generic bisphosphonates [34]. The use of more expensive drugs increases the 10-year fracture probability at which intervention is cost effective. Thus, the decision to treat with more expensive drugs that may be indicated in selected patients should be individualized. BHOF guidelines should not be applied to individuals living in different countries, as the BHOF guidelines are based upon a United States-specific economic analysis. Intervention thresholds have been estimated for other countries, and country-specific guidelines are available or are in development. (See 'Patient selection' above and "Osteoporotic fracture risk assessment", section on 'Clinical application of fracture risk assessment'.)
Choice of drug — In the absence of high quality head-to-head drug comparison trials to determine the relative efficacy of the individual drugs, choice of therapy should be based upon efficacy, safety, cost, convenience, and other patient-related factors [35-40]. All patients treated with pharmacologic therapy should have normal serum calcium and 25-hydroxyvitamin D levels prior to starting therapy, and they should receive supplemental calcium and vitamin D if dietary intake is inadequate (algorithm 1). (See 'Calcium/vitamin D' above and "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Pretreatment evaluation'.)
Systematic reviews of trials published between 2005 and 2018 confirmed that many drugs prevent fractures compared with placebo [35,41,42]. In a 2019 meta-analysis of 107 trials evaluating pharmacologic therapies in postmenopausal women with osteoporosis, alendronate, zoledronic acid, risedronate, denosumab, romosozumab, and estrogen with progesterone reduced the risk of hip fracture [38]. Alendronate, zoledronic acid, risedronate, ibandronate, denosumab, abaloparatide, teriparatide, parathyroid hormone 1-84, romosozumab, raloxifene, bazedoxifene, lasofoxifene, estrogen with progesterone, tibolone, and calcitonin reduced the risk of vertebral fractures. The anabolic agents (teriparatide, abaloparatide, romosozumab) and denosumab were associated with the highest relative efficacy, although there are few trials directly comparing the drugs in preventing fractures.
Initial therapy — For most postmenopausal women with osteoporosis, we suggest oral bisphosphonates as first-line therapy. We prefer oral bisphosphonates as initial therapy because of their efficacy, favorable cost, and the availability of long-term safety data. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Choice of bisphosphonate' and "Risks of bisphosphonate therapy in patients with osteoporosis".)
We suggest alendronate or risedronate as our choice of bisphosphonate due to efficacy in reducing vertebral and hip fracture. We most commonly use alendronate, in part due to direct evidence showing residual fracture benefit in selected patients after completing a five-year course of therapy [43]. Generic alendronate and risedronate are available in many countries, including the United States. Most patients prefer the convenience of the once-weekly regimen. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Choice of bisphosphonate'.)
Contraindications/intolerance to oral bisphosphonates — Oral bisphosphonates should not be used as initial therapy in patients with esophageal disorders, an inability to follow the dosing requirements (eg, stay upright for at least 30 to 60 minutes), or chronic kidney disease (CKD; estimated glomerular filtration [eGFR] rate <30 mL/min) (algorithm 1). Oral bisphosphonates should also be avoided after certain types of bariatric surgery in which surgical anastomoses are present in the gastrointestinal tract (eg, Roux-en-Y gastric bypass). (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Contraindications to bisphosphonates'.)
The choice of initial agent in patients with contraindications or intolerance to oral bisphosphonates depends upon the nature of the contraindication/intolerance, the severity of the osteoporosis, and subsequent risk for fracture.
●Gastrointestinal disease or difficulty with dosing requirements – For patients with esophageal disorders, gastrointestinal intolerance, history of Roux-en-Y gastric bypass, or an inability to follow the dosing requirements of oral bisphosphonates, including an inability to sit upright for 30 to 60 minutes and/or to swallow a pill, we suggest IV bisphosphonates. We prefer IV zoledronic acid, which has been demonstrated to reduce vertebral and hip fractures. IV ibandronate is also available; however, there is no direct fracture prevention data for IV ibandronate. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Gastrointestinal' and "Bisphosphonate therapy for the treatment of osteoporosis", section on 'IV regimen'.)
Denosumab is an alternative to IV zoledronic acid for women at high risk for fracture (such as older patients) who have difficulty with the dosing requirements of oral bisphosphonates, who prefer to avoid IV bisphosphonates due to side effects (eg, acute phase reaction), or who have impaired renal function. However, emerging data have raised concern about increased risk of vertebral fracture after discontinuation of denosumab. Thus, the need for indefinite treatment should be addressed with patients before denosumab is initiated. (See "Denosumab for osteoporosis", section on 'Patient counseling' and "Denosumab for osteoporosis", section on 'Duration of therapy'.)
Anabolic agents are rarely used as initial therapy, but they could be prescribed as an alternative to IV zoledronic acid for postmenopausal women with severe osteoporosis (T-score of ≤ -3.0 even in the absence of fractures, or T-score of ≤ -2.5 plus a fragility fracture) or in patients who were treated initially with oral bisphosphonates but who are unable to tolerate them. (See 'Severe osteoporosis' below and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis".)
●Other intolerance – Patients who are allergic to bisphosphonates or who develop severe bone pain with them require an alternative treatment. (See 'Contraindications/intolerance to any bisphosphonates' below.)
●CKD – Oral and IV bisphosphonates should not be used routinely in patients with CKD and an eGFR <30 to 35 mL/min. There are few data evaluating fracture prevention efficacy and long-term adverse effects in patients with reduced renal function. Both oral bisphosphonates and denosumab have been studied in this population. However, use of any bisphosphonate in patients with an eGFR<30 mL/minute should only be considered by specialists in metabolic bone disease and after biochemical testing and/or bone biopsy (for patients with eGFR <15 mL/minute) exclude renal osteodystrophy. The evaluation of osteoporosis and unique management issues in patients with CKD are reviewed in detail separately. (See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation".)
Contraindications/intolerance to any bisphosphonates — For patients who cannot receive or are intolerant of oral and IV bisphosphonates, the choice of agent depends on risk of fracture (eg, history of prior fragility fractures, BMD T-scores, comorbidities), efficacy, adverse effect profile, and patient preferences.
●For postmenopausal women at very high risk of fracture (eg, T-score of ≤-3.0 in the absence of fragility fracture, T-score of ≤-2.5 plus a fragility fracture, severe or multiple vertebral fractures), we suggest an anabolic agent (teriparatide, abaloparatide, romosozumab). Of these, we prefer teriparatide or abaloparatide because of efficacy and longer-term safety data (particularly for teriparatide). Teriparatide and abaloparatide must be injected subcutaneously daily, whereas romosozumab is injected once monthly. (See 'Severe osteoporosis' below.)
While use of anabolic agents is generally reserved for individuals at very high risk of fracture, they can be used in patients with less severe osteoporosis (eg, T-scores ≤-2.5 without a fragility fracture) who are unable to tolerate oral or IV bisphosphonates.
●For patients at high risk for fracture (eg, osteoporosis by BMD in the absence of fragility fracture, T-score > -2.5 with a fragility fracture, single vertebral fracture), denosumab is a reasonable option, particularly in patients with impaired renal function. As discussed above, because of emerging concerns about an increased risk of vertebral fracture after discontinuation of denosumab, the need for indefinite administration of denosumab should be discussed with patients prior to its initiation. (See "Denosumab for osteoporosis", section on 'Duration of therapy'.)
●Since the anti-resorptive effects of raloxifene are less than those of bisphosphonates, we reserve the use of this drug for postmenopausal women with osteoporosis and no history of fragility fractures who cannot tolerate any bisphosphonates or denosumab, or who have an increased risk of invasive breast cancer. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis" and "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention", section on 'Raloxifene'.)
Severe osteoporosis — For patients with severe osteoporosis (eg, T-score of ≤-3.0 even in the absence of fractures, T-score of ≤-2.5 plus a fragility fracture, severe or multiple vertebral fractures), some UpToDate experts prefer initial treatment with an anabolic agent (teriparatide, abaloparatide, romosozumab), whereas other UpToDate experts prefer initial treatment with bisphosphonates because of the cost of anabolic therapy, subcutaneous route of administration, and long-term safety concerns (algorithm 1). In a double-blind, double-placebo controlled trial comparing teriparatide with risedronate in 680 postmenopausal women (mean age 72.1 years) with severe osteoporosis (mean number of prevalent fractures 2.7), there were fewer new radiographic vertebral fractures in the teriparatide group (5.4 versus 12 percent) and fewer clinical fractures at all sites (4.8 versus 9.8 percent) [44]. There was no difference in the incidences of nonvertebral fractures. The majority of women had received at least one previous osteoporosis medication (median duration of previous bisphosphonate use 3.6 years).
When a decision has been made to treat with an anabolic agent, we suggest teriparatide or abaloparatide. Romosozumab is an alternative [40]. Teriparatide has a long track record of safety, whereas there is less experience with the long-term use of abaloparatide. Romosozumab induces a greater BMD response than either abaloparatide or teriparatide, but treatment is indicated for only one year because clinical experience is limited and the long-term side effects uncertain.
Because treatment with teriparatide/abaloparatide is limited to 18 to 24 months, and romosozumab to 12 monthly doses, patients with severe osteoporosis who are treated initially with an anabolic agent are typically treated with an anti-resorptive agent (preferably a bisphosphonates) after discontinuation, to preserve the gains in BMD achieved with the anabolic agent. For women who are unable to tolerate oral or IV bisphosphonates, denosumab or raloxifene are post-anabolic agent alternatives. A persistent reduction in fracture risk with the use of anti-resorptive therapy after PTH is discontinued has not yet been firmly established. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Patient selection' and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Management after teriparatide' and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Choice of therapy'.)
Response to therapy
Monitoring — Monitoring the response to therapy is important for identifying patients who may require a change in therapy (up to one-sixth of women taking alendronate continue to lose bone) [45]. While there are a number of approaches to monitoring therapy, there is no consensus on the optimal approach [46-49]. Serial dual-energy x-ray absorptiometry (DXA) measurements are typically used to assess the BMD response, although most of the efficacy of bisphosphonates in fracture reduction is not captured by DXA. Markers of bone turnover are infrequently used but may be helpful in select circumstances.
Our approach — Our approach to monitoring is similar to the International Society for Clinical Densitometry (ISCD) guidelines. (See 'Guidelines for monitoring response to therapy' below.)
●DXA – For patients starting on therapy, we suggest a follow-up DXA of hip and spine after two years, on the same instrument when possible. If BMD is stable or improved, we perform less frequent monitoring thereafter. (See "Overview of dual-energy x-ray absorptiometry", section on 'Serial BMD testing' and 'Bone mineral density stable or increased' below.)
●Bone turnover markers – Routine monitoring of patients on anti-resorptive therapy with bone turnover markers is not necessary. However, monitoring with markers of bone turnover is an additional option for patients who have conditions that might interfere with drug absorption or efficacy, such as small bowel resections or other types of malabsorption, or for patients who are reluctant to take anti-osteoporosis medications regularly. In such patients, we typically measure fasting urinary N-telopeptide (NTX) or serum carboxy-terminal collagen crosslinks (CTX) before and three to six months after starting bisphosphonate or other anti-resorptive therapy. A decrease of greater than 50 or 30 percent in urinary NTX excretion or serum CTX, respectively, provides evidence of compliance and drug efficacy. The patient can be reassured that the next BMD measurement will likely be stable or improved. In contrast, a decrease in markers of less than 30 percent may not necessarily indicate treatment failure. However, when this occurs, we question the patient about possible noncompliance or poor absorption (often related to an insufficient time interval between drug intake and food ingestion). (See "Use of biochemical markers of bone turnover in osteoporosis", section on 'Osteoporosis therapy'.)
This approach (with markers of bone resorption) is useful only with anti-resorptive therapy, not with recombinant PTH (markers would increase) or romosozumab (markers of bone formation increase, markers of bone resorption decrease). The approach to monitoring patients on anabolic therapy is discussed separately. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Monitoring'.)
Guidelines for monitoring response to therapy — There are several published guidelines for monitoring the response to osteoporosis therapy; all recommend follow-up BMD (DXA) testing. However, there is no consensus on the optimal frequency of monitoring and preferred site to monitor. The use of biochemical markers of bone turnover for monitoring response to therapy has not been addressed in current guidelines, and there are no prospective trials to define the most optimal approach for incorporating markers into monitoring strategies [50]. (See "Bone physiology and biochemical markers of bone turnover" and "Use of biochemical markers of bone turnover in osteoporosis".)
●ISCD – The ISCD recommends follow-up BMD testing (DXA spine and hip) when the expected change in BMD equals or exceeds the least significant change (LSC), which is typically one to two years after initiation or change of therapy, with longer intervals once therapeutic effect is established. In conditions associated with rapid bone loss, such as glucocorticoid therapy, testing more frequently is appropriate [51].
●BHOF – The BHOF recommends repeat BMD assessments (DXA spine or hip) one to two years after initiating therapy and then at individualized intervals thereafter, with more frequent testing in certain clinical situations [27].
●AACE – The American Association of Clinical Endocrinologists (AACE) recommends repeat DXA of the LS and total hip every one to two years until stability is achieved, and every two years or at less frequent intervals thereafter [52].
●NAMS – The North American Menopause Society (NAMS) recommends repeat DXA one to two years after initiating therapy or when there may be a change in osteoporosis therapy [53].
●ACP – The American College of Physicians (ACP) recommends against monitoring during therapy, as many women treated with anti-resorptive therapy have a reduction in fracture even when BMD does not increase [41].
Bone mineral density stable or increased — BMD that is stable or improving is evidence for a treatment response. In order for a change in BMD to be considered significant, it should be greater than the LSC for the densitometer in question. (See "Overview of dual-energy x-ray absorptiometry", section on 'Precision assessment'.)
Some [54-58], but not all [59], studies suggest that changes in BMD during therapy correlate with reduction in fracture risk. In one study, the greatest fracture reduction occurred in those who gained BMD, although those with stable BMD still had fewer fractures than those who lost BMD [54]. A meta-analysis of 12 clinical trials concluded that improvement in spine BMD accounts for a predictable but small part of the reduction in fracture risk [60].
Bone mineral density decreased or fracture during therapy — The finding of a BMD decrease greater than the LSC or a new fracture in a treated patient should trigger additional evaluation for contributing factors, which may include poor adherence to therapy, inadequate gastrointestinal absorption, inadequate intake of calcium and vitamin D, or the development of a disease or disorder with adverse skeletal effects [61,62]. Calcium and vitamin D supplementation should be verified, and some evaluation for secondary causes of bone loss should be performed. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women", section on 'Evaluation'.)
If the patient is otherwise well and taking the drug and supplements correctly, the correct action is controversial. Some clinicians believe that the decrease in BMD truly reflects a treatment failure and would consider modification of the primary treatment for the osteoporosis. Others believe that the decline in BMD does not necessarily imply inadequate therapy, but could be ascribed to measurement error [63]. They would repeat BMD one year later, taking action only if the decline is reaffirmed. There are few clinical trial data to support either action. In this situation, we recommend the following:
●Decline in BMD
•When the change in BMD is <5 percent and the patient is taking the drug correctly and has no discernible contributing factors, we suggest continuing the same therapy and repeating the BMD two years later.
•When the decline in BMD is ≥5 percent, we usually switch from an oral bisphosphonate to an IV bisphosphonate, typically zoledronic acid. If the lack of response is related to poor absorption, switching to an IV preparation should result in a more favorable response. Other alternatives include switching to denosumab, teriparatide, abaloparatide, or romosozumab.
●Fracture while taking bisphosphonates – Switching to an anabolic agent is a good option for patients with severe osteoporosis (T-score ≤-2.5 and at least one fragility fracture) who continue to fracture after one year of bisphosphonates. Teriparatide is effective in increasing BMD in women previously treated with bisphosphonates, although the improvement may be less than in women not previously exposed to bisphosphonates.
Abaloparatide, romosozumab, and denosumab are alternative options for patients who are unresponsive to other therapies and in those with impaired renal function. If there are no contraindications, it may be beneficial to treat with the anabolic agent first (maximum of one to two years, depending on the drug), followed by denosumab, to preserve the gains in BMD achieved with the anabolic agent. Because of emerging concerns about an increased risk of vertebral fracture after discontinuation of denosumab, the need for indefinite administration of denosumab should be discussed with patients prior to its initiation. (See "Denosumab for osteoporosis", section on 'Patient counseling' and "Denosumab for osteoporosis", section on 'Duration of therapy' and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Management after teriparatide'.)
Duration of therapy — The ideal duration of osteoporosis therapies is reviewed separately. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Duration of therapy' and "Denosumab for osteoporosis", section on 'Duration of therapy' and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Duration of therapy' and "Selective estrogen receptor modulators for prevention and treatment of osteoporosis", section on 'Duration of therapy'.)
Special populations
Post-fracture — A history of a fragility (low-trauma) fracture is an important risk factor for subsequent fracture in both males and females. Thus, it is important to inform such patients of the diagnosis of osteoporosis and the increased risk of subsequent fracture [28]. Pharmacologic therapy (typically bisphosphonates) should be initiated in patients with fragility fracture to prevent subsequent fracture, and treatment need not be delayed for bone density testing. Although BMD is not necessary for initiating treatment in patients with fragility fracture, BMD is helpful to monitor response to treatment. (See 'Patient selection' above and 'Initial therapy' above.)
There are few trials evaluating the initiation of bisphosphonates in the immediate post-fracture period. In most patients, a recent fracture should not preclude use of bisphosphonates, which can be initiated two weeks post-fracture as long as the patient is able to sit upright for at least 30 minutes (oral bisphosphonates). This topic is reviewed elsewhere. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Use immediately after fracture'.)
In the United States and Europe, the majority of patients who have had fragility fractures (or are at risk for fracture) do not subsequently receive osteoporosis therapy [64-66], despite data demonstrating a beneficial effect in reducing the risk of a second fracture.
Glucocorticoid-induced osteoporosis — Glucocorticoid therapy is associated with an appreciable risk of bone loss, which is most pronounced in the first few months of use. In addition, glucocorticoids increase fracture risk, and fractures occur at higher BMD values than occur in postmenopausal osteoporosis. The evaluation, prevention, and treatment of glucocorticoid-induced osteoporosis is reviewed separately. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Chronic kidney disease — Patients with osteoporosis and CKD present unique management challenges. With progression of renal failure, serum PTH concentrations rise and the bone morphologic features of renal osteodystrophy (osteitis fibrosis cystica [due to secondary hyperparathyroidism], osteomalacia, adynamic bone disease, and/or mixed osteodystrophy), rather than osteoporosis, become predominant. The principal goal with regard to bone disease in patients with significant renal dysfunction is to prevent or manage renal osteodystrophy, largely by controlling secondary hyperparathyroidism; preventing oversuppression of PTH, which can lead to adynamic bone disease; and treating acidosis and vitamin D deficiency. In this setting, the diagnosis of osteoporosis should be made only after excluding renal osteodystrophy. The diagnosis, evaluation, and management of osteoporosis in patients with CKD is reviewed separately. (See "Osteoporosis in patients with chronic kidney disease: Diagnosis and evaluation".)
Overview of available therapies
Anti-resorptive agents
Bisphosphonates — Alendronate, risedronate, ibandronate, and zoledronic acid are effective for both the prevention and treatment of osteoporosis. These drugs increase bone mass and reduce the incidence of fractures. General principles of bisphosphonate administration, adverse effects, duration of use, and drug holidays are discussed in detail elsewhere. (See "Bisphosphonate therapy for the treatment of osteoporosis" and "Risks of bisphosphonate therapy in patients with osteoporosis".)
Denosumab — Denosumab is not considered initial therapy for most patients with osteoporosis. However, denosumab could be used as initial therapy in certain patients at high risk for fracture, such as older patients who have difficulty with the dosing requirements of oral bisphosphonates or who have markedly impaired renal function. In addition, denosumab is an option for patients who are intolerant of or unresponsive to other therapies (including IV bisphosphonates) and in those with impaired renal function.
In several trials, denosumab has been shown to improve BMD and reduce the incidence of new vertebral, hip, and nonvertebral fractures in postmenopausal women. However, emerging data have raised concern about increased risk of vertebral fracture after discontinuation of denosumab. If denosumab is discontinued, administering an alternative therapy (typically a bisphosphonate) to prevent rapid bone loss and vertebral fracture is advised. (See "Denosumab for osteoporosis", section on 'Increased vertebral fractures' and "Denosumab for osteoporosis", section on 'Sequential osteoporosis therapy'.)
Selective estrogen receptor modulators — There are nonskeletal considerations with SERMs that may play an important role in the selection of postmenopausal women for therapy, including potential beneficial effects on breast cancer risk reduction, but an increase in thromboembolic events and possibly hot flashes, and no apparent effect on heart disease or the endometrium. Raloxifene inhibits bone resorption and reduces the risk of vertebral fracture, and it is our SERM of choice because it has eight-year safety and efficacy data and also reduces the risk of breast cancer. Raloxifene is usually chosen for osteoporosis when there is an independent need for breast cancer prophylaxis.
Tamoxifen is another SERM used primarily for the prevention and management of breast cancer. It is not typically used for osteoporosis, but postmenopausal women who are receiving treatment with tamoxifen for breast cancer are probably receiving effective bone protection.
Bazedoxifene, another SERM, is available in Europe and Japan for the treatment of postmenopausal osteoporosis in women at increased risk for fracture. Although it has similar efficacy as raloxifene in preventing and treating postmenopausal osteoporosis, there are few long-term safety data, and it has not been adequately studied for breast cancer prevention. It is not available as a standalone drug in the United States; however, it is available in combination with conjugated estrogen for prevention of osteoporosis [67]. The SERMs are discussed in more detail elsewhere. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis" and "Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention".)
Estrogen/progestin therapy — Estrogen-progestin therapy is no longer a first-line approach for the treatment of osteoporosis in postmenopausal women, because of increased risk of breast cancer, stroke, venous thromboembolism (VTE), and perhaps coronary disease (although the risk-benefit profile in the unopposed estrogen trial was different) [68]. (See "Menopausal hormone therapy: Benefits and risks".)
Possible indications for estrogen-progestin therapy in postmenopausal women include persistent menopausal symptoms and women with an indication for anti-resorptive therapy who cannot tolerate the other drugs. In the Women's Health Initiative (WHI), both combined estrogen-progestin and unopposed estrogen treatment reduced hip and vertebral fracture risk (figure 1). The use of estrogen for osteoporosis is reviewed in detail elsewhere. (See "Menopausal hormone therapy in the prevention and treatment of osteoporosis".)
Anabolic agents
Parathyroid hormone/parathyroid hormone-related protein analog — The anabolic agents, teriparatide and abaloparatide, are not considered initial therapy for most patients. Possible candidates for anabolic agents include men or postmenopausal women with severe osteoporosis (T-score of ≤-3.5 even in the absence of fractures, or T-score of ≤-2.5 plus a fragility fracture), patients with osteoporosis who are unable to tolerate bisphosphonates or who have contraindications to oral bisphosphonates (achalasia, scleroderma involving the esophagus, esophageal strictures), and patients who fail other osteoporosis therapies (fracture with loss of BMD in spite of compliance with therapy).
In contrast to anti-resorptive agents, anabolic agents stimulate bone formation and activate bone remodeling. The use of anabolic agents as a therapy for osteoporosis is reviewed in detail elsewhere. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis".)
Romosozumab — Romosozumab is an anabolic agent approved by the US Food and Drug Administration (FDA) in 2019 based on trials showing a reduction in vertebral and nonvertebral fractures with romosozumab compared with placebo or with alendronate [69].
Romosozumab is not considered initial therapy for most patients with osteoporosis. Possible candidates include patients at with multiple fragility fractures, those at high risk for fracture who cannot tolerate any other osteoporosis therapies, or those who fail other osteoporosis therapies (fracture with loss of BMD in spite of compliance with therapy).
Romosozumab is a monoclonal anti-sclerostin antibody. Sclerostin is produced by osteocytes and inhibits bone formation. Sclerostin knockout mice have increased bone formation and high bone mass [70]. It follows that inhibition of sclerostin should enhance osteoblast function and improve bone mass and reduce fractures.
●Bone mineral density – In a phase II trial in postmenopausal women, all doses of a monoclonal anti-sclerostin antibody (romosozumab) increased bone density at the LS, total hip, and femoral neck [71,72]. In this one-year trial, 419 postmenopausal women with low bone mass (T-score between -2.0 and -3.5 at the LS, total hip, or femoral neck) were randomly assigned to subcutaneous romosozumab (variable dosing once monthly or once every three months), an active comparator (oral alendronate, 70 mg weekly, or subcutaneous teriparatide, 20 mcg daily), or placebo injections (monthly or every three months). The greatest increase in LS bone density was seen in the group receiving romosozumab 210 mg monthly (11.3 percent compared with 4.1 and 7.1 percent in the alendronate and teriparatide groups, respectively). There was a transient increase in bone formation markers and a more sustained decrease in bone resorption markers, a pattern that has not been seen among available osteoporosis therapies.
Romosozumab has also been evaluated in patients previously treated with alendronate. In a phase III, open-label trial, 436 postmenopausal women with osteoporosis who had taken an oral bisphosphonate for at least three years (mean 6.2 years), had low BMD (≤-2.5 at the hip or spine), and had a history of fracture were randomly assigned to romosozumab (210 mg subcutaneously once monthly) or teriparatide (20 mcg subcutaneously once daily) [73]. After 12 months, the mean change from baseline in total hip (+2.6 versus -0.6 percent) and LS (+9.8 versus +5.4 percent) BMD was better with romosozumab. Fracture data were collected as adverse events and occurred in a similar proportion of patients (3 to 4 percent).
●Fracture reduction – In two subsequent trials specifically designed to assess fracture outcomes, treatment with romosozumab reduced the incidence of radiographic vertebral [74,75] and, in one study, nonvertebral [75] fractures.
•In one trial, 7180 postmenopausal women with osteoporosis (mean T scores at the LS, total hip, and femoral neck of -2.72, -2.47, and -2.75, respectively) were randomly assigned to romosozumab (210 mg subcutaneously once monthly) or placebo for 12 months [74]. Thereafter, all women received denosumab (60 mg subcutaneously every six months) for an additional 12 months. After 12 (0.5 versus 1.8 percent) and 24 months (0.6 versus 2.5 percent), the incidence of radiographic vertebral fracture was lower in the romosozumab group than in the placebo group (risk ratio at 12 months 0.27, 95% CI 0.16-0.47). The reduction in the incidence of nonvertebral fracture, a secondary endpoint, was not significant (1.6 versus 2.1 percent, hazard ratio [HR] 0.75, 95% CI 0.53-1.05).
•In another trial, 4093 postmenopausal women with osteoporosis and prior fragility fracture (mean T-scores at the LS, total hip, and femoral neck of -2.96, -2.80, and 2.90, respectively) were randomly assigned to monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) for 12 months [75]. All patients subsequently received weekly oral alendronate. After 24 months, there were fewer radiographic vertebral fractures in the romosozumab-to-alendronate group than the alendronate-to-alendronate group (6.2 versus 11.9 percent, RR 0.52, 95% CI 0.40-0.66). At the time of the primary analysis, the risk of clinical fractures (9.7 versus 13 percent), nonvertebral fractures (8.7 versus 10.6 percent), and hip fractures (2.0 versus 3.2 percent) was also lower in the romosozumab group. Romosozumab followed by alendronate appears to be more effective than alendronate alone in postmenopausal women with established osteoporosis.
●Adverse effects/contraindications – In the romosozumab trials, there was an increased frequency of injection site reactions in the romosozumab group [73-75]. There were no cases of atypical femoral fractures or osteonecrosis of the jaw in two trials [73,75], whereas there were two cases of osteonecrosis of the jaw and one atypical femoral fracture in the other (all in the romosozumab group) [74].
In one trial, more patients in the romosozumab group had serious cardiovascular events (cardiac ischemic, and cerebrovascular accidents [0.8 versus 0.3 percent]) [75]. Further evaluation is needed to determine the etiology of the cardiovascular events. In the interim, romosozumab should not be offered to women with prior history or at increased risk of myocardial infarction or stroke.
●Duration of therapy – Treatment with romosozumab (210 mg monthly by subcutaneous injection) is limited to 12 monthly doses. Patients with severe osteoporosis who are treated initially with an anabolic agent are typically treated with an anti-resorptive agent (preferably a bisphosphonates) after discontinuation, to preserve the gains in BMD achieved with the anabolic agent [40,75].
Therapies not recommended — Several therapies have been evaluated for the treatment of osteoporosis with disappointing or conflicting results. We typically do not recommend the following therapies:
Combination therapy — We suggest not using combination therapy, as the additional BMD benefits are small and there is no proven additional fracture benefit. Combination osteoporosis therapies are discussed separately. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Combination therapy not recommended' and "Menopausal hormone therapy in the prevention and treatment of osteoporosis", section on 'Estrogen versus bisphosphonate therapy' and "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Choice of bisphosphonate'.)
Calcitonin — We prefer other drugs to calcitonin because of its relatively weak effect on BMD and poor antifracture efficacy compared with bisphosphonates and PTH [76]. There is concern about the long-term use of calcitonin for osteoporosis and an increase in cancer rates. This is reviewed separately. (See "Calcitonin in the prevention and treatment of osteoporosis", section on 'Concerns about the use of calcitonin'.)
Other — Additional therapies for postmenopausal osteoporosis are either under investigation or are used in some countries. We do not routinely use any of these therapies.
●Calcitriol – The results of clinical trials of calcitriol in postmenopausal osteoporosis have been mixed. (See "Calcium and vitamin D supplementation in osteoporosis".)
However, calcitriol has been reported to be effective in preventing glucocorticoid-induced and post-transplant-related bone loss. (See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Calcium and vitamin D' and "Osteoporosis after solid organ or stem cell transplantation", section on 'Contraindications/intolerance to bisphosphonates'.)
Patients treated with calcitriol should be given a low-calcium diet and monitored for hypercalcemia, hypercalciuria, and renal insufficiency. These potential problems plus the lack of proven consistent benefit have appropriately limited the use of calcitriol.
●Strontium ranelate – Because strontium ranelate is a weak anti-resorptive agent [77] and there are more effective osteoporosis agents in the United States and most countries, we do not use strontium ranelate in postmenopausal women with osteoporosis.
Strontium ranelate, an orally active drug consisting of two atoms of stable strontium and an organic moiety (ranelic acid), had been available for use in Europe for the treatment of osteoporosis. However, the manufacturer discontinued marketing and distribution in 2017 [78-80].
In 2014, the European Medicines Agency had recommended restriction in the use of strontium based upon an analysis of pooled data showing an increased risk of myocardial infarction with use of strontium ranelate and other serious risks (severe skin reactions, thromboembolic disease) previously identified [77,81-86]. However, in subsequent observational studies (United Kingdom Clinical Practice Research Datalink and a nationwide Danish study), the risk of myocardial infarction with use of strontium ranelate was not increased [87,88].
●Vitamin K – We do not recommend routine vitamin K supplementation for the maintenance of skeletal health or the prevention of fractures in high-risk individuals.
Exogenous vitamin K is required for the carboxylation of osteocalcin, which in turn allows osteocalcin to bind to hydroxyapatite mineral. A vitamin K2 preparation (menatetrenone) is widely used for the treatment of osteoporosis in Japan, based upon clinical trial data showing improvement in BMD and a reduction in fracture risk in postmenopausal Japanese women [89-91]. However, the data are conflicting, and no benefit has been demonstrated in other populations [92-94].
●Tibolone – Tibolone, a synthetic steroid whose metabolites have estrogenic, androgenic, and progestogenic properties [95], is used for osteoporosis management in some countries (but is not available in the United States). Tibolone improves BMD in older postmenopausal women with established osteoporosis and prevents bone loss in early postmenopausal women without osteoporosis [96-99].
Tibolone also reduces vertebral fracture risk. The Long-Term Intervention on Fractures with Tibolone (LIFT) trial, a trial designed to examine the effect of tibolone on vertebral fracture in postmenopausal women, reported a reduction in the absolute risk of vertebral and nonvertebral fracture (8.6 and 6.9 per 1000 person-years, respectively; relative hazards of 0.55, 95% CI 0.41-0.74 and 0.74, 95% CI 0.58-0.93, respectively) [100]. However, this trial was discontinued early due to an excess risk of stroke.
Other effects of tibolone are discussed separately. (See "Preparations for menopausal hormone therapy", section on 'Tibolone'.)
●Folate/vitamin B12 – We do not recommend supplemental folic acid or vitamin B12 for the treatment of osteoporosis or primary prevention of fracture. Folate and B12 supplementation did not reduce the incidence of vertebral or nonvertebral fractures in adults at high risk for cardiovascular disease, who had normal baseline homocysteine concentrations [101].
●Androgens – We do not recommend androgen therapy for osteoporosis management in women. The effect of treatment with androgen plus estrogen on BMD does not appear superior to the effect of estrogen alone, and androgen has unwelcome virilizing effects [102]. Furthermore, the presumed beneficial effects of testosterone on bone in men may be mediated by its conversion to estrogen, as evidenced by the marked improvement in low bone mass following estrogen therapy in men with aromatase deficiency, which impairs the conversion of androgen to estrogen [103,104]. (See "Etiology of osteoporosis in men" and "Overview of androgen deficiency and therapy in women".)
●Isoflavones – We do not recommend isoflavone supplements as a strategy to prevent or treat osteoporosis.
Isoflavones (a type of phytoestrogen) are micronutrient substances that have properties similar to estrogen. Two types of isoflavones, genistein and daidzein, are found in soybeans, chickpeas, and lentils and are thought to be the most potent phytoestrogens. Ipriflavone is a synthetic isoflavone derivative and is widely available as an over-the-counter product in many countries.
Some studies have reported that phytoestrogens have a beneficial effect on markers of bone resorption, BMD, and fracture risk in animal models [105] and in postmenopausal women [106-108], while others have not [109-112]. The differences may be due, in part, to the composition of the isoflavones studied. There are no randomized trials that assess the effect of isoflavones on fracture as a primary outcome.
●Fluoride – Given the availability of other therapies, including teriparatide (anabolic agent), we do not recommend fluoride for the treatment of patients with osteoporosis.
There is historical interest in fluoride as an anabolic agent for the treatment of postmenopausal osteoporosis. Although fluoride increases BMD substantially, clinical trials of fluoride have not consistently demonstrated fracture reduction [113-117]. While some studies demonstrated a decrease in the incidence of new vertebral fracture [114,115,117], others reported no change [116] or even an increase in nonvertebral fractures [113,118]. Fluoride impairs bone mineralization, even when the dose is as low as 20 mg daily [118].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Osteoporosis (The Basics)" and "Patient education: Calcium and vitamin D for bone health (The Basics)" and "Patient education: Medicines for osteoporosis (The Basics)")
●Beyond the Basics topics (see "Patient education: Osteoporosis prevention and treatment (Beyond the Basics)" and "Patient education: Calcium and vitamin D for bone health (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Lifestyle measures – Lifestyle measures should be adopted universally to reduce bone loss in postmenopausal women. Lifestyle measures include adequate calcium and vitamin D, exercise, smoking cessation, counseling on fall prevention, and avoidance of heavy alcohol use. In general, 1200 mg of elemental calcium daily, total diet plus supplement, and 800 international units of vitamin D daily are advised. Postmenopausal women who are getting adequate calcium from dietary intake alone do not need to take calcium supplements (table 1). If dietary intake is inadequate, we suggest calcium supplementation (Grade 2B). (See 'Lifestyle measures' above.)
Many patients require vitamin D supplementation as it is difficult to achieve goals with diet alone (table 3). (See "Calcium and vitamin D supplementation in osteoporosis".)
●Patient selection for osteoporosis pharmacologic therapy
•We recommend that postmenopausal women with established osteoporosis (T-score ≤-2.5) or fragility fracture be treated with a pharmacologic agent (Grade 1A). (See 'Patient selection' above.)
•For the treatment of high-risk postmenopausal women with T-scores between -1.0 and -2.5, we also suggest pharmacologic therapy (Grade 2B). A reasonable cutpoint that may be cost effective in some settings is a 10-year probability of hip fracture or combined major osteoporotic fracture of ≥3.0 or ≥20 percent, respectively. (See 'Patient selection' above.)
●Choice of initial therapy
•Most women – For the initial treatment of osteoporosis in postmenopausal women, we suggest oral bisphosphonates (algorithm 1) (Grade 2B). We prefer oral bisphosphonates as initial therapy because of their efficacy, favorable cost, and the availability of long-term safety data. For most postmenopausal women with osteoporosis, we suggest either alendronate or risedronate as the initial choice of bisphosphonate (Grade 2B). Oral ibandronate may be more convenient for patients, but a reduction in hip fracture risk has not been established in randomized trials. (See 'Initial therapy' above and "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Choice of bisphosphonate'.)
•Severe osteoporosis – For postmenopausal women with severe osteoporosis, some UpToDate experts prefer initial treatment with an anabolic agent, whereas other UpToDate experts prefer initial treatment with bisphosphonates because of the cost of anabolic therapy, subcutaneous route of administration, and long-term safety concerns (algorithm 1). When a decision has been made to treat with an anabolic agent, we suggest teriparatide or abaloparatide (Grade 2B). Romosozumab is an alternative. Teriparatide has a long track record of safety, whereas there is less experience with the long-term use of abaloparatide. Romosozumab induces a greater BMD response than either abaloparatide or teriparatide, but treatment is indicated for only one year because clinical experience is limited and the long-term side effects uncertain. (See 'Severe osteoporosis' above and 'Choice of drug' above and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Choice of therapy'.)
●Contraindications to bisphosphonates
•Oral bisphosphonates – Patients who have esophageal disorders (achalasia, scleroderma involving the esophagus, esophageal strictures, varices), gastrointestinal intolerance to oral bisphosphonates, history of Roux-en-Y gastric bypass, or an inability to follow the dosing requirements of oral bisphosphonates, including an inability to sit upright for 30 to 60 minutes and/or to swallow a pill, should not be treated with oral bisphosphonates and can be treated instead with intravenous (IV) bisphosphonate therapy (algorithm 1). Zoledronic acid is the only IV bisphosphonate that has demonstrated efficacy for fracture prevention and is, therefore, our agent of choice. (See 'Contraindications/intolerance to oral bisphosphonates' above.)
•Oral and IV bisphosphonates – For patients who cannot receive or are intolerant of oral and IV bisphosphonates, the choice of agent depends on risk of fracture (eg, history of prior fragility fractures, BMD T-scores, comorbidities), efficacy, adverse effect profile, and patient preferences. (See 'Contraindications/intolerance to any bisphosphonates' above and 'Choice of drug' above.)
-Very high risk of fracture – For patients at very high risk of fracture (eg, T-score of ≤-3.0, T-score of ≤-2.5 plus a fragility fracture, severe or multiple vertebral fractures), we suggest an anabolic agent (Grade 2B). Although use of anabolic agents is generally reserved for individuals at very high risk of fracture, they can be used in patients with less severe osteoporosis (eg, T-scores ≤-2.5 without a fragility fracture) who are unable to tolerate oral or IV bisphosphonates. (See 'Severe osteoporosis' above and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Overview of approach'.)
-High risk of fracture – For patients at high risk for fracture (eg, osteoporosis by BMD in the absence of fragility fracture, T-score >-2.5 with a fragility fracture, single vertebral fracture), we suggest denosumab rather than an anabolic agent (Grade 2B). Because of emerging concerns about an increased risk of vertebral fracture after discontinuation of denosumab, the need for indefinite administration of denosumab should be discussed with patients prior to its initiation. (See "Denosumab for osteoporosis", section on 'Duration of therapy'.)
-High risk of breast cancer – For patients with no history of fragility fractures, raloxifene is a reasonable alternative, particularly in women at high risk for breast cancer. (See "Selective estrogen receptor modulators for prevention and treatment of osteoporosis", section on 'Choice of drug'.)
●Monitoring – For patients starting on therapy, we obtain a follow-up dual-energy x-ray absorptiometry (DXA) of the hip and spine after two years, and if BMD is stable or improved, less frequent monitoring thereafter. (See 'Our approach' above.)
The finding of a clinically significant BMD decrease or a new fracture in a treated patient should trigger additional evaluation for contributing factors, which may include poor adherence to therapy, inadequate gastrointestinal absorption, inadequate intake of calcium and vitamin D, or the development of a disease or disorder with adverse skeletal effects. (See 'Bone mineral density decreased or fracture during therapy' above.)
•Decrease in BMD <5 percent – For patients who have a decrease in BMD (<5 percent) while correctly taking bisphosphonates orally and who have no discernible contributing factors, we suggest continuing the same therapy (Grade 2C). We repeat the BMD two years later. An alternative option is to switch therapies at the time of the initial decrease in BMD. (See 'Bone mineral density decreased or fracture during therapy' above.)
•Decrease in BMD ≥5 percent – For patients who have a decrease in BMD (≥5 percent) while correctly taking bisphosphonates orally, we suggest switching from an oral to an IV bisphosphonate (Grade 2C). If the lack of response is related to poor absorption, switching to an IV preparation should result in a more favorable response. Other alternatives include switching to denosumab, teriparatide, abaloparatide, or romosozumab. (See 'Bone mineral density decreased or fracture during therapy' above.)
•Fracture while taking bisphosphonates – For postmenopausal women with severe osteoporosis (T-score of ≤-2.5 plus a fragility fracture) who continue to fracture after one year of bisphosphonate therapy, we suggest discontinuing the bisphosphonate and switching to teriparatide (Grade 2B). (See 'Bone mineral density decreased or fracture during therapy' above and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Management after teriparatide'.)
Abaloparatide, romosozumab, and denosumab are alternative options for patients who are unresponsive to other therapies and in those with impaired renal function. In the absence of contraindications, it may be beneficial to treat with an anabolic agent first (maximum of one to two years, depending on the drug), followed by denosumab, to preserve the gains in BMD achieved with the anabolic agent. Because of emerging concerns about an increased risk of vertebral fracture after discontinuation of denosumab, the need for indefinite administration of denosumab should be discussed with patients prior to its initiation. (See "Denosumab for osteoporosis", section on 'Duration of therapy'.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Marc K Drezner, MD, who contributed to an earlier version of this topic review.
