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Bisphosphonate therapy for the treatment of osteoporosis

Bisphosphonate therapy for the treatment of osteoporosis
Author:
Harold N Rosen, MD
Section Editors:
Clifford J Rosen, MD
Kenneth E Schmader, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Dec 2022. | This topic last updated: Jul 21, 2022.

INTRODUCTION — Osteoporosis is caused by the cumulative effect of bone resorption in excess of bone formation. Bisphosphonates inhibit bone resorption with relatively few side effects. As a result, they are widely used to prevent osteoporotic fractures.

The use of bisphosphonates for the management of osteoporosis will be reviewed here. An overview of other treatment options for osteoporosis is discussed separately. (See "Overview of the management of osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men" and "Evaluation and treatment of premenopausal osteoporosis" and "Prevention of osteoporosis".)

Bisphosphonates are also used in the management of hypercalcemia, Paget disease, and a number of malignancies, including multiple myeloma, breast cancer, and prostate cancer. These topics are all reviewed separately in the appropriate topic reviews.

GENERAL PRINCIPLES

Lifestyle measures — Lifestyle measures include adequate calcium and vitamin D, exercise, smoking cessation, counseling on fall prevention, and avoidance of heavy alcohol use. These measures should be adopted universally to reduce bone loss in people with osteoporosis. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Lifestyle measures' and "Treatment of osteoporosis in men", section on 'Lifestyle measures'.)

Pharmacologic therapy — In addition to lifestyle measures, patients at high risk for fracture should receive pharmacologic therapy. Recommendations in whom to initiate pharmacologic therapy are reviewed elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Patient selection' and "Treatment of osteoporosis in men", section on 'Candidates for therapy'.)

In the absence of specific contraindications, oral bisphosphonates are considered initial pharmacologic therapy for most patients at high risk for fracture. We prefer oral bisphosphonates as initial therapy because of their efficacy, favorable cost, and the availability of long-term safety data. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Initial therapy' and "Treatment of osteoporosis in men", section on 'Bisphosphonates' and 'Choice of bisphosphonate' below.)

Contraindications to bisphosphonates — Oral bisphosphonates should not be used in the following settings:

As initial therapy in patients with esophageal disorders (eg, achalasia, esophageal stricture, esophageal varices, Barrett's esophagus) or with an inability to follow the dosing requirements (eg, stay upright for at least 30 minutes).

After certain types of bariatric surgery in which surgical anastomoses are present in the gastrointestinal (GI) tract (eg, Roux-en-Y gastric bypass).

For patients with contraindications to oral bisphosphonates, GI intolerance to oral bisphosphonates, or an inability to follow the dosing requirements (eg, stay upright for at least 30 minutes), we suggest an intravenous (IV) bisphosphonate formulation. (IV bisphosphonates are acceptable after bariatric procedures as long as vitamin D has been assessed and is in the normal range.) (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Contraindications/intolerance to oral bisphosphonates' and 'Choice of bisphosphonate' below.)

Oral and IV bisphosphonates should not be used routinely in patients with chronic kidney disease (CKD) and an estimated glomerular filtration rate (eGFR) <30 to 35 mL/min. (See 'Use in chronic kidney disease' below.)

Additional therapies for patients with contraindications to bisphosphonates are reviewed elsewhere. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Contraindications/intolerance to any bisphosphonates' and "Treatment of osteoporosis in men", section on 'Contraindications/intolerance to any bisphosphonates'.)

CHOICE OF BISPHOSPHONATE

Oral – We suggest alendronate or risedronate as the initial choice of oral bisphosphonate (table 1). 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 [1]. Generic alendronate and risedronate are available in many countries, including the United States. Most patients prefer the convenience of the once-weekly regimen.

For people with well-controlled gastroesophageal reflux or peptic ulcer disease, initial therapy with either risedronate or alendronate is also acceptable.

For people with a history of gastrointestinal (GI) side effects to alendronate (but without esophageal disorders), risedronate can be substituted as some patients may have fewer GI side effects.

Intravenous (IV) – For patients with contraindications or intolerance to oral bisphosphonates, we suggest IV zoledronic acid because it has been shown to prevent fractures in clinical trials (table 1). Generic zoledronic acid is available in the United States, United Kingdom, and other countries.

Alendronate, risedronate, ibandronate, and zoledronic acid have all been shown to improve bone mineral density (BMD) in postmenopausal women and in men with osteoporosis [2,3]. In addition, a systematic review of trials published between 2005 and 2019 confirmed the vertebral fracture prevention efficacy of several bisphosphonates, including alendronate, risedronate, zoledronic acid, and ibandronate, compared with placebo [4,5]. Alendronate, risedronate, and zoledronic acid also reduce the risk of hip and other nonvertebral fractures [4-6]. Bisphosphonates also reduce vertebral fracture in men. (See "Treatment of osteoporosis in men", section on 'Bisphosphonates'.)

AlendronateAlendronate increases BMD (figure 1) and decreases the risk of vertebral fractures in women with and without a prior history of vertebral fracture [7-10]. In a meta-analysis of 11 trials of alendronate therapy in postmenopausal women, there were fewer vertebral fractures with alendronate for both primary prevention (1.4 versus 3.4 percent, RR 0.55, 95% CI 0.38-0.80) and secondary prevention (6.2 versus 12.2 percent, relative risk [RR] 0.55, 95% CI 0.43-0.69) [11]. In addition, alendronate reduced nonvertebral fractures (7.3 versus 9.3 percent, RR 0.77, 95% CI 0.64-0.92) and hip fractures (0.3 versus 1.3 percent, RR 0.47, 95% CI 0.26-0.85) in patients with a previous fracture (secondary prevention) [11]. Alendronate has been shown to be effective in Black American women [12] and in older women in long-term care facilities [13,14].

RisedronateRisedronate improves BMD and reduces fracture risk in postmenopausal osteoporosis [15-21]. In a meta-analysis of eight randomized trials of risedronate versus placebo in postmenopausal women with established osteoporosis, risedronate reduced the risk of vertebral (RR 0.64, 95% CI 0.54-0.77) and nonvertebral (RR 0.73, 95% CI 0.61-0.87) fracture [16].

In one of the larger trials in the meta-analysis, the three-year rates of new vertebral fractures with risedronate versus placebo were 11.3 and 16.3 percent (RR 0.59, 95% CI 0.42-0.82), and 5.2 versus 8.4 percent for nonvertebral fractures (RR 0.61, 95% CI 0.39-0.94) [15].

In the largest trial evaluating hip fracture efficacy, risedronate significantly reduced the risk of hip fracture among older women with confirmed osteoporosis (1.9 versus 3.2 percent with placebo [RR 0.6, 95% CI 0.4-0.9]) but not among older women (>80 years) selected primarily on the basis of nonskeletal risk factors, such as poor gait, smoking, and propensity to fall (4.2 versus 5.1 percent [RR 0.8, 95% CI 0.6-1.2]) [21].

Alendronate versus risedronateAlendronate and risedronate have been compared in one randomized trial and in some retrospective observational trials. In the randomized trial, alendronate increased bone density more than risedronate at all sites after 12 months [22]. Results persisted in year 2 of the study [23]. However, there were no differences in the incidence of fractures, which were reported only as adverse events. In one observational study, treatment with risedronate was associated with a decreased risk of fracture in the first year of therapy compared with alendronate [24]. However, this study was limited by the inability to accurately characterize fracture risk at baseline between the two groups. A prospective randomized trial with fracture as a defined endpoint is necessary to determine if there is a difference in fracture prevention efficacy between the two bisphosphonates, and it is very unlikely such a trial will ever be conducted.

Zoledronic acidZoledronic acid is a bisphosphonate that is administered as a 30-minute intravenous infusion once yearly. It increases BMD and reduces fracture risk [25-28]. In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) studies, yearly IV zoledronic acid (for three consecutive years) compared with placebo [25,26]:

Improved BMD.

Decreased vertebral (3.3 versus 10.9 percent [RR 0.30, 95% CI 0.24-0.38]) and hip (1.4 versus 2.5 percent [HR 0.59, 95% CI 0.42-0.83]) fractures in postmenopausal women with BMD T-score ≤-2.5 or with T-score ≤-1.5 and radiologic evidence of vertebral fracture(s).

Decreased any new clinical fracture in men and women with recent hip fracture (8.6 and 13.9 percent [HR 0.65, 95% CI 0.50-0.84]).

Decreased all-cause mortality, a secondary safety endpoint, in men and women with recent hip fracture (9.6 versus 13.3 percent [HR 0.72, 95% CI 0.56-0.93]).

Ibandronate Ibandronate increases BMD and reduces the risk of vertebral fracture; a significant reduction in hip fracture has not been demonstrated [29-34]. Meta-analyses of phase III studies, in which fracture data were collected as adverse effects, have shown a reduction in nonvertebral fractures with higher doses of ibandronate (pooled data from IV dosing [2 or 3 mg every 2 to 3 months] and oral dosing [150 mg monthly]) [33,34]. However, there are no direct nonvertebral fracture efficacy data for IV ibandronate.

Therapies/regimens not recommended – A number of other bisphosphonates are available, but they are no longer used for osteoporosis.

Etidronate was the first bisphosphonate used in the treatment of osteoporosis. It increased BMD and decreased vertebral, but not nonvertebral, fractures, and it was never approved for treating postmenopausal osteoporosis. In addition, there was concern that long-term use may cause osteomalacia. Therefore, it has been superseded by other bisphosphonates.

Tiludronate, an effective therapy for Paget disease of bone, has not been demonstrated to be effective for the treatment or prevention of osteoporosis. (See "Treatment of Paget disease of bone".)

Pamidronate, an IV preparation, has been used primarily for the treatment of hypercalcemia and prevention of skeletal complications in multiple myeloma, breast cancer, and prostate cancer. (See "Treatment of hypercalcemia".)

Pamidronate is also effective for osteoporosis and has been used for patients with osteoporosis who could not tolerate oral bisphosphonates [35]. However, it has been superseded by zoledronic acid (and in some cases IV ibandronate) because these drugs have fracture efficacy data.

We also suggest not using bisphosphonates in combination with other osteoporosis drugs, as the additional BMD benefits are small, and there is no proven additional fracture benefit [36-41]. Furthermore, there is theoretical concern that combination antiresorptive therapy could oversuppress bone turnover and cause increased skeletal fragility. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Atypical femur fracture'.)

Because teriparatide (parathyroid hormone [PTH]) stimulates bone formation and bisphosphonates reduce bone resorption, it has been hypothesized that combining the two therapies would increase bone density more than either therapy alone. However, the addition of a bisphosphonate to teriparatide therapy provides little additional benefit for BMD, and in some studies, the addition of bisphosphonates actually reduced the increase in BMD from teriparatide. It is important to note that fracture data are unavailable for combination therapy. (See "Treatment of osteoporosis in men", section on 'Combination therapy' and "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Combination therapy not recommended'.)

PRACTICAL MANAGEMENT ISSUES

Pretreatment evaluation — Before starting bisphosphonates, patients should be evaluated to detect potentially remediable causes of or other contributing factors to osteoporosis.

Biochemical assessment – This evaluation includes assessment for hypocalcemia, vitamin D deficiency, and renal impairment by measuring serum (algorithm 1):

Calcium

25-hydroxyvitamin D (25[OH]D)

Creatinine

For both oral and intravenous (IV) bisphosphonates, correction of hypocalcemia and/or vitamin D deficiency (to at least 20 ng/mL [50 nmol/L]) is necessary prior to administration. (See "Calcium and vitamin D supplementation in osteoporosis" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

Assess comorbidities – In addition, assessment for comorbidities that may preclude use or alter the administration of bisphosphonates is necessary. For oral bisphosphonates, this typically includes a careful history to detect any abnormalities of the esophagus (stricture, achalasia) and an inability to remain upright for at least 30 to 60 minutes.

Plans for invasive dental procedures – For both oral and IV bisphosphonates, we also inquire about imminent plans for invasive dental procedures (extractions, implants) and discuss risk factors for developing osteonecrosis of the jaw (ONJ), a rare complication of IV or oral therapy. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the jaw'.)

If a dental implant or extraction is already planned, we frequently delay bisphosphonate therapy for a few months until healing of the jaw is complete. If a patient is already taking bisphosphonates, the approach is uncertain and there are few data to guide management. Some clinicians ask patients to discontinue bisphosphonates and resume again when healing is complete, while others suggest not stopping bisphosphonates. Guidelines from the American Association of Oral and Maxillofacial Surgeons suggest performing dentoalveolar surgery, such as extractions and implants, as usual in patients who have been treated with oral bisphosphonates for less than four years and have no clinical risk factors [42]. They suggest discontinuing bisphosphonates if a patient has been treated for more than four years or has taken concomitant glucocorticoids. This topic is reviewed in more detail separately. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the jaw'.)

Oral regimen — Bisphosphonates are poorly absorbed orally (less than 1 percent of the dose) [43] and must be taken on an empty stomach for maximal absorption. The following regimen is recommended to maximize absorption and minimize the risk of esophageal adverse effects. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Gastrointestinal'.)

Bisphosphonates should not be given to patients with active upper gastrointestinal (GI) disease.

Bisphosphonates should be discontinued in patients who develop any symptoms of esophagitis.

Bisphosphonates should be taken alone on an empty stomach first thing in the morning with at least 240 mL (8 oz) of water. After administration, the patient should not have food, drink, medications, or supplements for at least one half-hour (alendronate, risedronate) or one hour (ibandronate).

The reason for taking 8 oz of water is to minimize the risk of the tablet getting stuck in the esophagus. The reason for taking the medication while fasting and waiting one half-hour until eating or drinking is that bioavailability may be seriously impaired by ingestion with liquids other than plain water, such as mineral water, coffee, or juice; by retained gastric contents, as with insufficient fasting time or gastroparesis; or by eating or drinking too soon afterwards.

The regimen for enteric-coated, delayed-release risedronate is different from that of other bisphosphonates. The enteric-coated, delayed-release formulation is taken immediately after breakfast with 4 oz of water [44].

Patients should remain upright (sitting or standing) for at least 30 minutes after administration to minimize the risk of reflux.

Compliance is also important for optimal fracture reduction [45-47].

Timing of dose — Administration of bisphosphonates first thing in the morning, prior to breakfast, appears to be important for bioavailability and subsequent suppression of bone turnover. This was illustrated in a randomized trial of nursing home residents who were assigned to risedronate or placebo between meals (after a two-hour fast) for 12 weeks, rather than before breakfast or the first liquid of the day [48]. Markers of bone turnover were not suppressed as they typically would be with before-breakfast administration, suggesting that this alternative schedule may not provide the desired effects on bone mineral density (BMD).

Calcium/vitamin D — Vitamin D insufficiency and inadequate calcium intake are common in patients with osteoporosis. In the majority of bisphosphonate trials described below, calcium and vitamin D supplements were also administered. Therefore, patients receiving bisphosphonates should take supplemental calcium and vitamin D. However, calcium and other mineral (eg, magnesium, iron) supplements can interfere with the absorption of bisphosphonates, and they should not be taken for at least one hour after taking oral bisphosphonates. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Calcium/vitamin D' and "Calcium and vitamin D supplementation in osteoporosis", section on 'Summary and recommendations'.)

IV regimen — Intravenous (IV) bisphosphonates (zoledronic acid and ibandronate) provide an alternative option for patients who cannot tolerate oral bisphosphonates or who have difficulty with dosing requirements, including an inability to sit upright for 30 to 60 minutes and/or to swallow a pill. Zoledronic acid (5 mg) is administered yearly and must be infused over a period of at least 30 minutes, whereas ibandronate is administered every 3 months as a 15- to 30-second IV injection.

Prior to receiving IV bisphosphonates, patients should be assessed for hypocalcemia, vitamin D deficiency, and renal impairment by measuring serum calcium, creatinine, and 25(OH)D, as described above. (See 'Pretreatment evaluation' above.)

Hypocalcemia may occur in patients treated with IV bisphosphonates (see "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Hypocalcemia'). It is more likely to occur in those individuals with vitamin D deficiency and, therefore, can be minimized by vitamin D and calcium supplementation. Individuals with vitamin D deficiency (25[OH]D <20 ng/mL [50 nmol/L]) should be treated prior to the infusion, until the serum 25(OH)D level is above 20 ng/mL. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

There have been isolated reports of renal impairment and acute renal failure after zoledronic acid administration, particularly in patients with multiple myeloma but also rarely in those treated for osteoporosis and those receiving concurrent diuretic therapy [49-51]. This occurrence may be related to infusion of zoledronic acid too rapidly. Prior to each zoledronic acid infusion, clinicians should measure serum creatinine and make sure that patients are adequately hydrated. Zoledronic acid should be infused over a period of at least 30 minutes. In patients taking other nephrotoxic drugs or diuretics, periodic postinfusion measurement of serum creatinine should be considered. Zoledronic acid is not recommended for use in patients with creatinine clearance ≤35 mL/min [49]. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Impaired kidney function'.)

IV bisphosphonates may be associated with flu-like symptoms, which can be minimized by infusion for at least 30 minutes and can be treated by acetaminophen or ibuprofen [52]. IV bisphosphonates may also cause hypocalcemia, which can be minimized by delaying infusion until vitamin D deficiency has been corrected. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Flu-like symptoms'.)

MONITORING RESPONSE TO THERAPY — Serial bone mineral density (BMD) measurements are performed to assess the clinical response to therapy. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Monitoring'.)

BMD that is stable or improving is evidence for a treatment response. (See 'Duration of therapy' below.)

The finding of a clinically significant BMD decrease in a treated patient should trigger additional evaluation for contributing factors, which may include poor adherence to therapy, inadequate gastrointestinal (GI) absorption, inadequate intake of calcium and vitamin D, or the development of a disease or disorder with adverse skeletal effects. Calcium and vitamin D supplementation should be verified, and some evaluation for secondary causes of bone loss should be performed. (See "Overview of dual-energy x-ray absorptiometry", section on 'Interpretation of BMD changes' and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women", section on 'Evaluation'.)

When to switch and which therapy to select for patients who fail initial therapy are reviewed separately. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Bone mineral density decreased or fracture during therapy'.)

DURATION OF THERAPY

Our approach

Risk stratified management — For patients taking alendronate or risedronate for five years or who received zoledronic acid once yearly for three years, our approach is based upon the clinical risk for subsequent fracture. The potential benefits of continued fracture reduction, however, must be considered in light of the potential risks of long-term therapy. Duration of therapy should be individualized based upon patient characteristics and preferences. This approach is largely consistent with that of a Task Force of the American Society of Bone and Mineral Research [53].

Low risk for fracture – For patients at low risk for fracture in the near future (eg, stable bone mineral density [BMD], no previous vertebral or hip fractures), we suggest discontinuing the drug (after three years for zoledronic acid, five years for alendronate or risedronate), as there appears to be residual BMD and fracture benefit. (See 'Alendronate' below and 'Risedronate' below and 'Zoledronic acid' below and 'Length of holiday' below.)

High risk for fracture – For patients at highest risk for fracture (history of osteoporotic fracture before or during therapy, T-score below -3.0 in the absence of fractures) who are taking alendronate or risedronate, we suggest continuing therapy for up to 10 years as clinical trial data show maintenance of BMD and fracture benefits with no increased risk of adverse events [54]. For similar women treated with zoledronic acid, we would continue therapy up to six years. Alendronate, risedronate, and zoledronic acid have demonstrated efficacy for 10, 7, and 6 years, respectively [54-57].

There are few data to guide decisions about duration of therapy [57-59]. A systematic review showed that after three to five years of bisphosphonate therapy, bisphosphonate continuation compared with discontinuation reduced the risk of radiographic (zoledronic acid) and clinical (alendronate) vertebral fracture, but it did not reduce nonvertebral fracture [57].

The US Food and Drug Administration (FDA) performed an analysis of the three major bisphosphonate extension studies [60,61]. In two of these trials (described in detail below), postmenopausal women who had taken bisphosphonates for three to five years were randomly assigned to continue bisphosphonates or switch to placebo, and they were followed for three to five years [1,56,62].

Femoral neck BMD was maintained in patients who continued to take bisphosphonates. In patients randomly assigned to placebo, femoral neck BMD decreased during the first one to two years of placebo and then stabilized and remained higher than baseline. Bone density of the spine continued to increase in groups taking bisphosphonates and placebo.

Fracture rates (vertebral and nonvertebral combined) in patients who received bisphosphonate treatment for six or more years were similar to those in patients who switched to placebo (9.3 to 10.6 versus 8.0 to 8.8 percent) [60]. The fracture assessment was limited by the small sample size in the extension trials, differences in study design of the individual trials, and post hoc nature of the analysis.

Additional data examining the risk of fracture after discontinuation of bisphosphonate therapy are needed to better define the duration of therapy for individual patients and for the specific bisphosphonate [58].

Alendronate — For some women, stopping alendronate after five years is reasonable as there appears to be a residual benefit on BMD and fractures for up to five years. This was illustrated in the Fracture Intervention Trial Long-term Extension (FLEX) with 1099 postmenopausal women who had previously received alendronate for five years in the Fracture Intervention Trial (FIT) [1].

At the completion of FIT, women were randomly assigned to an additional five years of alendronate (5 or 10 mg daily) or placebo. Women at highest risk for fracture were excluded from FLEX (those with FLEX baseline T-scores either below -3.5, or below their FIT baseline).

In women who were switched to placebo after five years of alendronate, the following results were seen [1]:

A gradual decline in BMD (-2.4 and -3.7 percent at the total hip and spine, respectively), but mean BMD remained at or higher than levels 10 years earlier.

A gradual rise in biochemical markers of bone turnover. However, the values were still lower than 10 years previously.

No significant difference between placebo and alendronate groups in the rate of nonvertebral (18.9 and 19.0 percent) or morphometric vertebral fractures detected by lateral spine radiographs (11.3 and 9.8 percent [relative risk (RR) 0.86, 95% CI 0.60-1.22]). However, there was a higher risk of vertebral fractures clinically detected by participants' clinicians and spine radiograph (5.3 and 2.4 percent for placebo and alendronate, respectively [RR 0.45, 95% CI 0.24-0.85]).

The two groups did not differ in adverse events. No one developed osteonecrosis of the jaw (ONJ). Bone biopsy showed no qualitative abnormalities in either group.

In a post hoc analysis of women without vertebral fracture at FLEX baseline, continuation of alendronate compared with placebo reduced the number of participants with nonvertebral fracture in the subgroup of women with FLEX baseline femoral neck T-scores of -2.5 or less (16 versus 21 participants) but not with T-scores better than -2.5 (45 versus 27 participants) [63]. This study was limited by the small numbers of nonvertebral fractures within the subgroups and the post hoc nature of the analysis.

In summary, stopping alendronate after five years of therapy results in a gradual decline in BMD and increase in biochemical markers of bone turnover but no significantly higher risk of fracture (except for clinical vertebral fracture) in most women. Thus, stopping bisphosphonate therapy after five years may be reasonable for some low-risk women (eg, no history of fracture and T-scores better than -2.5) as long as they are followed carefully by BMD and assessment of risk factors.

However, the FLEX trial does not address the impact of stopping therapy in women at highest risk for fracture (T-score below -3.5), as they were excluded from the trial. In these women, we suggest continuing alendronate for up to 10 years as BMD and fracture benefits were maintained with no increased risk of adverse events.

Risedronate — In the absence of direct evidence, our suggestion for discontinuing risedronate is based upon indirect evidence from the alendronate extension trial (FLEX) [1]. We typically discontinue risedronate after five years of use in low-risk women (eg, no history of fracture and T-scores better than -2.5) as long as they are followed carefully by BMD and assessment of risk factors.

There are no randomized extension trial data comparing continuous treatment with risedronate versus switching to placebo. When risedronate is discontinued after three years, its beneficial effects on BMD and markers of bone turnover appear to revert partially or completely within one year, as reported in an extension of the Vertebral Efficacy with Risedronate Therapy (VERT) trial [15,62]. In this observational extension study, women who received risedronate or placebo for three years were reassessed one year after stopping therapy (but continuing vitamin D supplementation) [62]. BMD of the lumbar spine and femoral neck decreased (0.83 and 1.23 percent, respectively) in the group previously taking risedronate, although mean values remained higher than baseline (lumbar spine) and placebo (lumbar spine and femoral neck). However, markers of bone turnover returned to baseline and were the same as the placebo group within one year. Nonetheless, the incidence of new vertebral fractures in patients previously treated with risedronate remained lower (6.5 versus 11.6 percent).

Zoledronic acid — The majority of patients who receive zoledronic acid once yearly for three years do not require subsequent infusions of zoledronic acid for at least the next three years. However, in patients at high risk for fractures (eg, existing vertebral fracture or femoral neck BMD T-score <-2.5 after an initial course of therapy), continuing yearly zoledronic acid beyond three years may provide some benefit, but the potential benefits must be considered in light of the potential risks of long-term therapy. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the jaw'.)

The beneficial effects of a three-year course of zoledronic acid (5 mg yearly) appear to be maintained in the subsequent three years, as illustrated by the finding of an extension of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial [25], in which a subset of women (n = 1233 of 3889) who had received zoledronic acid (5 mg yearly) for three years in the core study were randomly assigned to three additional years of zoledronic acid or placebo [56]. The mean change in femoral neck BMD (the primary endpoint) from year 3 to 6 was +0.24 and -0.80 percent, respectively. The mean change in lumbar spine (a secondary endpoint) was +3.2 and +1.18, respectively. There were fewer morphometric vertebral fractures (a secondary endpoint) in the group that received zoledronic acid for six years (3 versus 6.2 percent; odds ratio [OR] 0.51, 95% CI 0.26-0.95). However, the overall fracture event rate was low, reducing the precision of the analysis. There was no difference in the incidence of nonvertebral, clinical vertebral, or all clinical fractures. Markers of bone turnover remained below pretreatment values in both groups. A greater proportion of patients in the active treatment group had transient increases in serum creatinine (>0.5 mg/dL). There were no cases of atypical fractures, and there was one case of ONJ in the group receiving zoledronic acid for six years. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Osteonecrosis of the jaw'.)

Length of holiday — We typically restart bisphosphonates within the first five years of the drug holiday when any of the following occur:

Reproducible bone loss (approximately 5 percent) on at least two dual-energy x-ray absorptiometry (DXA) measurements taken at least two years apart, using the same make and model DXA scanner.

Evidence of bone loss on one DXA measurement at the spine and the hip.

Evidence of bone loss on one DXA measurement at either site and accompanied by a fasting C-terminal telopeptide of type I collagen (CTX) >600 pg/mL (ie, above the upper limit of the premenopausal reference range).

As an alternative, bisphosphonates can be restarted after a three- to five-year holiday in women who showed improvement during their initial course of bisphosphonates and did not have a previous fracture.

There are no data to support one strategy over another for determining when to restart bisphosphonates after a drug holiday. In clinical practice, the decision to resume the drug is often based on a combination of factors, including duration of the holiday, decrease in BMD, clinical risk factors for fracture, a new osteoporotic fracture, and increase in markers of bone turnover [53,64-67]. (See "Use of biochemical markers of bone turnover in osteoporosis", section on 'Duration of therapy'.)

ADVERSE EFFECTS — The risks of bisphosphonates in patients treated for osteoporosis are reviewed in detail separately. (See "Risks of bisphosphonate therapy in patients with osteoporosis".)

SPECIAL POPULATIONS

Use in chronic kidney disease — Bisphosphonates are generally not recommended for those with creatinine clearance below 30 to 35 mL/min. Patients with chronic kidney disease (CKD) with creatinine clearance above 30 to 35 mL/min are usually managed similarly to patients with normal renal function [68-70]. However, there are few data about fracture prevention efficacy and long-term adverse effects in subjects with reduced renal function.

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".)

Use immediately after fracture — A history of a fragility (low-trauma) fracture is an important risk factor for subsequent fracture. If a patient is not already treated, pharmacologic therapy (typically bisphosphonates) should be initiated in patients with fragility fracture to prevent subsequent fracture [71]. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Patient selection'.)

Bisphosphonates inhibit bone resorption by suppressing osteoclast activity. There is theoretical concern that bisphosphonates may impair fracture healing because fracture healing requires callus remodeling and the coupled activity of osteoclasts and osteoblasts. Thus, important questions are whether bisphosphonates can be initiated in the immediate postfracture period and whether there is delayed fracture healing in patients who fracture while on therapy. There are few data to guide these clinical decisions [72-75].

Treatment-naive patients – We typically initiate bisphosphonates two weeks postfracture, as long as the patient is able to sit upright for at least 30 minutes (oral bisphosphonates). This is also a time when patients are more mobile, taking less pain medication, and may therefore have fewer gastrointestinal (GI) symptoms that might otherwise be ascribed to oral bisphosphonates.

In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial, older adults with hip fracture were randomly assigned to receive intravenous (IV) zoledronic acid or placebo within three months of surgical repair of the hip fracture [26]. In a preplanned secondary analysis of the data, the overall incidence of delayed healing in the zoledronic acid and placebo groups was similar (3.2 and 2.7 percent, respectively) [76]. In a post hoc analysis, there was also no difference in nonunion rates between zoledronic acid and placebo when zoledronic was administered early (within two weeks), between two and four weeks, four and six weeks, or six weeks after hip fracture repair [76].

In another trial specifically designed to assess the effect of bisphosphonates on fracture healing, 50 women who had surgical repair of an osteoporotic distal radial fracture were randomly assigned to initiation of bisphosphonates two weeks or three months after the surgery [77]. There was no significant difference between the two groups in time to radiographic union (6.7 weeks). Similarly, initiation of risedronate one week, one month, or three months after internal fixation for repair of an intertrochanteric fracture did not have any effect on mean time to fracture healing, rate of nonunion at 24 weeks, or functional outcomes at one year [78].

Patients already taking bisphosphonates – A separate question is whether patients already taking bisphosphonates at the time of fracture will have a delay in fracture healing.

Typical fragility fractures – In most postmenopausal women who have been taking bisphosphonates for <5 years and who have a typical osteoporotic fragility fracture, we do not discontinue bisphosphonates because of concern about delayed fracture healing. However, if there is concern that the fracture occurred because the patient is not absorbing or responding to bisphosphonates, additional evaluation and consideration of alternative therapy is warranted. (See 'Monitoring response to therapy' above.)

In a retrospective study, 196 patients treated for a distal radius fracture were evaluated [79]. Compared with patients not taking bisphosphonates (n = 153), those taking bisphosphonates at the time of the injury had a longer mean time to radiographic union (55 versus 49 days). Although statistically significant, this difference is unlikely clinically relevant.

In a nested case-control study of 19,731 patients with fractures of the humerus, radiographic nonunion occurred in 81 (0.4 percent) [80]. There was no difference in pre-fracture bisphosphonate exposure in patients with nonunion and 810 matched controls without nonunion (3.7 and 3.5 percent, respectively).

Atypical femur fractures – In patients with atypical femur fractures who have been taking bisphosphonates, we discontinue bisphosphonates as delayed healing has been reported in such patients [81]. There is theoretical concern that prolonged bisphosphonate therapy can lead to oversuppression of bone turnover ("frozen bone") and increased skeletal fragility, resulting in atypical fracture (particularly subtrochanteric or diaphyseal fractures). The absolute risk of an atypical fracture is low. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Atypical femur fracture'.)

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: Medicines for osteoporosis (The Basics)")

Beyond the Basics topics (see "Patient education: Osteoporosis prevention and treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Overview of bisphosphonates – Bisphosphonates, one of the available therapeutic options for the management of osteoporosis, inhibit bone resorption with relatively few side effects. As a result, they are widely used for the prevention of osteoporotic fractures (table 1). (See "Overview of the management of osteoporosis in postmenopausal women" and "Prevention of osteoporosis" and "Treatment of osteoporosis in men", section on 'Bisphosphonates'.)

Initial treatment of osteoporosis – For the initial treatment of osteoporosis, we suggest oral bisphosphonates (Grade 2B). (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Choice of drug' and "Treatment of osteoporosis in men", section on 'Choice of therapy'.)

We prefer oral bisphosphonates (over other osteoporosis drugs) as initial therapy because of their efficacy, favorable cost, and the availability of long-term safety data (algorithm 1). (See 'Choice of bisphosphonate' above.)

Choice of oral bisphosphonate – We suggest either alendronate or risedronate as the initial choice of bisphosphonate (Grade 2B). Individuals with well-controlled gastroesophageal reflux or peptic ulcer disease can also take alendronate or risedronate.

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. Generic alendronate and risedronate are available in many countries, including the United States. Most patients prefer the convenience of the once-weekly regimen. Although once-monthly oral ibandronate may be more convenient for patients, a reduction in hip fracture risk has not been established, and if the patient likes the once-monthly regimen, risedronate can be given that way. (See 'Choice of bisphosphonate' above.)

Contraindications to oral bisphosphonatesZoledronic acid administered intravenously should be used instead of a bisphosphonate administered orally in patients who have esophageal disorders (achalasia, scleroderma involving the esophagus, esophageal strictures, varices), certain types of bariatric surgery in which surgical anastomoses are present in the gastrointestinal (GI) tract (eg, Roux-en-Y gastric bypass), GI intolerance to oral bisphosphonates, 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 (algorithm 1). Zoledronic acid is the only intravenous (IV) bisphosphonate that has demonstrated efficacy for fracture prevention and is, therefore, our agent of choice. (See 'Contraindications to bisphosphonates' above and 'Choice of bisphosphonate' above and "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Gastrointestinal'.)

Monitoring – Serial bone mineral density (BMD) measurements are performed to assess the clinical response to therapy. The finding of a clinically significant BMD decrease in a treated patient should trigger additional evaluation for contributing factors, which may include poor adherence to therapy, inadequate GI absorption, inadequate intake of calcium and vitamin D, or the development of a disease or disorder with adverse skeletal effects. (See 'Monitoring response to therapy' above.)

Duration of therapy – For patients taking alendronate or risedronate for five years or who received zoledronic acid once yearly for three years, who have a stable BMD, no previous vertebral fractures, and who are at low risk for fracture in the near future, we suggest discontinuing the drug (Grade 2C). (See 'Our approach' above.)

However, for women at highest risk for fracture (history of osteoporotic fracture before or during therapy, T-score below -3.0 in the absence of fractures) who are taking alendronate or risedronate, we continue therapy for up to 10 years as clinical trial data show maintenance of BMD and fracture benefits with no increased risk of adverse events. For similar women treated with zoledronic acid, we would continue therapy up to six years.

After discontinuation – For patients in whom bisphosphonates have been discontinued, we monitor BMD. We typically restart bisphosphonates when there is persistent bone loss (approximately 5 percent) at the femoral neck on at least two dual-energy x-ray absorptiometry (DXA) measurements taken at least two years apart, using the same make and model DXA scanner. (See 'Length of holiday' above.)

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