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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 for the prevention and treatment of osteoporosis.
The use of bisphosphonates in postmenopausal women with osteoporosis will be reviewed here. An overview of other treatment options for osteoporosis in women and men 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.
OVERVIEW OF APPROACH — The treatment of osteoporosis consists of lifestyle measures and pharmacologic therapy. 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 postmenopausal women. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Lifestyle measures'.)
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 'Candidates for therapy'.)
In the absence of specific contraindications, oral bisphosphonates are considered initial pharmacologic therapy for most postmenopausal women 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 'Choice of bisphosphonate' below.)
For patients with contraindications to oral bisphosphonates (eg, achalasia, esophageal stricture, esophageal varices, Barrett's esophagus), gastrointestinal (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. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Contraindications/intolerance to oral bisphosphonates' and 'Choice of bisphosphonate' below and 'Contraindications/intolerance' below.)
Choice of bisphosphonate
●Oral – We suggest alendronate or risedronate as the initial choice of oral bisphosphonate. We most commonly use alendronate. Generic alendronate and risedronate are available in many countries, including the United States. Most patients prefer the convenience of the once-weekly regimen.
●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. 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 with osteoporosis [1,2]. In addition, a systematic review of trials published between 2005 and 2014 confirmed the vertebral fracture prevention efficacy of several drugs, including alendronate, risedronate, zoledronic acid, and ibandronate, compared with placebo . Alendronate, risedronate, and zoledronic acid also reduce the risk of hip and other nonvertebral fractures [3,4].
The efficacy and dosing of the individual bisphosphonates are reviewed below. (See 'Overview of available bisphosphonates' below.)
Contraindications/intolerance — Oral bisphosphonates should not be used 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). Oral bisphosphonates should also be avoided after certain types of bariatric surgery in which surgical anastomoses are present in the GI tract (eg, Roux-en-Y gastric bypass); IV bisphosphonates are acceptable as long as vitamin D has been assessed and is in the normal range.
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'.)
Practical management issues — There are several general principles for the use of the bisphosphonates, as outlined below.
Pretreatment evaluation — Before starting bisphosphonates, patients should be evaluated to detect potentially remediable causes of or other contributing factors to osteoporosis.
This evaluation includes assessment for hypocalcemia, vitamin D deficiency, and renal impairment by measuring serum:
●25-hydroxyvitamin D (25[OH]D)
For both oral and IV bisphosphonates, correction of hypocalcemia and/or vitamin D deficiency is necessary prior to administration. (See "Calcium and vitamin D supplementation in osteoporosis" and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)
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.
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 . 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)  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 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. (See 'Formulations' below.)
●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 [7-9].
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 . 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 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 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 is administered yearly and must be infused over a period of at least 15 minutes, whereas ibandronate is administered every three 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 25 to 30 ng/mL (62 to 75 nmol/L) (see "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment"). Some clinicians also advise patients to increase calcium supplementation (doubling of usual dose) for five to seven days starting on the day of the infusion as this may also minimize hypocalcemia, although there are no data to support this practice.
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 [11-13]. This occurrence may be related to zoledronic acid infusing 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 15 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 . (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Renal'.)
IV bisphosphonates may be associated with flu-like symptoms and hypocalcemia. Acetaminophen or ibuprofen can be administered to prevent or treat flu-like symptoms . (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Flu-like symptoms'.)
Response to therapy — Serial 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.
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. 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 of low bone mass'.)
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 — For patients taking alendronate or risedronate for five years or who received zoledronic acid once yearly for three years, have a stable BMD, have no previous vertebral fractures, and are at low risk for fracture in the near future, we suggest discontinuing the drug 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.)
However, for women at highest risk for fracture (history of osteoporotic fracture before or during therapy, T-score below -3.5 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 . 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 [15-17]. However, the potential benefits 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 .
There are few data to guide decisions about duration of therapy. The US Food and Drug Administration (FDA) performed an analysis of the three major bisphosphonate extension studies [19,20]. 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 [17,21,22]. 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.
In a pooled analysis of all data on osteoporotic fractures (vertebral and nonvertebral combined), fracture rates 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) . 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.
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) .
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). The BMD, bone marker, and fracture data in the women who continued alendronate for 10 years were similar to those described above .
In women who were switched to placebo after five years of alendronate, the following results were seen:
●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). However, there was a slightly higher risk of vertebral fractures clinically detected by participants' clinicians and spine radiograph (5.3 and 2.4 percent for placebo and alendronate, respectively).
The two groups did not differ in adverse events. No one developed 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) . 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) . 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 [22,24]. 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) . BMD of the lumbar spine (LS) and femoral neck decreased (0.83 and 1.23 percent, respectively) in the group previously taking risedronate, although mean values remained higher than baseline (LS) and placebo (LS 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 described below , 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 . 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 LS (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 — 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, and increase in markers of bone turnover [18,26-29].
We typically restart bisphosphonates when there is persistent 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.
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. Some clinicians restart therapy when markers of bone turnover have risen above the normal premenopausal range, although there is no evidence to support this practice. (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".)
Combination therapy — We suggest not using combination therapy, as the additional BMD benefits are small and there is no proven additional fracture benefit.
●With estrogen or raloxifene – We suggest not using combination bisphosphonate-estrogen therapy or bisphosphonate-raloxifene therapy, as the additional benefits are small and there is an increase in potential side effects. In addition, the indications for using estrogen have been diminished since the results of the Women's Health Initiative (WHI) were published (see "Menopausal hormone therapy: Benefits and risks" and "Overview of the management of osteoporosis in postmenopausal women"). Furthermore, there is theoretical concern that combination antiresorptive therapy could over-suppress bone turnover and cause increased skeletal fragility. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Atypical femur fractures'.)
Although estrogen and bisphosphonates both inhibit bone resorption, they do so through different mechanisms. Their effects on BMD appear to be similar, and the combination of the two may be slightly more effective, although the additional benefit is modest [30-34]. The rate of bone loss may be accelerated after withdrawing estrogen therapy but not after withdrawing alendronate or combination therapy .
The combination of alendronate and raloxifene has a greater effect on BMD and markers of bone turnover when compared with either drug alone . However, the benefit of combined versus monotherapy for fracture reduction is unknown.
●With parathyroid hormone (PTH) – Because teriparatide (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. In the absence of fracture data, we suggest not using combination bisphosphonate and PTH/teriparatide for osteoporosis treatment. (See "Parathyroid hormone/parathyroid hormone-related protein analogs for osteoporosis", section on 'Combination therapy' and "Treatment of osteoporosis in men", section on 'Combination therapy'.)
Use in chronic kidney disease — Bisphosphonates are generally not recommended for those with creatinine clearance below 30 to 35 mL/min. Patients with CKD with creatinine clearance above 30 to 35 mL/min are usually managed similarly to patients with normal renal function [37-39]. 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, evaluation, and management".)
Use immediately after fracture — Bisphosphonates inhibit bone resorption by suppressing osteoclast activity. Because fracture healing requires callus remodeling and the coupled activity of osteoclasts and osteoblasts, there is theoretical concern that bisphosphonates may impair fracture healing. 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 [40-43].
●When to initiate bisphosphonates – We typically initiate bisphosphonates four to six 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 GI symptoms that might otherwise be ascribed to oral bisphosphonates.
In the HORIZON Recurrent Fracture Trial described below (see 'Efficacy' below), older adults with hip fracture were randomly assigned to receive IV zoledronic acid or placebo within three months of surgical repair of the hip fracture . 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) . 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 .
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 . 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 .
●Fracture healing in 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. 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 'Response to therapy' above.)
In a retrospective study, 196 patients treated for a distal radius fracture were evaluated . 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) . There was no difference in prefracture bisphosphonate exposure in patients with nonunion and 810 matched controls without nonunion (3.7 and 3.5 percent, respectively).
●Atypical femur fractures – 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. In patients with atypical femur fractures who have been taking bisphosphonates, we discontinue bisphosphonates as delayed healing has been reported in such patients . (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Atypical femur fractures'.)
OVERVIEW OF AVAILABLE BISPHOSPHONATES — We prefer oral bisphosphonates as initial therapy because of their efficacy, favorable cost, and the availability of long-term safety data. We suggest alendronate or risedronate as the initial choice of oral bisphosphonate.
Alendronate — Alendronate is effective for both the treatment and prevention of osteoporosis in postmenopausal women. Alendronate is also effective for African American women  and older women with osteoporosis [52,53].
Efficacy — Alendronate is effective when dosed daily or weekly.
●Daily dosing – A number of randomized trials have demonstrated that alendronate increases bone mineral density (BMD) (figure 1) and decreases the risk of osteoporotic fractures [54-59]. In a meta-analysis of 11 trials of alendronate therapy in postmenopausal women, the relative risk (RR) of vertebral fractures in patients given a dose of 10 mg daily was 0.55 (95% CI 0.45-0.67) . The RR of nonvertebral fractures in patients given 10 mg of alendronate was 0.84 (95% CI 0.74-0.94). Improvements in bone density with alendronate increased with both dose and time. The risk of side effects was similar for doses of 5 mg and ≥10 mg. For all doses combined, there was no evidence of an excess risk of gastrointestinal (GI) side effects.
In the Fracture Intervention Trial (FIT), one of the largest trials in postmenopausal women with low bone density, there were two study arms comparing daily alendronate and placebo.
•In the vertebral fracture study arm, in 2027 women with a low femoral neck bone density (T-score <-2.1) and at least one vertebral fracture at baseline, alendronate therapy increased femoral neck and spine BMD by 4.1 and 6.2 percent, respectively, and reduced the risk of vertebral fracture by approximately 50 percent and hip and wrist fractures by approximately 30 percent .
•The clinical fracture study arm included 4432 postmenopausal women with a low femoral neck bone density (T-score <-1.6) but no vertebral fracture at baseline . Alendronate therapy (5 mg per day for two years followed by 10 mg per day for the remainder of the trial) increased BMD and reduced the risk of vertebral fractures (diagnosed by radiograph) by 44 percent but did not significantly decrease the risk of hip, wrist, or all clinical fractures. However, in a subgroup of the subjects who had osteoporosis (baseline femoral neck T-score of -2.5 or less), alendronate reduced the risk of hip and all clinical fractures by 56 and 36 percent, respectively.
●Weekly dosing – Weekly administration of alendronate is as effective as daily dosing. In a two-year, randomized trial comparing once-weekly (70 mg) and daily alendronate (10 mg), the regimens were similar for increasing BMD and had similar low rates of side effects . The rates of clinical fractures were captured as adverse experiences and were similar among the groups.
Formulations — Several formulations of alendronate are available:
●For treatment of osteoporosis, a 10 mg daily or 70 mg once-weekly tablet is available. The 70 mg dose is also available in an effervescent formulation (dissolved over at least five minutes in 4 oz of tap water) . Most patients prefer the convenience of the once-weekly regimen.
●For prevention of osteoporosis: 5 mg daily or 35 mg once-weekly tablets.
●Generic formulations have been available since 2008.
Instructions for administration are found above. (See 'Oral regimen' above.)
Risedronate — Risedronate is effective and well tolerated for up to seven years, as illustrated in a trial of 164 women, in whom improvements in BMD continued over the seven years of therapy, with no apparent loss of fracture risk reduction .
Efficacy — Risedronate is effective when dosed daily, weekly, or monthly.
●Daily dosing – Risedronate improves BMD, reduces fracture risk, and is well tolerated in postmenopausal women with osteoporosis [64-66]. In a meta-analysis of eight randomized trials of risedronate versus placebo in postmenopausal women with established osteoporosis, the pooled RR for vertebral and nonvertebral fractures with risedronate was 0.64 and 0.73, respectively .
In one of the larger trials, the Vertebral Efficacy with Risedronate Therapy (VERT) study, 2458 postmenopausal women with osteoporosis (either two or more vertebral fractures or one vertebral fracture and lumbar spine [LS] T-score of -2.0 or less) were randomly assigned to risedronate (5 mg/day) or placebo for three years with the following results :
•Bone density at the LS, femoral neck, and trochanter increased by 5.4, 1.6, and 3.3 percent, respectively, in the risedronate group, as compared with 1.1, -1.2, and -0.7 percent, respectively, in the placebo group.
•The risk of vertebral and nonvertebral fractures was reduced by 41 and 39 percent, respectively, with risedronate. The three-year rates of new vertebral fractures with risedronate versus placebo were 11 and 16 percent, respectively, and 5 and 8 percent, respectively, for nonvertebral fractures.
•GI and other adverse effects occurred with similar (low) frequency in both groups.
●Weekly dosing – Weekly risedronate (35 mg) is as effective and well tolerated as daily administration of 5 mg [68-70]. An enteric-coated, delayed-release formulation of risedronate is also available for weekly administration (35 mg) . Compared with risedronate 5 mg daily, increases in bone density at the LS and hip were similar with the delayed-release formulation .
●Older women – Risedronate reduces the risk of hip fracture among older women with confirmed osteoporosis but not among older women selected primarily on the basis of risk factors. This was illustrated in a randomized trial of 5445 women aged 70 to 79 years with osteoporosis (group 1) and 3886 women aged 80 years or older selected primarily on the basis of nonskeletal risk factors (poor gait, smoking, propensity to fall) (group 2) . Although risedronate decreased overall hip fracture risk by 30 percent, the rate of hip fracture was reduced only in group 1 (1.9 and 3.2 percent of women experienced hip fracture in the drug and placebo groups, respectively; RR 0.6, 95% CI 0.6-0.9) but not in group 2, where hip fracture rate was similar (4.2 and 5.1 percent of women, respectively).
Alendronate versus risedronate — Alendronate and risedronate have been compared in one prospective, randomized and some retrospective, observational trials. In the randomized trial, alendronate increased bone density more than risedronate at all sites after 12 months . Results persisted in year 2 of the study . 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 . However, this study was limited by the inability to accurately characterize fracture risk at baseline between the two groups. Thus, although alendronate may have a greater effect on BMD when compared with risedronate, the clinical relevance of this finding is unclear. 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.
Formulations — Risedronate formulations available for clinical use include: a daily (5 mg), weekly (35 mg), weekly delayed-release (35 mg), and monthly (single 150 mg tablet) dose (all used for the treatment and prevention of postmenopausal and glucocorticoid-induced osteoporosis).
Unlike immediate-release risedronate and other oral bisphosphonates, delayed-release risedronate is taken immediately after breakfast and with at least four oz of water. Patients should remain upright (sitting or standing) for at least 30 minutes. General instructions for administration are found above. (See 'Oral regimen' above.)
In addition, a 30 mg once-daily formulation is available for the treatment of Paget disease. (See "Treatment of Paget disease of bone", section on 'Use of nitrogen-containing bisphosphonates'.)
Zoledronic acid — Zoledronic acid is an intravenous (IV) bisphosphonate that is administered once yearly (as a 15-minute infusion). It increases BMD and reduces fracture risk.
●In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Pivotal Fracture Trial, 7765 postmenopausal women with osteoporosis were randomly assigned to 5 mg of zoledronic acid or placebo, administered IV (infused over 15 minutes) once yearly for three consecutive years . BMD increased at the spine, total hip, and femoral neck, and markers of bone turnover decreased in the zoledronic acid group compared with placebo.
In addition, there was a significant reduction in fracture. The three-year incidence of vertebral fracture was 10.9 percent in the placebo group versus 3.3 percent in the zoledronic acid group, a reduction of 70 percent (RR 0.30, 95% CI 0.24-0.38). The incidence of hip fracture was 2.5 and 1.4 percent in the placebo and zoledronic acid groups, respectively, a 41 percent reduction (hazard ratio [HR] 0.59, 95% CI 0.42-0.83).
●In the HORIZON Recurrent Fracture Trial, 2127 men and women with hip fracture were randomly assigned to receive yearly zoledronic acid (5 mg) or placebo within three months of surgical repair . Subjects also received vitamin D (50,000 to 125,000 international units 14 days prior to infusion, if 25-hydroxyvitamin D [25(OH)D] concentration was <15 mg/dL or unknown, and 800 to 1200 international units daily thereafter) and calcium. After a median follow-up of 1.9 years, new fractures occurred in 8.6 and 13.9 percent of individuals in the zoledronic acid and placebo groups, respectively, representing a RR reduction of 35 percent (HR 0.65, 95% CI 0.50-0.84). All-cause mortality, a secondary safety endpoint, was lower in the zoledronic acid compared with placebo group (HR 0.72, 95% CI 0.56-0.93).
Although there were no differences in serious adverse events or discontinuation because of adverse events, zoledronic acid was associated with an expected increase in postinfusion flu-like symptoms and mild transient hypocalcemia in both HORIZON studies. In addition, in the Pivotal Fracture Trial, there was an unexpected increase in atrial fibrillation, which was not seen in the Recurrent Fracture Trial. There were no long-term adverse effects on renal function. A thorough search of the safety database yielded two cases of potential osteonecrosis of the jaw (ONJ), one in the zoledronic acid group and one in the placebo group. (See "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Risks specific to oral bisphosphonates'.)
Thus, in the HORIZON studies, yearly IV zoledronic acid was associated with an improvement in BMD, a decrease in spine and hip fractures in postmenopausal women with osteoporosis (Pivotal Fracture Trial), and a decrease in recurrent clinical fractures in men and women with recent hip fracture (Recurrent Fracture Trial). The infusions were relatively well tolerated, given the known association between IV bisphosphonates and flu-like symptoms.
Dosing — IV zoledronic acid offers an alternative option for individuals who cannot tolerate oral bisphosphonates or who find the yearly dosing regimen more convenient. Zoledronic acid must be infused over a period of at least 15 minutes. (See 'IV regimen' above.)
In a two-year, interim analysis of a three-year trial of zoledronic acid (single dose of 5 mg) versus placebo in postmenopausal women with osteopenia, markers of bone turnover remained decreased and BMD remained higher in the zoledronic acid group compared with placebo . These data suggest that a single 5 mg dose of zoledronic acid may have a sustained benefit for up to two years and that less frequent dosing may be needed. However, the antifracture efficacy of such a regimen is unknown.
Ibandronate — Ibandronate is available for the prevention and treatment of osteoporosis . In the absence of consistent clinical trial data that ibandronate reduces hip fracture risk, we suggest alendronate or risedronate as our first choice for bisphosphonate therapy in patients at high risk for fractures.
●Daily dosing – A daily oral regimen (2.5 mg/day) and an intermittent oral regimen (20 mg every other day for 12 doses every three months) are equally effective for increasing BMD and reducing vertebral fracture risk, when compared with placebo . However, a significant reduction in hip fracture was not seen. The daily formulation was approved for use in 2003 but was never marketed.
●Monthly dosing – A once-monthly, 150 mg oral formulation is available for both prevention and treatment of osteoporosis [83,84]. In a trial of 1609 postmenopausal women with osteoporosis randomly assigned to receive daily ibandronate (2.5 mg), ibandronate 50 + 50 mg once monthly (single doses given on consecutive days), 100 mg once monthly, or 150 mg once monthly, the following results were seen after two years of follow-up :
•Increases in LS bone density were observed in all treatment groups (5.0, 5.3, 5.6, and 6.6 percent in the daily, 50 + 50 mg, 100 mg, and 150 mg groups, respectively). The increases in the 50 + 50 and 100 mg group were not statistically different from the 2.5 mg daily group, while the increase in the 150 mg group was significantly greater than the 2.5 mg daily group.
•Similar results were seen for hip bone density.
•No differences in adverse events were noted.
•Fracture data were not reported.
Thus, monthly ibandronate (150 mg) appears to improve BMD more than daily administration (2.5 mg). The manufacturer of the monthly formulation will also provide monthly reminders for patients. The monthly formulation may therefore increase overall compliance with therapy .
●Intravenous – In the absence of fracture prevention data with IV ibandronate, zoledronic acid is our first choice for IV bisphosphonate therapy in patients who cannot tolerate oral therapy. (See 'Zoledronic acid' above and 'IV regimen' above.)
An IV formulation of ibandronate (3 mg every three months) appears to improve BMD to a similar or greater degree than daily oral ibandronate (2.5 mg/day) [86,87]. 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 two to three months] and oral dosing [150 mg monthly]) [88,89]. However, there are no direct fracture efficacy data for IV ibandronate.
OTHER BISPHOSPHONATES — A number of other bisphosphonates are available but are used less often (or not at all) for osteoporosis.
Etidronate — Etidronate was the first bisphosphonate used in the treatment of osteoporosis. It increased bone mineral density (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 — 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 — Pamidronate, an intravenous (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 . However, it has been superseded by zoledronic acid, and in some cases IV ibandronate, because these drugs have fracture efficacy data.
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.)
●Beyond the Basics topics (see "Patient education: Osteoporosis prevention and treatment (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●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 and treatment of osteoporosis. (See "Overview of the management of osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men", section on 'Bisphosphonates' and "Prevention of osteoporosis".)
●For the treatment of postmenopausal women with osteoporosis, we suggest oral bisphosphonates as first-line therapy (Grade 2B). (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Candidates for 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. (See 'Choice of bisphosphonate' above and 'Overview of available bisphosphonates' above.)
●For postmenopausal women with osteoporosis, we suggest either alendronate or risedronate as the initial choice of bisphosphonate (Grade 2B). We most commonly use alendronate. 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 and 'Alendronate' above and 'Risedronate' above and 'Ibandronate' above.)
●For women with well-controlled gastroesophageal reflux or peptic ulcer disease, we also suggest initial therapy with either risedronate or alendronate (Grade 2B). However, oral bisphosphonates should not be used as initial therapy in patients with esophageal disorders (eg, achalasia, esophageal stricture, Barrett's esophagus), after certain types of bariatric surgery in which surgical anastomoses are present in the gastrointestinal (GI) tract (eg, Roux-en-Y gastric bypass), or in patients with an inability to follow the dosing requirements (eg, stay upright for at least 30 to 60 minutes). (See 'Choice of bisphosphonate' above and 'Contraindications/intolerance' above and "Risks of bisphosphonate therapy in patients with osteoporosis", section on 'Gastrointestinal'.)
●Patients who have esophageal disorders (achalasia, scleroderma involving the esophagus, esophageal strictures, varices), 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, should not be treated with oral bisphosphonates and can be treated instead with intravenous (IV) bisphosphonate therapy. Zoledronic acid is the only IV bisphosphonate that has demonstrated efficacy for fracture prevention and is, therefore, our agent of choice. (See 'Choice of bisphosphonate' above and 'Zoledronic acid' above.)
●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 'Response to therapy' above.)
●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 -3.5 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.
●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 'Our approach' above and 'Length of holiday' above.)
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