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Risks of bisphosphonate therapy in patients with osteoporosis

Risks of bisphosphonate therapy in patients with osteoporosis
Literature review current through: Sep 2023.
This topic last updated: Aug 10, 2023.

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.

This topic will review the risks of bisphosphonates in patients with osteoporosis. The therapeutic use of bisphosphonates in men and postmenopausal women with osteoporosis and their side effects in other conditions (such as advanced malignancy) are reviewed separately.

(See "Bisphosphonate therapy for the treatment of osteoporosis".)

(See "Treatment of osteoporosis in men", section on 'Patient selection'.)

(See "Prevention and treatment of glucocorticoid-induced osteoporosis", section on 'Bisphosphonates'.)

(See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)

RISKS SPECIFIC TO ORAL BISPHOSPHONATES

Gastrointestinal

Reflux, esophagitis, ulcers — Upper gastrointestinal (GI) side effects (reflux, esophagitis, esophageal ulcers) are a commonly cited reason for oral bisphosphonate intolerance [1]. The side effects are attributed to the local effects of oral bisphosphonates on the esophagus and/or gastric mucosa. The incidence of these side effects is very low if proper administration instructions are followed [2-5], and the risk increases in patients unable to comply with the dosing instructions. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Oral regimen'.)

Oral bisphosphonates should not be used at all in patients with esophageal disorders (eg, achalasia, esophageal stricture, Barrett's esophagus, esophageal varices) or with an inability to follow the dosing requirements (eg, stay upright for at least 30 to 60 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). (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Contraindications to bisphosphonates'.)

Alendronate — In clinical trials, the incidence of upper GI problems in women receiving alendronate daily [5,6] or once weekly [7] was not different from those receiving placebo. However, pill-induced esophagitis and esophageal ulcers can occur, and they may be disabling and require hospitalization or rarely lead to esophageal stricture [8,9]. The risk may be potentiated by concomitant use of a nonsteroidal antiinflammatory drug (NSAID) [10].

These complications may be more frequent in ordinary practice than in clinical trials because patients with dyspepsia were excluded from the trials [11]. However, in a study of 72 patients who discontinued alendronate because of GI side effects and who were then randomly assigned to a rechallenge with either alendronate or placebo, 15 percent of the patients taking alendronate and 17 percent of those taking placebo stopped treatment because of GI side effects. These data suggest that many of the GI side effects seen reflect a high background incidence of GI complaints, rather than an alendronate-specific effect [12-14].

Risedronate — The risk of upper GI side effects with risedronate also appears to be low, even in patients with a history of GI symptoms.

In clinical trials, the incidence of GI side effects was not different from placebo [15].

In a pooled analysis of nine clinical trials that included 10,068 patients randomly assigned to risedronate (5 mg/day) or placebo for up to three years, upper GI tract adverse events were no different between the two groups (29.8 and 29.6 percent, respectively) [16]. Unlike clinical trials with alendronate, patients with active GI disease were not excluded from the studies. (See "Pill esophagitis".)

The enteric-coated, delayed-release formulation of risedronate may cause more upper and lower GI side effects than risedronate (5 mg/day). In a trial comparing enteric-coated, delayed-release risedronate (35 mg weekly) with daily risedronate (5 mg), diarrhea (8.8 versus 4.9 percent) and abdominal pain (5.2 versus 2.9 percent) occurred slightly, but not significantly more frequently, in patients assigned to the delayed-release formulation [17,18].

Risedronate versus alendronate — Although in clinical practice some patients have fewer GI side effects with risedronate compared with alendronate, in one- and two-year randomized trials directly comparing the effects of once-weekly risedronate versus alendronate on bone density, there was no difference in the incidence of upper GI side effects (23 versus 25 percent) [19,20].

In addition, in a population-based study of GI side effects in 10,416 new users of weekly oral alendronate or risedronate, there was no significant difference in rates of hospitalization for upper GI bleeding after a mean of 88 days of therapy [21]. There were also no differences between the two groups in the outpatient diagnosis of GI diseases (reflux, gastritis, peptic ulcer disease), GI symptoms (heartburn, nausea, vomiting, dyspepsia, abdominal pain), upper GI procedures, or use of proton pump inhibitors or H2-receptor antagonists.

However, there was a significantly higher rate of switching between therapies in alendronate users (5.9 versus 4.0 percent; adjusted hazard ratio [HR] 0.67, 95% CI 0.49-0.92), which is of uncertain significance. Among women with a known prior history of upper GI events, risedronate users had lower rates of endoscopy (HR 0.70, 95% CI 0.49-0.99).

In short-term endoscopic trials comparing daily dosing of the two drugs, gastric ulcers were detected less frequently in risedronate than alendronate users [22,23]. As an example, in a trial of 515 postmenopausal women randomly assigned to risedronate (5 mg/day) or alendronate (10 mg/day) for two weeks, significantly fewer patients in the risedronate group had endoscopically diagnosed gastric ulcers (4.1 versus 13.2 percent for alendronate) [22]. In another trial, in which much larger daily doses (30 to 40 mg) of bisphosphonates were taken for one month, the incidence of gastric ulcers (approximately 3 percent) was similar between the two groups [24].

Esophageal cancer — From 1995 to 2009, the US Food and Drug Administration (FDA) received reports of 34 patients in the United States who received a diagnosis of esophageal cancer while taking alendronate. In addition, 34 patients from Europe and Japan were reported as having esophageal cancer after using bisphosphonates [25,26]. Results from meta-analyses of observational studies are inconsistent [27-29]. Reports using data from European national registers and records of Medicare beneficiaries in the United States have not shown an increased risk of esophageal cancer among individuals with osteoporosis or fracture who were receiving oral bisphosphonates compared with those who were not [30-32]. Studies using data from the United Kingdom General Practice Research Database (UKGPRD) report conflicting results, as illustrated by the following:

In a case-cohort study, over 46,000 bisphosphonate users were compared with a similar number of age- and sex-matched controls [33]. Mean follow-up time was 4.5 and 4.4 years in the bisphosphonate and control cohorts, respectively. All of the bisphosphonate cohort and 9 percent of the control cohort received at least one prescription for oral bisphosphonates during follow-up. There was no difference in the risk of esophageal and gastric cancer combined or esophageal cancer alone (HR 1.07, 95% CI 0.77-1.49) between the two cohorts.

In a nested case-control analysis, over 15,000 adults with GI cancer (2954 patients with esophageal cancer) were compared with 77,750 controls [34]. The mean observation period was 7.5 years. Compared with patients who did not receive a prescription for a bisphosphonate, those who received at least one prescription had an increased risk of esophageal cancer (adjusted relative risk [RR] 1.30, 95% CI 1.02-1.66). In addition, the risk of esophageal cancer was significantly higher in patients receiving 10 or more prescriptions than in those who received one to nine prescriptions (RR 1.93 and 0.66, respectively), and the risk was also increased with duration of use. The risk of gastric or colorectal cancers was not increased after prescription of bisphosphonates.

Subsequent case-control studies continue to report conflicting findings [35-37]. The discrepancy in the findings may be explained by differences in study design and duration of follow-up. Further research is required to confirm or refute the potential association, particularly the association between esophageal cancer and different types and formulations of bisphosphonates.

The reasons for any potential association of esophageal cancer and bisphosphonates are not understood, although crystalline material similar to alendronate has been identified in biopsies of patients with erosive esophagitis, suggesting a possible mechanism for chronic inflammation [38,39]. At present, the FDA recommends that bisphosphonates not be used in patients with Barrett's esophagus [25].

RISKS SPECIFIC TO INTRAVENOUS BISPHOSPHONATES

Flu-like symptoms — Intravenous (IV) bisphosphonates are often associated with an acute-phase reaction within 24 to 72 hours of the infusion, characterized by low-grade fever, myalgias, and arthralgias. Treatment with antipyretic agents (ibuprofen or acetaminophen) generally improves the symptoms, and the recurrence of symptoms decreases with subsequent infusions.

In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial, the most commonly reported side effects were fever, flu-like symptoms, myalgia, headache, and arthralgia, which occurred within three days after the first infusion in 32 percent of individuals in the zoledronic acid group [40]. Post-dose symptoms decreased in frequency in the zoledronic acid group after the second and third infusion (6.6 and 2.8 percent, respectively).

RISKS SHARED BY ORAL AND IV BISPHOSPHONATES

Hypocalcemia — Both oral and intravenous (IV) bisphosphonates can cause transient hypocalcemia, but it occurs more frequently after IV than oral administration. The risk of hypocalcemia is higher and the duration longer in patients with hypoparathyroidism, vitamin D deficiency, or inadequate calcium intake [41-43].

In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) trial, hypocalcemia (calcium <8.3 mg/dL [2.075 mmol/L]) occurred more commonly with IV zoledronic acid than with placebo (1.3 versus 0.02 percent) [40]. Hypocalcemia was noted 9 to 11 days post-infusion and was reported to be transient and asymptomatic. All patients in this trial received daily oral calcium and vitamin D supplementation. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'IV regimen'.)

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 "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Calcium/vitamin D'.)

Musculoskeletal pain — Although rare, some patients have experienced severe musculoskeletal pain (bone, joint, and/or muscle pain) within days, months, or years after starting a bisphosphonate, and symptoms do not always resolve completely with discontinuation of therapy [44,45]. An alert by the US Food and Drug Administration (FDA) advises clinicians prescribing bisphosphonates to discuss musculoskeletal symptoms with their patients, and patients should promptly contact their doctor if such symptoms occur [46]. In patients who develop severe musculoskeletal pain, bisphosphonates should be discontinued.

Impaired kidney function — Bisphosphonates are not recommended for use in patients with creatinine clearance below 30 (risedronate, ibandronate) to 35 (alendronate, zoledronic acid) mL/min. There have been isolated reports of kidney function impairment and acute kidney injury after zoledronic acid administration, particularly in patients with multiple myeloma but also rarely in those treated for osteoporosis and those receiving concurrent diuretic therapy. 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. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'IV regimen' and "Osteoporosis in patients with chronic kidney disease: Management".)

Ocular side effects — Ocular side effects including pain, blurred vision, conjunctivitis, uveitis, and scleritis have been reported with most bisphosphonates [47]. However, these complications appear to be rare [48-52].

Atrial fibrillation — Bisphosphonates in general have not been associated with atrial arrhythmias. However, in the HORIZON Pivotal Fracture Trial, the number of patients who had arrhythmia, including serious atrial fibrillation (AF), was greater in the zoledronic acid compared with placebo group (1.3 versus 0.5 percent) [40]. In contrast, an increase in atrial arrhythmia was not seen in the HORIZON Recurrent Fracture Trial, which included older individuals and identical dosing. In addition, an increase in AF was not noted in the HORIZON Pivotal Fracture Extension Trial [53]. Hypocalcemia may be related to AF. However, most of the events occurred more than 30 days after the infusion, at which time mild, transient hypocalcemia would have resolved. Whether the acute-phase reaction contributes to the risk of AF is unclear [54].

This finding in the HORIZON Pivotal Fracture Trial prompted additional review, as illustrated by the following observations:

In a meta-analysis of datasets from four randomized trials of bisphosphonates versus placebo for osteoporosis or fracture, bisphosphonates were associated with risk of AF serious adverse events (odds ratio [OR] 1.47, 95% CI 1.01-2.14), but not all AF events (serious and nonserious; OR 1.14, 95% CI 0.96-1.36) [55]. In three trial datasets, there was no increase in the risk of stroke or cardiovascular mortality.

In a population-based, case-control study from Denmark that evaluated 13,586 patients with atrial arrhythmia and 68,054 population controls, current, former, or new use of bisphosphonates (etidronate and alendronate) was not associated with an increased risk of AF or flutter (adjusted relative risk [RR] for current use compared with nonuse 0.95, 95% CI 0.84-1.07) [56].

In another case-control study from the United States (719 women with AF, 966 control subjects), ever use of alendronate was associated with a higher risk of AF than never use (OR 1.86, 95% CI 1.09-3.15) [57]. However, the risk of AF was increased in past (OR 3.27, 95% CI 1.43-7.47), but not current (OR 1.42, 95% CI 0.78-2.59), users. In addition, the risk was not temporally related to the interval since first prescription or dose of alendronate.

Thus, data on the potential increased risk of AF with bisphosphonates are conflicting [55-62]. However, the large observational study from Denmark and the absence of an association between current use and AF in the United States case-control study suggest that the risk of AF from oral bisphosphonates is small, if it exists at all [63].

The observed association between IV zoledronic acid and AF may be plausible, but the studies do not prove causality. Osteoporosis and AF are more common in older adults and share similar risk factors, which may explain the reported findings [60,61]. In the absence of more definitive data, the benefits of fracture prevention must be weighed against the potential risk of AF, and some caution should be employed when considering IV bisphosphonates for patients with serious underlying heart disease and/or a history of AF.

Osteonecrosis of the jaw — Osteonecrosis of the jaw (ONJ, or avascular necrosis of the jaw), often associated with pain, swelling, exposed bone, local infection, and pathologic fracture of the jaw, is a rare complication of bisphosphonate therapy [64-66]. When it occurs in a patient treated with bisphosphonates for osteoporosis, therapy should be discontinued [64].

Prevalence and risk factors – Although most cases have been in cancer patients or in patients with a compromised immune system (particularly multiple myeloma and metastatic breast cancer) who were treated with high doses of IV bisphosphonates, cases have been noted in patients with postmenopausal osteoporosis taking oral bisphosphonates [67]. It has been estimated that the risk of ONJ is approximately 1 in 10,000 to 1 in 100,000 patient-years in patients taking oral bisphosphonates for osteoporosis [66].

Risk factors for developing ONJ while taking bisphosphonates include IV administration, cancer and anticancer therapy, dose and duration of exposure, dental extractions, dental implants, poorly fitting dentures, glucocorticoids, smoking, diabetes, and preexisting dental disease [66]. There are few data on the risk of ONJ in patients using IV bisphosphonates at doses recommended for the treatment of osteoporosis. In two clinical trials of zoledronic acid versus placebo for the treatment of osteoporosis, there were two potential cases of ONJ (one in each group) [40,53].

Prevention – In patients initiating or continuing treatment with oral bisphosphonates for the treatment of osteoporosis, the American Society of Bone and Mineral Research (ASBMR) recommends that clinicians discuss the risk, signs, and symptoms of ONJ and the risk factors for developing ONJ [68]. Although good oral hygiene and regular dental visits are encouraged, a dental visit prior to beginning oral bisphosphonates is not necessary. However, if an invasive dental procedure (eg, 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 [69]. In particular, there are no data to suggest that discontinuing bisphosphonates prior to invasive dental procedures would lower ONJ risk. Some clinicians ask patients to discontinue bisphosphonates and resume again when healing is complete, while others suggest not stopping bisphosphonates. We typically follow guidelines from the American Association of Oral and Maxillofacial Surgeons, which 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 [70]. They suggest discontinuing bisphosphonates for two months prior to performing the dental surgery if a patient has been treated for more than four years or has taken concomitant glucocorticoids. Bisphosphonates are restarted when the bone has healed.

These criteria were chosen on the basis of bone physiology and the pharmacokinetics of antiresorptive medications, as well as studies which show improved outcome of ONJ treatment with discontinuation of bisphosphonates [71]. The use of markers of bone turnover to make continuation/discontinuation decisions is not recommended. (See "Use of biochemical markers of bone turnover in osteoporosis", section on 'Dental procedures'.)

An International Task Force on Osteonecrosis of the Jaw suggests discontinuing bisphosphonates in patients at high risk for ONJ but low risk for adverse consequences for bone health [66]. High-risk patients include those requiring extensive invasive oral surgery and those with multiple risk factors for ONJ (cancer and anticancer therapy, diabetes, periodontal disease, glucocorticoids, smoking).

Treatment – The treatment of ONJ, once present, is similar in patients with osteoporosis or cancer. Treatment is reviewed separately. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'General approach'.)

Atypical femur fracture — Atypical femur fracture is a rare complication of chronic (median treatment seven years) bisphosphonate therapy [64,72,73]. Treatment of osteoporosis with bisphosphonates for up to five years is typically not associated with atypical fractures and is not a reason to defer bisphosphonate therapy in women who are at high risk for osteoporotic fracture [74].

A reasonable approach for women at low short-term risk for fracture (eg, stable bone mineral density [BMD], no previous vertebral fractures, absence of glucocorticoid therapy) is to stop bisphosphonate therapy after three to five years and follow BMD and risk factor assessment. This approach is consistent with reports from an ASBMR-appointed international task force on atypical diaphyseal and subtrochanteric femoral fractures [72,73]. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Our approach'.)

Magnitude of risk – Most, but not all, observational studies show a small increase in risk of atypical fracture with bisphosphonate use [75-81]. In a meta-analysis of six cohort and five case-control studies examining the association of bisphosphonates and atypical fractures, the risk of atypical fracture was increased in bisphosphonate users (risk ratio 1.70, 95% CI 1.22-2.37) [74]. The meta-analysis was limited by heterogeneity, likely related to differences in study design, patient characteristics, selection of controls, and varying definitions of atypical fracture.

Although, the long-term use (median treatment seven years) of bisphosphonates increases the relative risk of atypical fractures, the absolute risk is low (3.2 to 50 cases per 100,000 person-years). The risk may rise with duration of bisphosphonate exposure (100 per 100,000 person-years). A patient with an atypical femur fracture in one leg is at risk for a fracture in the other leg. When bisphosphonates are stopped, the risk of atypical fracture declines [72,73].

In a prospective cohort study of 196,129 women ≥50 years of age with any bisphosphonate use, there were 277 atypical femur fractures during the 10-year follow-up (1.74 fractures per 10,000 person-years) [82]. The risk of atypical fractures increased with longer duration of bisphosphonate use (particularly beyond three to five years of use), age 65 to 84 years compared with younger or older women, glucocorticoid use ≥1 year, shorter height, higher weight, and in Asian Americans compared with White Americans. The risk decreased with discontinuation of bisphosphonates. Overall, the absolute risk of atypical fractures was low compared with reduction in osteoporotic fractures, particularly for White American women. After three years of bisphosphonate use in White American women, 149 hip fractures were prevented, and two bisphosphonate-associated atypical fractures occurred. In Asian American women, 91 hip fractures were prevented, and eight atypical fractures occurred [74-81].

Mechanism of fracture – Bisphosphonates inhibit bone resorption by suppressing osteoclast activity. Although clinical trial data clearly support the beneficial effect of bisphosphonates on the prevention of osteoporotic fracture, prolonged therapy can lead to oversuppression of bone turnover ("frozen bone") and increased skeletal fragility [83,84]. In animal studies, high-dose bisphosphonate accumulation results in microscopic damage [85]. Although similar findings do not appear to be common by histomorphometry in postmenopausal women taking long-term bisphosphonate therapy [86], individual cases of atypical fracture (particularly subtrochanteric or diaphyseal fractures) and severely suppressed bone turnover have been reported [74,87-91].

The evidence suggests that atypical fractures are stress fractures. Bisphosphonates accumulate in areas that are developing stress fractures and suppress intracortical remodeling, impairing normal healing of the stress fracture. Lower limb geometry may contribute to the risk of developing an atypical fracture [72,73]. (See "Overview of stress fractures".)

Clinical presentation and evaluation – Atypical fractures evolve over time, and typically, patients have prodromal symptoms, including dull or aching pain in the groin or thigh. In retrospect, there may be cortical thickening on plain radiographs obtained prior to fracture. Thus, evaluation is recommended in patients with new onset of groin or mid-thigh pain who have been taking bisphosphonates, particularly for more than 3 to 10 years [72,73].

Conventional radiography is usually the initial imaging procedure, followed by magnetic resonance imaging (MRI) or bone scintigraphy if indicated (eg, evidence of periosteal thickening and cortical lucency in the region of periosteal thickening on plain radiographs). In high-risk groups (long-term bisphosphonate or denosumab treatment, particularly in the setting of long-term use of glucocorticoids), some experts obtain dual-energy x-ray absorptiometry (DXA) with full femur-length images to screen for atypical fractures [92,93]. If an abnormality in the spectrum of atypical femur fracture is identified, additional imaging should be obtained; the specific findings on screening dictate the optimal strategy for follow-up imaging. Additional studies are needed to determine the role of DXA with full femur-length images for the screening of atypical femur fractures.

Management – Bisphosphonates should be discontinued and adequate calcium and vitamin D supplementation prescribed for patients with atypical fractures or stress reaction on radiographs. (See "Calcium and vitamin D supplementation in osteoporosis", section on 'Optimal intake'.)

Orthopedic intervention – Orthopedic intervention is necessary for patients with complete fractures and for those with incomplete fractures accompanied by significant pain [72,73]. Conservative management (limited weight bearing, calcium and vitamin D, observation) may be adequate for patients with incomplete fracture and minimal pain. Reduced activity is continued until there is no edema on MRI or no increased activity on bone scan. Orthopedic intervention may be necessary to prevent complete fracture if there is no radiographic improvement after two to three months.

Parathyroid hormone (PTH) analog therapy – Another option in some cases is the use of PTH analog therapy in conjunction with comprehensive orthopedic intervention and surveillance. In a meta-analysis of six observational studies in 214 individuals with atypical femur fracture, those who received teriparatide (n = 93) had a lower rate of delayed union (OR 0.24, 95% CI 0.11-0.52) and shorter fracture healing time (mean difference -1.7 months) compared with those who did not receive teriparatide (n = 121) . No randomized trials have assessed the efficacy of teriparatide in patients with atypical fractures. Trials of teriparatide or PTH (1-84) in patients with distal radial or pelvic fractures (ie, not atypical fractures) are reviewed elsewhere. (See "Parathyroid hormone/parathyroid hormone-related protein analog therapy for osteoporosis", section on 'Fracture healing'.)

Cutaneous reactions — Rash is a rare side effect of both oral and intravenous (IV) bisphosphonates [94]. Urticaria, angioedema, and photosensitivity also have been reported with bisphosphonate use. Oral bisphosphonate therapy has been implicated in very rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis, although direct causality has not been established [94]. If any of these cutaneous adverse reactions occur during bisphosphonate use, the bisphosphonate should be discontinued immediately. If a severe cutaneous reaction develops during bisphosphonate treatment, this medication class should be avoided without rechallenge given the potentially causal role of the bisphosphonate. (See "Drug eruptions" and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae".)

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" and "Society guideline links: Medication-related osteonecrosis of the jaw".)

SUMMARY AND RECOMMENDATIONS

Risks specific to oral bisphosphonates – Oral bisphosphonates may cause local irritation of the upper gastrointestinal (GI) mucosa, resulting in reflux, esophagitis, and/or esophageal ulcers. The incidence of these side effects is very low if proper administration instructions are followed. (See 'Reflux, esophagitis, ulcers' above.)

Oral bisphosphonates should not be used at all in patients with esophageal disorders (eg, achalasia, esophageal stricture, esophageal varices, Barrett's esophagus), history of Roux-en-Y gastric bypass, or with an inability to follow the dosing requirements (eg, stay upright for at least 30 to 60 minutes). (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Contraindications to bisphosphonates'.)

Risks specific to intravenous (IV) bisphosphonates – IV bisphosphonates are often associated with an acute-phase reaction within 24 to 72 hours of the infusion, characterized by low-grade fever, myalgias, and arthralgias. Treatment with antipyretic agents (ibuprofen or acetaminophen) generally improves the symptoms, and recurrence of symptoms decreases with subsequent infusions. (See 'Flu-like symptoms' above.)

Risks shared by oral and IV bisphosphonates

Hypocalcemia – Both oral and IV bisphosphonates can cause transient hypocalcemia, but more frequently after IV than oral administration. The risk of hypocalcemia is higher and duration longer in patients with hypoparathyroidism, vitamin D deficiency, or inadequate calcium intake. 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 'Hypocalcemia' above and "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Practical management issues'.)

Musculoskeletal pain – Rarely, patients have experienced severe musculoskeletal pain (bone, joint, and/or muscle pain) within days, months, or years after starting a bisphosphonate, and symptoms do not always resolve completely with discontinuation of therapy. (See 'Musculoskeletal pain' above.)

Impaired kidney function – Bisphosphonates are not recommended for use in patients with creatinine clearance below 30 (risedronate, ibandronate) to 35 (alendronate, zoledronic acid) mL/min. (See 'Impaired kidney function' above and "Osteoporosis in patients with chronic kidney disease: Management".)

Osteonecrosis of the jaw (ONJ) – ONJ is a rare complication of bisphosphonate therapy for the treatment of osteoporosis. Risk factors for developing ONJ include cancer and anticancer therapy, invasive dental procedures (dental extractions, dental implants), poorly fitting dentures, glucocorticoids, smoking, diabetes, and preexisting dental disease. (See 'Osteonecrosis of the jaw' above.)

-Prevention of ONJ – Good oral hygiene and regular dental visits are encouraged; however, a dental visit prior to beginning bisphosphonate therapy is not necessary. If an invasive dental procedure (eg, dental implant or extraction) is planned, we frequently delay initiation of bisphosphonate therapy for a few months until healing of the jaw is complete.

If a patient is already taking bisphosphonates and requires an invasive dental procedure, the approach is uncertain.

For patients who have been treated with oral bisphosphonates for less than four years and have no clinical risk factors for developing ONJ, we suggest performing dentoalveolar surgery, such as extractions and implants, without stopping bisphosphonates (Grade 2C). If a patient chooses to stop the bisphosphonate, however, it is unlikely that there would be short-term adverse consequences on bone mineral density (BMD) or fracture risk. (See 'Osteonecrosis of the jaw' above.)

If a patient has been treated for more than four years or has clinical risk factors for ONJ (eg, glucocorticoids, cancer and anticancer therapy), we suggest discontinuing bisphosphonates (Grade 2C). In this setting, bisphosphonates are discontinued two months prior to performing the dental surgery. However, there are no data to suggest that discontinuing bisphosphonates for dental procedures would lower ONJ risk. In addition, bisphosphonates stay in bone for years, not months. (See 'Osteonecrosis of the jaw' above.)

-Treatment of ONJ – When ONJ occurs in a patient treated with bisphosphonates for osteoporosis, bisphosphonates should be discontinued. The treatment of ONJ, once present, is similar in patients with osteoporosis or cancer. Treatment is reviewed separately. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'General approach'.)

Atypical femur fracture – Atypical femur fracture is an uncommon complication of chronic bisphosphonate therapy. The risk of atypical fractures increases with longer duration of bisphosphonate use (particularly beyond three to five years of use), age 65 to 84 years compared with younger or older women, glucocorticoid use ≥1 year, shorter height, higher weight, and in Asian Americans compared with White Americans. Atypical fractures evolve over time, and typically, patients have prodromal symptoms including dull or aching pain in the groin or thigh. For patients with atypical fractures or stress reaction on radiographs, bisphosphonates should be discontinued and adequate calcium and vitamin D supplementation prescribed. Orthopedic intervention may be required depending upon the findings on radiographs and degree of pain. (See 'Atypical femur fracture' above.)

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Topic 104424 Version 18.0

References

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