ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Risks of bisphosphonate therapy in patients with osteoporosis

Risks of bisphosphonate therapy in patients with osteoporosis
Literature review current through: Jan 2024.
This topic last updated: Jan 05, 2024.

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 [48-53].

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 [54]. 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 [55].

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) [56]. 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) [57].

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) [58]. 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 [56-63]. 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 [64].

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 [61,62]. 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 [65-67]. When it occurs in a patient treated with bisphosphonates for osteoporosis, therapy should be discontinued [65].

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 [68]. 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 [67].

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 [67]. 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) [40,54].

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 [69]. 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 few data exist to guide management. We typically continue bisphosphonate therapy during dental procedures; however, if the patient or treating dentist prefers a more cautious approach, bisphosphonate therapy may be discontinued two months prior to dental surgery and resumed after the bone has healed. Available data do not consistently suggest that discontinuing bisphosphonates prior to invasive dental procedures reduces ONJ risk, and no consensus approach was defined in guidelines from the American Association of Oral and Maxillofacial Surgeons [70]. Some experts suggest continuing bisphosphonate treatment without interruption.

Other experts ask selected patients to discontinue bisphosphonates prior to surgery and to resume treatment when healing is complete; factors that inform patient selection for a preoperative drug holiday may include duration of bisphosphonate therapy, comorbid conditions, concurrent medications (eg, glucocorticoids), and the scope of the surgical procedure.

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 [67]. 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).

The approach to preoperative drug holidays is based on bone physiology and the pharmacokinetics of antiresorptive medications, as well as studies that 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'.)

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 [65,72,73]. 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, expert approaches vary. We typically continue bisphosphonate therapy during dental procedures; however, if the patient or treating dentist prefers a more cautious approach, bisphosphonate treatment may be discontinued two months prior to dental surgery and resumed after the bone has healed. (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.)

  1. Reid IR. Bisphosphonates in the treatment of osteoporosis: a review of their contribution and controversies. Skeletal Radiol 2011; 40:1191.
  2. Liberman UA, Weiss SR, Bröll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 1995; 333:1437.
  3. Chesnut CH 3rd, McClung MR, Ensrud KE, et al. Alendronate treatment of the postmenopausal osteoporotic woman: effect of multiple dosages on bone mass and bone remodeling. Am J Med 1995; 99:144.
  4. Tucci JR, Tonino RP, Emkey RD, et al. Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. Am J Med 1996; 101:488.
  5. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996; 348:1535.
  6. Bauer DC, Black D, Ensrud K, et al. Upper gastrointestinal tract safety profile of alendronate: the fracture intervention trial. Arch Intern Med 2000; 160:517.
  7. Greenspan S, Field-Munves E, Tonino R, et al. Tolerability of once-weekly alendronate in patients with osteoporosis: a randomized, double-blind, placebo-controlled study. Mayo Clin Proc 2002; 77:1044.
  8. de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996; 335:1016.
  9. Levine J, Nelson D. Esophageal stricture associated with alendronate therapy. Am J Med 1997; 102:489.
  10. Graham DY, Malaty HM. Alendronate and naproxen are synergistic for development of gastric ulcers. Arch Intern Med 2001; 161:107.
  11. Kelly R, Taggart H. Incidence of gastrointestinal side effects due to alendronate is high in clinical practice. BMJ 1997; 315:1235.
  12. Miller PD, Woodson G, Licata AA, et al. Rechallenge of patients who had discontinued alendronate therapy because of upper gastrointestinal symptoms. Clin Ther 2000; 22:1433.
  13. Donahue JG, Chan KA, Andrade SE, et al. Gastric and duodenal safety of daily alendronate. Arch Intern Med 2002; 162:936.
  14. Cryer B, Bauer DC. Oral bisphosphonates and upper gastrointestinal tract problems: what is the evidence? Mayo Clin Proc 2002; 77:1031.
  15. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 1999; 282:1344.
  16. Taggart H, Bolognese MA, Lindsay R, et al. Upper gastrointestinal tract safety of risedronate: a pooled analysis of 9 clinical trials. Mayo Clin Proc 2002; 77:262.
  17. Highlights of prescribing information - Atelvia http://www.wcrx.com/pdfs/pi/pi_atelvia.pdf (Accessed on April 06, 2011).
  18. McClung MR, Miller PD, Brown JP, et al. Efficacy and safety of a novel delayed-release risedronate 35 mg once-a-week tablet. Osteoporos Int 2012; 23:267.
  19. Rosen CJ, Hochberg MC, Bonnick SL, et al. Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res 2005; 20:141.
  20. Bonnick S, Saag KG, Kiel DP, et al. Comparison of weekly treatment of postmenopausal osteoporosis with alendronate versus risedronate over two years. J Clin Endocrinol Metab 2006; 91:2631.
  21. Cadarette SM, Katz JN, Brookhart MA, et al. Comparative gastrointestinal safety of weekly oral bisphosphonates. Osteoporos Int 2009; 20:1735.
  22. Lanza FL, Hunt RH, Thomson AB, et al. Endoscopic comparison of esophageal and gastroduodenal effects of risedronate and alendronate in postmenopausal women. Gastroenterology 2000; 119:631.
  23. Thomson AB, Marshall JK, Hunt RH, et al. 14 day endoscopy study comparing risedronate and alendronate in postmenopausal women stratified by Helicobacter pylori status. J Rheumatol 2002; 29:1965.
  24. Lanza F, Schwartz H, Sahba B, et al. An endoscopic comparison of the effects of alendronate and risedronate on upper gastrointestinal mucosae. Am J Gastroenterol 2000; 95:3112.
  25. Wysowski DK. Reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 2009; 360:89.
  26. Wysowski DK. Oral bisphosphonates and oesophageal cancer. BMJ 2010; 341:c4506.
  27. Andrici J, Tio M, Eslick GD. Meta-analysis: oral bisphosphonates and the risk of oesophageal cancer. Aliment Pharmacol Ther 2012; 36:708.
  28. Sun K, Liu JM, Sun HX, et al. Bisphosphonate treatment and risk of esophageal cancer: a meta-analysis of observational studies. Osteoporos Int 2013; 24:279.
  29. Wright E, Schofield PT, Molokhia M. Bisphosphonates and evidence for association with esophageal and gastric cancer: a systematic review and meta-analysis. BMJ Open 2015; 5:e007133.
  30. Abrahamsen B, Eiken P, Eastell R. More on reports of esophageal cancer with oral bisphosphonate use. N Engl J Med 2009; 360:1789; author reply 1791.
  31. Abrahamsen B, Pazianas M, Eiken P, et al. Esophageal and gastric cancer incidence and mortality in alendronate users. J Bone Miner Res 2012; 27:679.
  32. Morden NE, Munson JC, Smith J, et al. Oral bisphosphonates and upper gastrointestinal toxicity: a study of cancer and early signals of esophageal injury. Osteoporos Int 2015; 26:663.
  33. Cardwell CR, Abnet CC, Cantwell MM, Murray LJ. Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA 2010; 304:657.
  34. Green J, Czanner G, Reeves G, et al. Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort. BMJ 2010; 341:c4444.
  35. Wright E, Schofield PT, Seed P, Molokhia M. Bisphosphonates and risk of upper gastrointestinal cancer--a case control study using the General Practice Research Database (GPRD). PLoS One 2012; 7:e47616.
  36. Vinogradova Y, Coupland C, Hippisley-Cox J. Exposure to bisphosphonates and risk of gastrointestinal cancers: series of nested case-control studies with QResearch and CPRD data. BMJ 2013; 346:f114.
  37. Vogtmann E, Corley DA, Almers LM, et al. Oral Bisphosphonate Exposure and the Risk of Upper Gastrointestinal Cancers. PLoS One 2015; 10:e0140180.
  38. Ribeiro A, DeVault KR, Wolfe JT 3rd, Stark ME. Alendronate-associated esophagitis: endoscopic and pathologic features. Gastrointest Endosc 1998; 47:525.
  39. Abraham SC, Cruz-Correa M, Lee LA, et al. Alendronate-associated esophageal injury: pathologic and endoscopic features. Mod Pathol 1999; 12:1152.
  40. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007; 356:1809.
  41. Schussheim DH, Jacobs TP, Silverberg SJ. Hypocalcemia associated with alendronate. Ann Intern Med 1999; 130:329.
  42. Rosen CJ, Brown S. Severe hypocalcemia after intravenous bisphosphonate therapy in occult vitamin D deficiency. N Engl J Med 2003; 348:1503.
  43. Maalouf NM, Heller HJ, Odvina CV, et al. Bisphosphonate-induced hypocalcemia: report of 3 cases and review of literature. Endocr Pract 2006; 12:48.
  44. The Pink Sheet 2005; 67:6.
  45. Wysowski DK, Chang JT. Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med 2005; 165:346.
  46. US Food and Drug Administration. Information for Healthcare Professionals: Bisphosphonates (marketed as Actonel, Actonel+Ca, Aredia, Boniva, Didronel, Fosamax, Fosamax+D, Reclast, Skelid, and Zometa). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124165.htm (Accessed on September 28, 2009).
  47. Etminan M, Forooghian F, Maberley D. Inflammatory ocular adverse events with the use of oral bisphosphonates: a retrospective cohort study. CMAJ 2012; 184:E431.
  48. Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular inflammation. N Engl J Med 2003; 348:1187.
  49. Fietta P, Manganelli P, Lodigiani L. Clodronate induced uveitis. Ann Rheum Dis 2003; 62:378.
  50. Sharma NS, Ooi JL, Masselos K, et al. Zoledronic acid infusion and orbital inflammatory disease. N Engl J Med 2008; 359:1410.
  51. Pazianas M, Clark EM, Eiken PA, et al. Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: cohort analysis using a national prescription database. J Bone Miner Res 2013; 28:455.
  52. Patel DV, Bolland M, Nisa Z, et al. Incidence of ocular side effects with intravenous zoledronate: secondary analysis of a randomized controlled trial. Osteoporos Int 2015; 26:499.
  53. Xie JS, Kaplan AJ. Anterior uveitis and diffuse scleritis after pamidronate infusion. CMAJ 2023; 195:E1722.
  54. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 2012; 27:243.
  55. Pazianas M, Compston J, Huang CL. Atrial fibrillation and bisphosphonate therapy. J Bone Miner Res 2010; 25:2.
  56. Loke YK, Jeevanantham V, Singh S. Bisphosphonates and atrial fibrillation: systematic review and meta-analysis. Drug Saf 2009; 32:219.
  57. Sørensen HT, Christensen S, Mehnert F, et al. Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study. BMJ 2008; 336:813.
  58. Heckbert SR, Li G, Cummings SR, et al. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 2008; 168:826.
  59. Cummings SR, Schwartz AV, Black DM. Alendronate and atrial fibrillation. N Engl J Med 2007; 356:1895.
  60. Karam R, Camm J, McClung M. Yearly zoledronic acid in postmenopausal osteoporosis. N Engl J Med 2007; 357:712.
  61. Abrahamsen B, Eiken P, Brixen K. Atrial fibrillation in fracture patients treated with oral bisphosphonates. J Intern Med 2009; 265:581.
  62. Bunch TJ, Anderson JL, May HT, et al. Relation of bisphosphonate therapies and risk of developing atrial fibrillation. Am J Cardiol 2009; 103:824.
  63. Grosso A, Douglas I, Hingorani A, et al. Oral bisphosphonates and risk of atrial fibrillation and flutter in women: a self-controlled case-series safety analysis. PLoS One 2009; 4:e4720.
  64. US Food and Drug Administration. Update of Safety Review Follow-up to the October 1, 2007 Early Communication about the Ongoing Safety Review of Bisphosphonates. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136201.htm (Accessed on March 29, 2012).
  65. Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research. J Bone Miner Res 2016; 31:16.
  66. Fedele S, Porter SR, D'Aiuto F, et al. Nonexposed variant of bisphosphonate-associated osteonecrosis of the jaw: a case series. Am J Med 2010; 123:1060.
  67. Khan AA, Morrison A, Hanley DA, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 2015; 30:3.
  68. Hess LM, Jeter JM, Benham-Hutchins M, Alberts DS. Factors associated with osteonecrosis of the jaw among bisphosphonate users. Am J Med 2008; 121:475.
  69. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007; 22:1479.
  70. Ruggiero SL, Dodson TB, Aghaloo T, et al. American Association of Oral and Maxillofacial Surgeons' Position Paper on Medication-Related Osteonecrosis of the Jaws-2022 Update. J Oral Maxillofac Surg 2022; 80:920.
  71. Damm DD, Jones DM. Bisphosphonate-related osteonecrosis of the jaws: a potential alternative to drug holidays. Gen Dent 2013; 61:33.
  72. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2010; 25:2267.
  73. Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2014; 29:1.
  74. Gedmintas L, Solomon DH, Kim SC. Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res 2013; 28:1729.
  75. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res 2009; 24:1095.
  76. Park-Wyllie LY, Mamdani MM, Juurlink DN, et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA 2011; 305:783.
  77. Kim SY, Schneeweiss S, Katz JN, et al. Oral bisphosphonates and risk of subtrochanteric or diaphyseal femur fractures in a population-based cohort. J Bone Miner Res 2011; 26:993.
  78. Schilcher J, Michaëlsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med 2011; 364:1728.
  79. Abrahamsen B, Eiken P, Eastell R. Cumulative alendronate dose and the long-term absolute risk of subtrochanteric and diaphyseal femur fractures: a register-based national cohort analysis. J Clin Endocrinol Metab 2010; 95:5258.
  80. Dell RM, Adams AL, Greene DF, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 2012; 27:2544.
  81. Schilcher J, Koeppen V, Aspenberg P, Michaëlsson K. Risk of atypical femoral fracture during and after bisphosphonate use. N Engl J Med 2014; 371:974.
  82. Black DM, Geiger EJ, Eastell R, et al. Atypical Femur Fracture Risk versus Fragility Fracture Prevention with Bisphosphonates. N Engl J Med 2020; 383:743.
  83. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005; 90:1294.
  84. Shane E. Evolving data about subtrochanteric fractures and bisphosphonates. N Engl J Med 2010; 362:1825.
  85. Mashiba T, Hirano T, Turner CH, et al. Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 2000; 15:613.
  86. Chapurlat RD, Arlot M, Burt-Pichat B, et al. Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study. J Bone Miner Res 2007; 22:1502.
  87. Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 2008; 358:1304.
  88. Visekruna M, Wilson D, McKiernan FE. Severely suppressed bone turnover and atypical skeletal fragility. J Clin Endocrinol Metab 2008; 93:2948.
  89. Odvina CV, Levy S, Rao S, et al. Unusual mid-shaft fractures during long-term bisphosphonate therapy. Clin Endocrinol (Oxf) 2010; 72:161.
  90. Rizzoli R, Akesson K, Bouxsein M, et al. Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report. Osteoporos Int 2011; 22:373.
  91. Meier RP, Perneger TV, Stern R, et al. Increasing occurrence of atypical femoral fractures associated with bisphosphonate use. Arch Intern Med 2012; 172:930.
  92. Cheung AM, McKenna MJ, van de Laarschot DM, et al. Detection of Atypical Femur Fractures. J Clin Densitom 2019; 22:506.
  93. van de Laarschot DM, Smits AA, Buitendijk SK, et al. Screening for Atypical Femur Fractures Using Extended Femur Scans by DXA. J Bone Miner Res 2017; 32:1632.
  94. Musette P, Kaufman JM, Rizzoli R, et al. Cutaneous side effects of antiosteoporosis treatments. Ther Adv Musculoskelet Dis 2011; 3:31.
Topic 104424 Version 20.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟