Mechanism of Action

Bisphosphonates consist of a group of compounds with a common phosphorus-carbon-phosphorus backbone that resembles the phosphorus-oxygen-phosphorus structure of native pyrophosphate, and different side chains that are specific to each compound. Their major pharmacologic property is inhibition of bone resorption, which is achieved through (1) strong attachment to the hydroxyapatite mineral found in bone, (2) uptake by osteoclasts resorbing bone, and (3) inhibition of osteoclast function or induction of osteoclast apoptosis. Reduced bone resorption results in improvement in bone mineral density and reduction in fracture rates. Bisphosphonates secondarily reduce bone formation due to the normal “coupling” between bone resorption and bone formation that occurs at individual resorption units.

Pharmacokinetics

Because of their high affinity to hydroxyapatite, bisphosphonates exhibit unique pharmacokinetic properties: after the ingestion of an oral bisphosphonate, less than 1% of the drug is absorbed from the gastrointestinal tract, whereas intravenous bisphosphonates are injected directly into the circulation. Of the fraction that reaches the circulation, approximately 50% is excreted unmetabolized in the urine, and the remaining 50% is taken up avidly in the skeleton, with little uptake by other tissues. Thereafter, bisphosphonates are slowly released back into circulation after uptake by osteoclasts at the surface of bone, and a much slower elimination phase is seen, with an estimated mean terminal half-life of greater than 10 years.

Pharmacology of Different Bisphosphonates

The mechanism through which osteoclast dysfunction occurs differs between nitrogen-containing bisphosphonates and non–nitrogen-containing bisphosphonates, or simple bisphosphonates. The nitrogen-containing bisphosphonate group (which includes alendronate, ibandronate, risedronate, and zoledronic acid [ZA]) exerts its effects through inhibiting the enzyme farnesyl pyrophosphate synthase (FFP synthase) that prevents the prenylation of small GTPases, thus reducing osteoclast activity. On the other hand, simple bisphosphonates (etidronate, clodronate, and tiludronate) are metabolized in the osteoclast cytosol to ATP analogs that induce osteoclast apoptosis. Even among the widely used nitrogen-containing bisphosphonates, the potency of individual bisphosphonates is further determined by the degree of affinity to hydroxyapatite and the extent of inhibition of FFP synthase.

Atypical Femoral Fractures

Bisphosphonate therapy has been shown in clinical trials to significantly decrease the rates of hip fractures in patients with osteoporosis. In 2005, a report was published describing patients treated long-term with oral bisphosphonates who developed unusual low-trauma fractures, often involving the femoral shafts. In subsequent years, a growing number of case reports and series were published citing an increased risk for atypical femoral fractures (AFFs) in patients treated with prolonged bisphosphonate therapy. This finding prompted the American Society for Bone and Mineral Research to convene a multidisciplinary task force, which published its findings on AFFs in a report in the fall of 2010, providing a definition of these fractures ( Table 1 ). The report stated that a causal link between AFFs and bisphosphonate use could not be established, but that a potential association with prolonged bisphosphonate use was noted. Shortly afterward, the FDA required a label change for oral bisphosphonates, describing the uncertainty regarding the optimal duration of bisphosphonate use for the treatment or prevention of osteoporosis.

Unlike the more prevalent osteoporotic femoral neck ( Fig. 1 A) and intertrochanteric fractures, AFFs are commonly located in the upper third of the femur but distal to the lesser trochanter. They may occur with minimal or no trauma, and be preceded by thigh or groin pain. Unlike the typical femoral shaft fractures (see Fig. 1 B), AFFs have distinctive radiographic features, including a transverse or short oblique configuration, and are noncomminuted (see Fig. 1 C). Complete fractures (see Fig. 1 C) extend through both cortices and may have a medial spike, whereas incomplete fractures (see Fig. 1 D) compromise only the lateral cortex. Other features that may be present include a localized periosteal reaction, increased cortical thickness, and delayed healing. AFFs may be bilateral in almost 50% of patients.

Sites of femur fractures. ( A ) Femoral neck fracture. ( B ) Typical femoral shaft fracture. ( C ) Complete atypical femoral shaft fracture. ( D ) Incomplete atypical femoral shaft fracture.

([ B, C ] Adapted from Lenart BA. Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int 2009;20:1353–62; with permission; and [ D ] From Compston J. Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw. Osteoporos Int 2011;22:2951–61; with permission.)

The true incidence of this condition is not known, although recent publications have examined this question. Dell and colleagues reported that the incidence of AFF in a group of 1.8 million older patients enrolled at Kaiser Southern California gradually increased from 1.78 per 100,000 person-years in patients receiving bisphosphonates for less than 2 years to 113.1 per 100,000 person-years in patients receiving therapy for 8.0 to 9.9 years ( Fig. 2 ). In a separate study from a single center, the incidence rate of AFF was low (3.2 cases per 100,000 person-years) and on average increased by 10.7% per year in patients receiving bisphosphonate therapy. Although these data do not prove a causal association between bisphosphonate use and AFF, the rising risk with increasing bisphosphonate exposure supports this association.

Age-adjusted incidence of hip fractures and atypical femoral fractures according to duration of bisphosphonate therapy. Data from 1,835,116 patients from a single integrated health care provider. Bisphosphonate exposure was derived from internal pharmacy records. ^a Atypical femoral fractures (continuous line) were identified by diagnostic or procedure codes for the 2007-2011 period and adjudicated by examination of radiographs. ^b Hip fractures (dotted line) were identified by diagnostic codes for the 2007-2009 period and were not further adjudicated. Note the exponential rise in atypical femoral fracture with increasing duration of bisphosphonate therapy. The rate of atypical femoral fractures remains much lower than the rate of hip fractures typically experienced by patients with osteoporosis.

( Adapted from Dell RM, Adams AL, Greene DF, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 2012 Jul 26. . [Epub ahead of print]; with permission.)

At the same time, the incidence of AFF seems to be rare compared with the incidence of osteoporotic hip (femoral neck) fractures. In the study by Dell and colleagues, the incidence of the more typical hip fractures was significantly higher than that of AFFs (see Fig. 2 ). In a study published by Wang and Bhattacharyya in 2011 examining the rates of AFF from 1996 to 2007, the reported age-adjusted rates for subtrochanteric fragility fractures increased among women, from 28.4 in 1999 to 34.2 per 100,000 patient-treatment years in 2007 (an increase of 20.4%), with no significant increase in men. In contrast, typical hip fractures decreased 31.6% (from 1020.5 to 697.4 per 100,000 patient-treatment years) among women and 20.5% (from 424.9 to 337.6 per 100,000 patient-treatment years) among men.

Considerable debate exists regarding the association between AFFs and long-term bisphosphonate use. This debate partly stems from early studies that found a higher risk for femoral shaft fractures in patients with osteoporosis regardless of bisphosphonate treatment, suggesting that AFFs are part of the spectrum of fragility (osteoporotic) fractures and that bisphosphonates are not as efficacious in preventing this type of fractures. A major limitation of these early studies is the reliance on International Classification of Diseases (ICD) codes without radiographic adjudication of AFF. Another argument against the theory that AFFs are typical fragility fractures is the recently published finding that the incidence of AFFs (adjudicated by blinded review of radiographs) was independent of bone mineral density and age, unlike the more traditional osteoporotic femoral neck fractures, which are more common in individuals of older age and with lower bone mineral density.

AFFs have also been reported in patients who never used bisphosphonates, suggesting that bisphosphonate use is not absolutely necessary for occurrence of these fractures. Nevertheless, the exponential increase in AFF incidence with longer bisphosphonate exposure and the progressive decline in AFF incidence in individuals who discontinue bisphosphonates highly suggest that bisphosphonate use worsens AFF risk. This contention is further supported by the significant increase in AFF incidence in U.S. women since the approval of oral bisphosphonates in 1996, whereas a contemporaneous decline has occurred in the incidence of the more common osteoporotic hip fractures. The lack of significant changes in the incidence of AFF and hip fractures in U.S. men during the same period has been attributed to their lower rate of bisphosphonate use.

The pathogenesis of AFF is not entirely understood, but decreased bone turnover has been suggested as the culprit. This notion is interesting when one considers the importance of decreasing bone turnover in the management of patients with osteoporosis, and the fact that not enough evidence shows that suppression is greater in those with than without AFF. The process through which decreased bone turnover could lead to increased risk for AFF includes alterations in the normal pattern of collagen cross-linking, microdamage accumulation, increased mineralization, reduced heterogeneity of mineralization, variations in the rate of bone turnover, and reduced vascularity and antiangiogenic effects. A recent publication nicely summarizes these changes and the potential pitfalls associated with the assumption that oversuppression of bone turnover is to be blamed. However, current knowledge regarding AFF suggests that during the process of suppressed bone turnover, increased production of advanced glycation end products may occur, with a reduction in the toughness of bone. Additionally, changes in the normal mineralization pattern to a more homogenous one has been shown in one study, but not in another, to increase the propagation of microcracks. Furthermore, accumulation of bisphosphonates at sites of microdamage could inhibit repair of these microcracks, resulting in their propagation and the development of a stress fracture. Bisphosphonates also seem to inhibit some growth factors that are implicated in angiogenesis, including vascular endothelial growth factor and platelet-derived growth factor, leading to decreased vascularization that could impair fracture healing.

The predisposing risk factors for AFF are not completely understood. Several studies have consistently found that long-term bisphosphonate use increases the risk for AFF. Furthermore, the risk conferred by the use of this group of medications seems to be independent of age and bone mineral density. It also seems that after discontinuation of bisphosphonate therapy, a 70% reduction in risk of AFF occurs for every year since the last use. Additional risk factors that have been reported in the literature include Asian ethnicity, the presence of thick cortices before initiation of bisphosphonate therapy, glucocorticoid use, and use of proton pump inhibitors. However, these results are inconsistent, and further evaluation to determine their true contribution to AFF is still needed.

Management of patients with complete AFF includes fracture fixation and initiation of medical management. Optimal surgical management is still unknown, but intramedullary reconstruction with full-length nails is preferred. Medical management should include the discontinuation of bisphosphonates and optimization of calcium and vitamin D intake to around 1000 to 1200 mg/d and at least 800 IU/d, respectively, between diet and supplements. In incomplete AFF, intramedullary nail fixation is recommended in patients with thigh pain, although initiation of teriparatide has been shown in case reports to decrease bone edema and favor the development of cortical bridging. Additionally, in 2 patients with delayed healing of incomplete AFF, strontium ranelate led to total closure of the fracture. After an AFF, practitioners must also remain vigilant for the development of symptoms (groin/thigh pain) that suggest an incipient stress fracture in the contralateral limb. Radiographic imaging or MRI of the contralateral femur should be conducted irrespective of the presence of thigh pain.

Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) was first described in the setting of bisphosphonate use in 2003. Bisphosphonate-associated ONJ was defined by the American Society of Bone and Mineral Research task force in 2007 as exposed bone in the maxillofacial region that does not heal within 8 weeks after identification by a heath care provider in a patient who was receiving or had been exposed to a bisphosphonate and had not had radiation therapy to the craniofacial region. However, ONJ has been described in patients not receiving bisphosphonates, and these patients would not be covered by this definition.

Clinical signs and symptoms of ONJ include pain, swelling, paresthesias, and suppuration, along with soft tissue ulceration and intra- or extraoral sinus tracts. Imaging studies may be normal or show radiolucencies or radio-opacities. The differential diagnosis of bisphosphonate-associated ONJ includes other common intraoral conditions, including periodontal disease, gingivitis or mucositis, temporomandibular joint disease, infectious osteomyelitis, sinusitis, periapical disease caused by a carious infection, osteoradionecrosis, neuralgia-inducing cavitational osteonecrosis, and bone tumors or metastases.

The incidence of ONJ in patients treated with bisphosphonates for osteoporosis remains unknown. During randomized controlled clinical trials, no cases of ONJ were reported. However, several cases of this condition have been reported in the literature in patients receiving bisphosphonates for both benign and malignant conditions. Based on these reports, the American Society for Bone and Mineral Research task force has estimated the incidence of ONJ in patients treated for osteoporosis to be between less than 1 and 10 per 100,000 patient-treatment years. Subsequent studies have reported a similar incidence of 15 to 20 per 100,000 patient-treatment years. This finding contrasts with the much higher incidence in patients receiving bisphosphonates for an oncologic indication (1000–10,000 per 100,000 patient-treatment years, depending on the duration of bisphosphonate therapy).

The risk of ONJ in patients treated for a malignancy-related indication is well established, and seems to have a linear relationship with the cumulative dose and/or duration of bisphosphonate therapy. Such a clear relationship has not been well established in patients receiving the lower doses of bisphosphonates currently used for the treatment of osteoporosis. Furthermore, not enough evidence exists to establish a definitive association with the use of bisphosphonates given that ONJ-like lesions occur in patients who have never received bisphosphonates. However, some of the available reports noted a greater risk of ONJ in patients with osteoporosis receiving intravenous bisphosphonates than in those using less-potent oral bisphosphonates. Additionally, suppuration, dental extraction, oral bone-manipulating surgery, poor-fitting dental appliances, intraoral trauma, glucocorticoid use, diabetes, preexisting dental or periodontal disease, tobacco/alcohol abuse, and treatment with bisphosphonates for more than 2 years have been identified as potential risk factors.

The pathogenesis of ONJ in patients receiving bisphosphonate therapy remains unclear. Some reports have suggested that ONJ is a result of low bone turnover and microdamage accumulation. Although attractive, this theory has left many unanswered questions, including the fact that well-established ONJ lesions show increased numbers of osteoclasts and that bone lysis is radiographically evident. Another alternative explanation has invoked bisphosphonate-induced cellular toxicity leading to impaired epithelial repair on bone surface. In the setting of oral trauma (eg, dental extraction), impaired epithelium provides greater microbial access to the bone surface, increased risk for bone infection, and subsequent biofilm formation. With the development of bone infection, bone resorption, bone necrosis, and exposed bone in the mouth occur, leading to the clinical entity of ONJ.

Treatment of ONJ is entirely empiric and based on available case reports of the condition and on position statements and recommendations made by professional bodies. Conservative measures, including oral antimicrobial rinses (eg, 0.12% chlorhexidine digluconate), systemic antimicrobial therapy if infection is documented, and pain control, have been advocated. Published case reports also exist of successful therapy with teriparatide and hyperbaric oxygen in addition to standard therapy, and of surgical debridement in patients for whom medical management failed, with or without the use of laser. Currently, no published data answer the question of whether stopping bisphosphonates will promote resolution of ONJ. The decision to stop bisphosphonates should therefore be made on an individual basis.

Before initiation of bisphosphonates, patients should be advised to have a dental evaluation, tooth treatment, and full epithelial healing, and undergo treatment of any active oral infections. In patients already receiving bisphosphonates who require dental intervention, the treatment should be conservative, and antibiotic therapy should be considered. Whether bisphosphonates should be stopped is a matter of debate, and currently evidence is insufficient to support discontinuation of therapy. However, practitioners should make decisions on a case-by-case basis.

Upper Gastrointestinal Side Effects

A significant proportion of patients ingesting alendronate in early clinical studies experienced esophageal discomfort and were diagnosed with esophagitis. Endoscopic findings in these patients included chemical esophagitis, erosions or ulcerations, exudative inflammation, and thickening of the esophageal wall, primarily affecting the distal third of the esophagus. Complications included strictures (<1%), and, rarely, hematemesis from esophageal hemorrhage. After early reports of complications, the incidence of esophageal side effects declined significantly once the importance of proper administration was explained to physicians. Subsequently, in the large clinical trials that led to the approval of alendronate for the treatment of postmenopausal osteoporosis, the incidence of upper gastrointestinal tract complaints (especially dyspepsia and abdominal pain) was high but similar in the alendronate and placebo groups (47.5% vs 46.2%; relative risk [RR], 1.02; 95% CI, 0.95–1.10). In these studies, alendronate treatment was not associated with an increased incidence of upper gastrointestinal tract events, even in high-risk subgroups. Esophagitis was more common in patients with preexisting esophageal disorders. In most patients, esophageal complications occur during the first month of oral bisphosphonate therapy, often because the patient takes the medication without an adequate quantity of water or fails to remain upright for 30 or more minutes afterwards. Reducing the frequency of administration (from daily to weekly to monthly dosing) may improve gastrointestinal tolerability, thus reducing the risk of esophageal injury. Switching to an alternate oral or an intravenous bisphosphonate is generally recommended in patients with persistent upper gastrointestinal symptoms.

Esophageal Cancer

Reports of cases of esophageal cancer in patients taking oral bisphosphonates that were voluntarily submitted to the FDA prompted a letter to the editor of the New England Journal of Medicine summarizing the available data in 2009. Several oral bisphosphonates were implicated, and pathologic findings included squamous cell carcinoma of the esophagus and adenocarcinoma of the esophagus. The mechanism invoked has implicated a local inflammatory process in response to the response to contact between the esophageal mucosa and oral bisphosphonates, leading to erosive and ulcerative esophagitis and subsequent progression to cancer. These case reports could not prove a causal effect of bisphosphonates in the pathogenesis of esophageal cancer. Subsequently, several reports from the United Kingdom, Denmark, the United States, and Taiwan have evaluated the potential risk of esophageal cancer associated with bisphosphonate use. Most case control studies comparing incidence of esophageal cancer in users versus nonusers of oral bisphosphonates have failed to show a link between bisphosphonate intake and esophageal cancer. Three studies found an increased risk with alendronate use, although the association was not believed to be causal because no dose–response or time relationship was present. One study comparing previous bisphosphonate use in patients with esophageal cancer and matched controls (without esophageal cancer) found an increased risk when bisphosphonates were prescribed 10 or more times, or for longer than 5 years. Finally, a recently published report found an early decrease in esophageal cancer rates with bisphosphonate use, which may be from greater use of endoscopy before starting alendronate. No excess risk of esophageal cancer death was seen with bisphosphonate use. Overall, problems with surveillance/detection bias, limited information regarding known confounders, and the potential for unmeasured confounding are all limitations of the published epidemiologic studies. Although the FDA acknowledges the conflicting published findings, its most recent communication from July 21, 2011 regarding its “Ongoing Safety Review of Oral Bisphosphonates and Potential Increased Risk of Esophageal Cancer” states that the agency “has not concluded that patients taking oral bisphosphonates have an increased risk of esophageal cancer.”

Atrial Fibrillation

Serious atrial fibrillation (Afib) emerged in 2007 as an unexpected but significant side effect of ZA in the phase 3, double-blind, placebo-controlled clinical trial that showed the efficacy of ZA in reducing osteoporotic fractures in postmenopausal women. In this multicenter trial conducted in 3889 women, serious Afib (defined as Afib that either was fatal or led to hospitalization) was reported in 50 women receiving ZA versus 20 women receiving placebo (1.3% vs 0.5%; P <.001). These events were uniformly distributed over time, with most occurring more than 30 days after ZA infusion, when blood ZA levels were undetectable. No statistically significant difference in the incidence of stroke, myocardial infarction, or cardiovascular death was noted between the groups. Furthermore, no other electrocardiographic abnormality was noted in the trial, and no plausible mechanism or correlation to electrolyte disturbance was identified. In an extension trial, 1233 postmenopausal women who received ZA for 3 years in that original study were further randomized to 3 additional years of ZA or placebo. Although numerically more Afib–related serious adverse events were seen in individuals who received a total of 6 years of ZA versus 3 years of ZA followed by 3 years of placebo (2.0% vs 1.1%), this difference was not statistically significant ( P = .26).

Before publication of the original ZA trial in 2007, there was no signal of cardiac arrhythmias associated with bisphosphonate use, but that publication led to a post hoc review of prior bisphosphonate clinical trials. Reanalysis of the largest placebo-controlled trial with alendronate found no increase in total Afib events ( P = .42), but noted a trend toward an increase in serious Afib events (47 cases with alendronate vs 31 cases with placebo; hazard ratio [HR], 1.5; 95% CI, 0.97–2.40; P = .07). In a recent meta-analysis of all Merck-conducted, placebo-controlled clinical trials of alendronate, no clear association was observed between overall bisphosphonate exposure and the rate of Afib, whether classified as serious (RR, 1.25; 95% CI, 0.82–1.93; P = .33) or nonserious (RR, 1.16; 95% CI, 0.87–1.55; P = .33). Reanalysis of pooled data from 5 clinical trials of risedronate comprising 15,066 subjects showed no increase in the risk of serious Afib ( P = .49) or Afib overall ( P = 1). Likewise, reanalysis of pivotal ibandronate clinical trials involving 8754 patients revealed that the incidence of Afib (ibandronate, 0.8% and placebo, 0.9%) and serious Afib (0.4% for both ibandronate and placebo) was comparable between the ibandronate and placebo groups. One additional placebo-controlled clinical trial with ZA administered after hip fracture also showed no increased risk of overall Afib ( P = .79) or serious Afib ( P = .84), and several clinical trials in patients with cancer using ZA at a higher frequency than approved for osteoporosis have not indicated any increased risk of Afib. The FDA has reviewed data provided by the manufacturers of the 4 bisphosphonates approved for osteoporosis treatment in the United States regarding 19,687 bisphosphonate-treated patients and 18,358 placebo-treated patients who were followed for 6 months to 3 years. The review found that the occurrence of Afib was rare within each study, and that the absolute difference in event rates between each of the bisphosphonate and placebo arms varied from 0 to 3 per 1000 patient-treatment years.

To overcome the limitations of the placebo-controlled clinical trials that were not designed nor powered to assess rare side effects such as Afib, several observational studies have also examined the association between bisphosphonate use and Afib incidence. A population-based cohort study from Denmark found a significantly higher incidence of serious Afib in fracture patients treated with bisphosphonates compared with matched fracture patients never exposed to bisphosphonates (adjusted HR, 1.13; 95% CI, 1.01–1.26), although the risk among bisphosphonate users was inversely proportional to adherence. In contrast, a separate population-based cohort study from Denmark, and others from the United States, Taiwan, and Korea, have all failed to show an association between bisphosphonate use and incident Afib. One case-control study suggested an increase in Afib risk in U.S. women with past but not current use of alendronate, whereas other studies with a similar case-control design from Denmark or the United Kingdom failed to show such an association. These observational studies vary in terms of which bisphosphonate was studied, method of identifying Afib occurrence, and confounders controlled for, which could explain some of the disparate findings. Furthermore, 4 separately published meta-analyses have pooled results from various studies, again reaching inconsistent conclusions depending on the studies included, with 2 meta-analyses associating bisphosphonate use with an increased incidence of serious Afib, and 2 others finding no such association.

Several mechanisms have been invoked to explain the potential association between Afib and bisphosphonate use, including the release of inflammatory molecules in the acute phase response after intravenous administration of bisphosphonates, changes in electrolytes that predispose to arrhythmias (eg, hypocalcemia), and/or atrial structural changes. However, these alternatives remain speculative and none is supported by solid evidence. Currently, the possible association of bisphosphonates with Afib is not well substantiated, and the FDA concluded that “across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was observed.”

Acute Phase Response

Although generally well tolerated, in a significant proportion (≈35%) of patients the initial doses of intravenous bisphosphonates are associated with a transient acute phase response similar to an influenza-like illness. This acute phase response was characterized in placebo-controlled clinical trials by a significantly more common occurrence of fever, chills, diffuse musculoskeletal pain, nausea, fatigue, and headache in patients treated with intravenous bisphosphonates than in those treated with placebo. Onset of symptoms is approximately 1 day after intravenous infusion, with a median duration of approximately 3 days, and symptoms rarely last beyond 2 weeks after infusion. Symptoms are rated as mild or moderate in 90% of cases. Risk factors for acute phase response identified in 1 large multinational study included younger age, non-Japanese Asian ethnicity, and use of nonsteroidal anti-inflammatory drugs, whereas prior exposure to oral bisphosphonate was associated with a lower incidence of acute phase response. Vitamin D insufficiency has also been associated with a higher incidence of acute phase response in adults and children receiving intravenous bisphosphonates. The acute phase response is specific to nitrogen-containing bisphosphonates, and its pathogenesis has been linked to the activation of γδT lymphocytes, with subsequent release of interferon-γ, tumor necrosis factor α, and interleukin-6. Patients with more severe acute phase response exhibited greater rises in these cytokines, strengthening the pathogenetic link between cytokine release and acute phase response. Although statins prevent bisphosphonate-induced γδT lymphocyte proliferation and activation in vitro, several clinical studies have failed to show a clinical benefit from use of fluvastatin, atorvastatin, or rosuvastatin before bisphosphonate infusion. In one study, acetaminophen given at 650 mg 4 times daily for 3 days starting before ZA infusion significantly reduced the incidence and severity of post-dose acute phase response, and attenuated increases in serum interleukin-6 and interferon-γ levels at 24 hours compared with placebo and fluvastatin. In view of the self-limited nature of the acute phase response, supportive and symptomatic management with acetaminophen is generally recommended. Although the acute phase response is the most common adverse reaction encountered with intravenous bisphosphonates, it does not seem to impact long-term adherence to bisphosphonates, because of its mild to moderate severity, short time course, and lower incidence with subsequent treatments.

Ocular Symptoms

Case reports of ocular inflammation occurring in the setting of bisphosphonate use have been reported since the 1990s. Described pathologies range from nonspecific transient conjunctivitis (conjunctival injection) and episcleritis (mild irritation, photophobia, erythema in episcleral vessels) to more serious abnormalities, such as scleritis (severe pain, orbital tenderness, scleral erythema) and anterior uveitis (ocular pain associated with injection of ciliary vessels, photophobia, and blurry vision). Although the exact underlying mechanisms are not entirely understood, bisphosphonate-induced release of inflammatory mediators has been invoked. In some cases, symptoms recur on rechallenge with the same or a different bisphosphonate, corroborating a causal relationship.

Ocular symptoms have been described with oral and intravenous bisphosphonates, and with both nitrogen-containing and non–nitrogen-containing bisphosphonates. In most cases, ocular symptoms occur within 2 to 3 days of exposure to intravenous bisphosphonates and 6 to 8 weeks after oral bisphosphonates, although reports of onset 1 to 3 years after oral bisphosphonate initiation have been described. Symptoms may be transient, such as in the majority of cases with intravenous bisphosphonates, or persist until discontinuation of oral bisphosphonates. Conjunctivitis might be self-limiting and decrease in intensity over subsequent exposures, providing an option for rechallenge. Potential complications of the more severe presentations (scleritis and anterior uveitis) include development of cataracts, glaucoma, macular edema, and scleral perforation, hence the need for early recognition and appropriate intervention, including bisphosphonate discontinuation.

The incidence of bisphosphonate-associated ocular symptoms has been estimated in 2 large cohort studies. A Canadian cohort examined claims from visits to an ophthalmologist between 2000 and 2007 for 934,147 people, including 10,827 first-time users of bisphosphonates. The incidence rate of uveitis was 29 per 10,000 person-years among first-time bisphosphonate users versus 20 per 10,000 person-years in nonusers. The incidence rates for scleritis were 63 per 10,000 person-years among first-time bisphosphonate users versus 36 per 10,000 person-years in nonusers. Thus, first-time users had a significantly elevated risk of uveitis (adjusted RR of 1.45; 95% CI, 1.25–1.68) and scleritis (adjusted RR, 1.51; 95% CI, 1.34–1.68). A similar RR of 1.23 for scleritis and uveitis was seen among bisphosphonate users in a cohort of U.S. veterans with a 1-year follow-up period.

Severe Musculoskeletal Pain

Between September 1995 (approval of alendronate) and June 2003, 124 cases of severe musculoskeletal pain in the setting of bisphosphonate use were reported to the FDA. Symptoms described included “extreme,” “disabling,” or “incapacitating” diffuse pain in bones, joints, and/or muscles. These symptoms occurred at different time points after bisphosphonate initiation, and were reported with alendronate use in some cases and risedronate in others, suggesting a class effect. Some patients reported relief of symptoms on bisphosphonate discontinuation, and a subset experienced pain recurrence on rechallenge with the same or a different bisphosphonate, suggesting a causal relationship. These findings prompted the FDA to require that a statement be included on the package insert of all bisphosphonates regarding the possible association of severe musculoskeletal pain, and recommending that patients alert their treating physician if these symptoms occur so that bisphosphonate discontinuation can be considered. Similar, although more transient, musculoskeletal pain has been described as part of the acute phase response (“flu-like symptoms”) after intravenous bisphosphonate infusion.

Determinants of the association between bisphosphonate and severe musculoskeletal pain were assessed in a cohort of 26,545 U.S. veterans aged 65 years or older. In this observational study, diffuse musculoskeletal pain identified by ICD-9 code was significantly more common among bisphosphonate users than nonusers (HR, 1.22; 95% CI, 1.04–1.44), but did not lead to more frequent bisphosphonate discontinuation in affected patients. Female sex, depression, anxiety, and the presence of a rheumatic condition were also significantly associated with the development of musculoskeletal pain in this cohort. After adjusting for these and other confounders, bisphosphonate use was no longer significantly associated with the diagnosis of diffuse musculoskeletal pain in multivariate analysis (HR, 1.10; 95% CI, 0.93–1.30). Similarly, in placebo-controlled clinical trials with oral bisphosphonates, the incidence of severe musculoskeletal pain was not different in the bisphosphonate versus placebo groups. Taken together, these findings do not suggest a strong association between bisphosphonate use and severe musculoskeletal pain, and no plausible mechanisms have been proven to explain such an association. Nevertheless, in patients who develop severe musculoskeletal pain with bisphosphonate use, discontinuation should be considered.

Renal Insufficiency

Administration of bisphosphonates in high doses and at a rapid rate in animal models induces a variety of adverse renal effects, from glomerular sclerosis to acute tubular necrosis. In humans, the most common adverse renal effect is a transient rise in serum creatinine with a subsequent return to baseline. This complication seems to be related to the maximum bisphosphonate plasma concentration (Cmax), because rapid infusion (5 minutes) of monthly pamidronate or ZA in oncology trials induced acute rises in serum creatinine, which was not seen with slower infusion rates (15 or 30 minutes) of the same doses. Pathologic findings in the limited cases in which a kidney biopsy was obtained include loss of tubular cell polarization, loss of brush border and apoptosis of proximal tubular cells, and increased proliferation, all hallmarks of acute tubular necrosis. At the dose and infusion rate approved for the treatment of osteoporosis (5 mg infused 15 minutes once a year), intravenous ZA induced transient increases in serum creatinine in a small but significant number of subjects, with return of serum creatinine to baseline levels before the next annual infusion. The incidence of renal adverse events was similarly low in the Dosing Intravenous Administration trial of intravenous ibandronate. After postmarketing reports of acute renal failure in patients with osteoporosis treated with intravenous ZA, the FDA sent a newsletter to physicians in 2011 reminding them of this potential risk. The FDA also requested a label revision, stating that Reclast is contraindicated in patients with creatinine clearance less than 35 mL/min or those with evidence of acute renal impairment. Screening of patients before administering Reclast to identify those at risk (use of diuretics or nephrotoxic drugs at the same time as Reclast, or severe dehydration occurring before or after Reclast is given) was also recommended. Still, the overall risk of kidney damage in patients receiving intravenous bisphosphonates for osteoporosis is very small, and can be further reduced through ensuring adequate hydration and use of appropriate infusion times. Glomerulosclerosis with nephrotic range proteinuria has been described in very few cases of patients receiving intravenous pamidronate, oral alendronate, and ZA. This renal complication of bisphosphonates is extremely rare and was not noted during any of the pivotal clinical trials.

Hypocalcemia

With the widespread use of bisphosphonates for various conditions and the introduction of more potent compounds, symptomatic hypocalcemia has been recognized as a complication associated with their use. Despite patients with diseases affecting bone metabolism being excluded from clinical trials of oral alendronate and risedronate, and the provision of calcium supplements to all participants in these trials, mild, transient, but statistically significant declines in serum calcium were noted with bisphosphonate use. In clinical trials of intravenously administered bisphosphonates, mild asymptomatic hypocalcemia was noted in 0.2% of patients with osteoporosis. In patients with cancer, Chennuru and colleagues reported the occurrence of hypocalcemia after 10% of 546 ZA infusions, with symptomatic hypocalcaemia requiring intravenous calcium supplementation in 8% of patients, despite ZA dose adjustment for creatinine clearance and prophylactic administration of oral calcium and vitamin D. Bisphosphonate-induced severe hypocalcemia has also been associated with the occurrence of seizures in several cases, likely through lowering the seizure threshold in patients with known epilepsy.

Mechanistically, bisphosphonates reduce calcium efflux from bone through inhibiting osteoclastic bone resorption, which is normally followed by a compensatory increase in parathyroid hormone secretion. This process in turn enhances the distal renal tubular calcium reabsorption and stimulates intestinal calcium absorption through increased renal production of 1,25-dihydroxyvitamin D. Hypocalcemia after bisphosphonate exposure has been associated with conditions that impair these compensatory mechanisms (eg, hypoparathyroidism and/or vitamin D deficiency) and with reduced renal function (which lowers bisphosphonate clearance, resulting in potentially greater antiresorptive action).

Case reports and series have reported vitamin D deficiency and/or hypoparathyroidism to be risk factors for bisphosphonate-induced hypocalcemia. In one study, more patients who became hypocalcemic developed worsening creatinine clearance post-ZA, suggesting that renal impairment occurring in the days after administration may increase the risk of hypocalcemia. Hypocalcemia tends to develop earlier with the use of more potent bisphosphonates. Hypomagnesemia occurs frequently in patients with bisphosphonate-induced hypocalcemia, and may contribute to this complication through blunting the compensatory increase in parathyroid hormone secretion. The product labels for approved bisphosphonates include specific warnings against their use in patients with these risk factors. Assessing renal function and vitamin D stores before bisphosphonate initiation has been suggested in patients for whom this therapy is contemplated, partly to prevent hypocalcemia.