Review
Bisphosphonate Therapy for Osteoporosis: Benefits, Risks, and Drug Holiday

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Abstract

The amino-bisphosphonates are first-line therapy for the treatment of most patients with osteoporosis, with proven efficacy to reduce fracture risk at the spine, hip, and other nonvertebral skeletal sites. Further, bisphosphonates have been associated with a significant decrease in morbidity and increase in survival. Following the use of bisphosphonates in millions of patients in clinical practice, some unexpected possible adverse effects have been reported, including osteonecrosis of the jaw, atypical femur fractures, atrial fibrillation, and esophageal cancer. Because bisphosphonates are incorporated into the skeleton and continue to exert an antiresorptive effect for a period of time after dosing is discontinued, the concept of a drug holiday has emerged, whereby the risk of adverse effects might be decreased while the patient still benefits from antifracture efficacy. Patients receiving bisphosphonates who are not at high risk for fracture are potential candidates for a drug holiday, while for those with bone mineral density in the osteoporosis range or previous history of fragility fracture, the benefits of continuing therapy probably far outweigh the risk of harm.

Section snippets

Long-Term Retention of Bisphosphonate in the Skeleton

The effects of most therapies resolve soon after discontinuation. Bisphosphonates are unique in that they bind to hydroxyapatite in bone and can remain there for years. During remodeling, which is significantly decreased by bisphosphonate therapy, some bound bisphosphonate is released from bone; a portion binds again to bone and is metabolically active. Skeletal binding affinity increases in rank order through risedronate, ibandronate, alendronate, and zoledronic acid.1 Bisphosphonates with

Antifracture and Clinical Efficacy of Bisphosphonates

Table 1 provides an overview of the antifracture efficacy with bisphosphonates in pivotal, registration trials. Alendronate, risedronate, and zoledronic acid decreased fracture risk at the spine, nonvertebral sites, and the hip alone,2 whereas ibandronate reduced vertebral but not nonvertebral fractures.15 In general, the efficacy of bisphosphonates changes with the patient's primary risk profile—those with the highest fracture risk tend to have the greatest absolute reduction in fracture risk.

Risks Associated With Bisphosphonate Therapy

The overall frequency of adverse events (any undesirable medical occurrence associated with the use of a medical product in a patient, irrespective of causality)26 or serious adverse events (life-threatening, resulting in death, hospitalization, prolongation of hospitalization, significant disability, or birth defect) did not differ between groups receiving bisphosphonates or placebo in pivotal clinical trials. Adverse events and serious adverse events that are attributable (ie, causally

Osteonecrosis of the Jaw

Bisphosphonate-associated osteonecrosis of the jaw (exposed bone in the maxillofacial region, with no healing within 8 weeks in a patient with bisphosphonate exposure and no history of craniofacial radiation therapy) is most often observed (95% of cases) after invasive dental procedures during oncology therapy, with high doses of intravenous bisphosphonates delivered frequently to an immunosuppressed population.28 The incidence of osteonecrosis of the jaw in patients receiving bisphosphonates

Atypical Femur Fractures

A consensus document defined the major features of an atypical femoral fracture (located in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, occurring spontaneously or after minimal trauma, possessing a medial spike, absence of comminution), distinguishing these fractures from the more common ”typical” femoral shaft fracture that is a complication of osteoporosis.38 Glucocorticoids and proton-pump inhibitor therapy have been identified as risk factors for

Atrial Fibrillation

An increased incidence of atrial fibrillation as a serious adverse event was reported in the pivotal phase III trial of annual intravenous zoledronic acid (1.3% in the treated group, 0.5% in the placebo group; P <.001),9 although there were no differences between groups in total cases of atrial fibrillation or other cardiovascular events. While cardiac abnormalities could be the result of a transient decrease in serum calcium, the serious adverse events were not clustered at the beginning of

Esophageal Cancer

Several cases of esophageal cancer occurring in patients with a history of oral bisphosphonate use have been reported.52 While one large case-control analysis reported a significant increase in the incidence of esophageal cancer with long-term oral bisphosphonate use,53 other reports found no significant increases.54, 55, 56 The US Food and Drug Administration has determined that, at this time, there is not enough information to make definitive conclusions about a possible association between

Gastrointestinal Intolerance

Although not observed in clinical trials, gastrointestinal intolerance, esophageal irritation, or erosion have been reported with oral bisphosphonate use, especially if taken incorrectly.6, 7, 8, 58, 59, 60, 61, 62, 63 Isolated cases of serious esophageal complications or upper gastrointestinal hemorrhage have occurred.64 Oral bisphosphonates are contraindicated in patients with impaired swallowing.

Impairment of Renal Function

Bisphosphonates can be nephrotoxic when high doses are administered rapidly.65, 66 Impaired renal

Bisphosphonate “Drug Holiday”

It is unusual to contemplate a drug holiday in the treatment of most chronic diseases because with most therapies, beneficial drug effects rapidly diminish with discontinuation. However, the long skeletal residence time of bisphosphonates and concern about the risks of rare adverse events with long-term therapy raise the possibility that bisphosphonate therapy may be interrupted for a “drug holiday,” during which antifracture benefit might persist for a period of time while potential risks are

Monitoring a Drug Holiday

There are no data providing information on how to monitor patients or when to restart therapy after a holiday. In trials with women who had previously been provided alendronate or zoledronic acid, women were followed for 5 and 3 years, respectively, after discontinuation of therapy, during which vertebral fracture risk increased in those who stopped the drug.12, 77 In the absence of guidance from clinical trials, empiric approaches are necessary. Although the approach has not been studied, bone

Weighing the Benefits and the Risks

When all of the evidence is considered, the antifracture benefit provided by the amino-bisphosphonates far outweighs the potential risks of therapy in most patients at high risk of fracture. Depending on the severity of osteoporosis, between 9 and 60 patients need to be treated for 3 years to prevent one vertebral fracture (Table 1); between 20 and 68 patients need to be treated for 3 years to avoid one nonvertebral fracture. Even discounting the increased risk of fracture with advancing age,

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  • Cited by (0)

    Funding: Unrestricted educational grants from Eli Lilly, Warner-Chilcott, Merck, Novartis, and Amgen were provided to the Western Osteoporosis Alliance for the development of this manuscript. The granting companies had no role in the development of the manuscript or any input as to where or if the resulting manuscript was submitted for publication.

    Conflict of Interest: M.R. McClung: Sponsored presentations: Amgen, Lilly, Merck, Novartis, and Warner-Chilcott. Consultation and/or Advisory Board: Amgen, Lilly, Merck, Novartis, and Warner-Chilcott. Grant/research support: Amgen and Merck. S.T. Harris: Sponsored presentations: Amgen, Eli Lilly & Company, Genentech, Gilead Sciences, Novartis, Roche, and Warner Chilcott. Consultation and/or Advisory Board: Amgen, Eli Lilly & Company, Gilead Sciences, Merck, and Roche. P.D. Miller: Sponsored presentations: Procter & Gamble Pharmaceuticals, Amgen, Novartis Pharmaceuticals, Roche Pharmaceuticals. Consultation and/or Advisory Board: Procter & Gamble Pharmaceuticals, Merck & Co., Eli Lilly, Amgen, Novartis Pharmaceuticals, Roche Pharmaceuticals, GlaxoSmithKline, Baxter, and Wright. Scientific grants: Procter & Gamble Pharmaceuticals, Sanofi/Aventis Pharmaceuticals, Roche, Pharmaceuticals, Eli Lilly, Merck & Co., Novartis Pharmaceuticals, Amgen, Takeda, Radius, and GE. D. Bauer: Scientific grants: Novartis and Amgen. K.S. Davison: Sponsored presentations: Amgen, Merck, Novartis, Warner-Chilcott. Consultation and/or Advisory Board: Amgen, Merck, Novartis, Warner-Chilcott. L. Dian: Sponsored presentations: Merck, Pfizer, Lilly and Co., Amgen, Warner Chilcott. Consultation and/or Advisory Board: Merck, Pfizer, Lilly and Co., Amgen, Warner Chilcott. D.A. Hanley: Sponsored presentations: Amgen, Merck, Eli Lilly, Novartis, Warner-Chilcott. Consultation and/or Advisory Board: Amgen, Merck, Eli Lilly, Novartis, Warner-Chilcott. Grant/research support: Amgen, Merck, Pfizer, NPS Pharmaceuticals, Eli Lilly, Novartis, Aventis/Procter and Gamble (now Warner-Chilcott). D.L. Kendler: Sponsored presentations: Novartis, Merck, Eli Lilly, Amgen, Warner Chilcott. Consultation and/or Advisory Board: Pfizer, Novartis, Merck, Eli Lilly, Amgen. Research grants: J&J, GSK, Pfizer, Novartis, Merck, Eli Lilly, Amgen. C.K. Yuen: Sponsored presentations: Pfizer, Merck and Amgen. Consultation and/or Advisory Board: Pfizer, Merck and Amgen. E.M. Lewiecki: Sponsored presentations: Amgen, Eli Lilly, Novartis. Consultation and/or Advisory Board: Amgen, Eli Lilly, Novartis, Merck & Co., GSK. Grant/research support: Amgen, Eli Lilly, Novartis, Merck, Warner Chilcott, GSK.

    Authorship: All authors had access to the data and a role in writing the manuscript.

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