Bisphosphonate Drug Holiday: Choosing Appropriate Candidates Authors
Current Therapeutics (SL Silverman, Section Editor)
First Online: 08 January 2013 DOI:
Cite this article as: Ro, C. & Cooper, O. Curr Osteoporos Rep (2013) 11: 45. doi:10.1007/s11914-012-0129-9 Abstract
Osteoporosis related fractures contribute to morbidity and mortality in U.S. patients, placing a heavy financial burden on society. Randomized clinical trials involving over 30,000 subjects have established bisphosphonates’ efficacy in reducing the incidence of fragility fractures. However, as bisphosphonates are retained for years in the skeleton, reports of adverse events from prolonged use are surfacing in the literature, namely, esophageal cancer, atrial fibrillation, osteonecrosis of the jaw, and atypical fracture development. The concept of a drug holiday has been proposed to potentially reduce incidence of these adverse events. This review will highlight the benefits and risks of bisphosphonate therapy and discuss the extension data available from the bisphosphonate trials. As randomized clinical trial evidence is not yet available on who may qualify for drug holiday, this review will provide suggestions for clinicians on identification of possible candidates and monitoring during a bisphosphonate drug holiday.
Keywords Osteoporosis Bisphosphonate Drug holiday Atypical fracture References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
National Osteoporosis Foundation: America’s bone health: the state of osteoporosis and low bone mass in our nation. Washington, DC. 2002.
Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22:465–75.
Forsen L, Sogaard AJ, Meyer HE, et al. Survival after hip fracture: short- and long-term excess mortality according to age and gender. Osteoporos Int. 1999;10:73–8.
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;348:1535–41.
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;282:1344–52.
Chesnut IC, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241–9.
McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344:333–40.
Haber SL, McNatty D. An evaluation of the use of oral bisphosphonates and risk of esophageal cancer. Ann Pharmacother. 2012;46:419–23.
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.
Cardwell CR, Abnet CC, Cantwell MM, et al. Exposure to oral bisphosphonates and risk of esophageal cancer. JAMA. 2010;304:657–63.
Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61:1115–7.
Mellstrom DD, Sorensen OH, Goemaere S, et al. Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int. 2004;75:462–8.
Hellstein JW, Adler RA, Edwards B, et al. Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc. 2011;142:1243–51.
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;22:1479–91.
Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809–22.
Black DM, Thompson DE, Bauer DC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab. 2000;85:4118–24.
Rhee CW, Lee J, Oh S, et al. Use of bisphosphonate and risk of atrial fibrillation in older women with osteoporosis. Osteoporos Int. 2012;23:247–54.
Barrett-Connor E, Swern AS, Hustad CM, et al. Alendronate and atrial fibrillation: a meta-analysis of randomized placebo-controlled clinical trials. Osteoporos Int. 2012;23:233–45.
• Schilcher J, Michaelsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. N Engl J Med. 2011;364:1728–37.
This study demonstrated the association of atypical femoral fractures with longer duration of bisphosphonate use.
Dell RM, Adams AL, Greene DF, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res. 2012;27:2544–50.
• Black DM, Kelly MP, Genant HK, et al. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med. 2010;362:1761–71.
This was a secondary analysis of 3 RCTs showing that atypical fractures were a rare occurrence and were not associated with use of bisphosphonates.
FDA. Bisphosphonates (Osteoporosis drugs): label change—atypical fractures update. Fosamax, Fosamax Plus D, Actonel, Actonel with calcium, Boniva, Atelvia, and Reclast. October 13, 2010.
Gibaldi M, Perrier D. Clinical pharmacology of alendronate sodium. In: Gibaldi M, Perrier D, editors. Pharmacokinetics. New York: Marcel Dekker; 1982. p. 145–98.
Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927–38.
•• Black DM, Reid IR, Boonen S, et al. The effect of 3 vs 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012;27:243–54.
This study provided extension data for Zoledronic acid.
NCT01406613: resolution of effect of bisphosphonates on bone in postmenopausal osteoporosis. Available at:
. Accessed November, 2012.
Watts NB, Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab. 2010;95:1555–65.
• Whitaker M, Guo J, Kehoe T, et al. Bisphosphonates for osteoporosis--where do we go from here? N Engl J Med. 2012;366:2048–51.
This is the FDA advisory which reviewed extension data and discussed the concern regarding atypical femoral fractures.
•• Black DM, Bauer DC, Schwartz AV, et al. Continuing bisphosphonate treatment for osteoporosis--for whom and for how long? N Engl J Med. 2012;366:2051–3.
This is the response to FDA advisory and provides guidance in selecting appropriate candidates for drug holiday.
Schwartz AV, Bauer DC, Cummings SR, et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res. 2010;25:976–82.
Russell RG, Watts NB, Ebetino FH, et al. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int. 2008;19:733–59.
Nancollas GH, Tang R, Phipps RJ, et al. Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006;38:617–27.
Rodan G, Reszka A, Golub E, et al. Bone safety of long-term bisphosphonate treatment. Curr Med Res Opin. 2004;20:1291–300.
The Endocrine Society recommends patient-centered approach to long-term bisphosphonate use for the treatment of osteoporosis: a review of the May 2012 FDA Analysis. 2012.
Ravn P, Weiss SR, Rodriguez-Portales JA, et al. Alendronate in early postmenopausal women: effects on bone mass during long-term treatment and after withdrawal. Alendronate Osteoporosis Prevention Study Group. J Clin Endocrinol Metab. 2000;85:1492–7.
Bieglmayer C, Dimai HP, Gasser RW, et al. Biomarkers of bone turnover in diagnosis and therapy of osteoporosis : a consensus advice from an Austrian working group.
Wiener Medizinische Wochenschrift. 2012;162:464–77.
Baxter I, Rogers A, Eastell R, et al. Evaluation of urinary N-telopeptide of type I collagen measurements in the management of osteoporosis in clinical practice.
. 2012. doi:
Looker AC, Bauer DC, Chesnut 3rd CH, et al. Clinical use of biochemical markers of bone remodeling: current status and future directions. Osteoporos Int. 2000;11:467–80.
Lee J, Vasikaran S. Current recommendations for laboratory testing and use of bone turnover markers in management of osteoporosis. Ann Lab Med. 2012;32:105–12.
Lenora J, Ivaska KK, Obrant KJ, et al. Prediction of bone loss using biochemical markers of bone turnover. Osteoporos Int. 2007;18:1297–305.
Vasikaran S, Eastell R, Bruyere O, et al. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporos Int. 2011;22:391–420.
• Watts NB, Bilezikian JP, Camacho PM, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract. 2010;16 Suppl 3:1–37.
These are current endocrine guidelines on management of osteoporosis.
PubMed Copyright information
© Springer Science+Business Media New York 2013