Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research

Abstract

Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between -2 and -2.5 in FLEX and below -2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long-term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations. © 2015 American Society for Bone and Mineral Research.

Keywords: BISPHOSPHONATES; DRUG HOLIDAY; LONG TERM-BISPHOSPHONATE USE; OTHER OSTEOPOROSIS THERAPIES; RISK BENEFIT.

Figure 1. Risks Associated with Bisphosphonate Use and Other Health Outcomes

Likelihood of suffering fractures and other adverse events in adult patients. For fractures, the risk of fractures on BP therapy, and for stroke, the risk on aspirin therapy is illustrated. Fracture incidence rates are age-standardized, while for others they represent crude rates in the US. For ONJ and AFF the risks represent those reported while on BP therapy for 10 years. Likelihood of suffering fractures and other adverse events in adult patients.^1–4 For fractures, the risk of fractures on BP therapy, and for stroke the risk on aspirin therapy is also illustrated. For ONJ⁵ and AFF⁶ the risks represent those reported while on BP therapy for 10 years. 1. Dell RM, Adams AL, Greene DF, Funahashi TT, Silverman SL, Eisemon EO et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res; 2012;27(12):2544-50. 2. Cauley JA, Chalhoub D, Kassem AM, Fuleihan Gel-H. Geographic and ethnic disparities in osteoporotic fractures. Nature Reviews Endocrinology; 2014;10:338-51. 3. Pedestrian Safety: Fact Sheet. 2013. (Accessed Accessed May 1, 2014, at http://www.cdc.gov/motorvehiclesafety/pedestrian_safety/factsheet.html.) 4. Homicide rates among persons aged 10–24-United States, 1981–2010. 2013. (Accessed Accessed May 1, 2014, at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6227a1.htm.) 5. Tennis P, Rothman KJ, Bohn RL, et al. Incidence of osteonecrosis of the jaw among users of bisphosphonates with selected cancers or osteoporosis. Pharmacoepidemiol Drug Saf; 2012;21:810-7. 6. 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;29:1–23.

Figure 2. Algorithm for the Management of Postmenopausal Women on Long-Term Bisphosphonate Therapy

(1) Based on evidence for vertebral fracture reduction in FLEX and Horizon extension studies, continue BP therapy for up to 10 years with oral or up to 6 years with intravenous BPs. For patients who fracture on therapy, assess adherence and rule out secondary causes of osteoporosis. Management in high risk patients after 10 years of BP therapy is discussed in the text. (2) The benefits of switching to an alternative anti-fracture therapy after prolonged bisphosphonate treatment have not been adequately studied. (3) Based on FLEX and Horizon extension study (Caucasian women), may not apply to other populations. (4) High fracture risk: defined by older age (70–75 yrs), other strong risk factors for fracture, or FRAX fracture risk score that is above country specific thresholds. The use of FRAX in patients on therapy was only assessed in the Manitoba observational cohort.⁽¹⁾ (5) Reassessment includes clinical evaluation, risk assessment including risk factors, and may include bone density measurement by DXA. The monitoring interval with DXA should be based upon changes that are detectable and clinically significant. Reassessment may be necessary at less than 2 years in patients with a new fracture, or in light of anticipated accelerated bone loss (e.g. institution of aromatase inhibitor or glucocorticoid therapy). References 1. Leslie WD, Lix LM, Johansson H, Oden A, McCloskey E, Kanis JA, et al. Does osteoporosis therapy invalidate FRAX for fracture prediction? J Bone Miner Res.2012;27(6):1243-51.