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Reference: N Engl J Med 2018 Dec 20;379(25):2407 (level 1 [likely reliable] evidence)
Osteopenia places postmenopausal women at a higher risk of fragility fracture which can increase morbidity and mortality. To date, no randomized trial has demonstrated therapeutic benefit of bisphosphonate therapy for fracture prevention in women with osteopenia. The American College of Physicians gives a weak recommendation based on low quality evidence to engage in shared decision making with patients with osteopenia about treatment decisions. Yet, many clinicians lack confidence in their recommendations in large part due to the paucity of data on therapeutic interventions, and as such may hesitate to actually engage the patient in that conversation.
New Zealand investigators conducted a randomized, double-blind, placebo-controlled trial comparing zoledronate 5 mg infusion every 18 months vs.placebo infusion to assess prevention of fragility fracture among women with osteopenia. Postmenopausal women aged ≥ 65 years with a total hip or femoral neck T score between -1 and -2.5 on either side were included in the trial. Over 95% of participants were of European descent. Women with a hip T score of less than -2.5 on one side but between -1 and -2.5 on the contralateral side were also included in the trial. Women with a history of fragility fracture were excluded, as were those with a history of bisphosphonate use or vertebral T score of lower than -3.0. Patients were followed for six years for the primary end point which was time to first occurence of a fragility fracture. Symptomatic fractures was one of several secondary endpoints.
In an intention-to-treat analysis, there was a statistically significant reduction in the cumulative incidence of first fragility fracture in the zoledronate group compared to placebo (NNT 15 over 6 years to prevent occurence of fragility fracture). There was also a statistically significant reduction in symptomatic fractures (hazard ratio 0.73, NNT 22 over 6 years). When women with an osteoporotic hip on one side were excluded from the analysis, there was still a statistically significant reduction in fragility fractures. Nearly twice as many women in the zoledronate group declined any additional infusion due to an acute reaction during the first infusion. The rate of adverse events was similar in the two groups, with no documented osteonecrosis of the jaw or atypical femur fractures. The zoledronate group experienced a significantly lower rate of cancers, although the clinical significance of this secondary outcome is uncertain. Short-term adverse events were not reported.
The degree of benefit seen is comparable on a relative basis to that seen with use of zoledronic acid 5 mg yearly for treatment of osteoporosis. The protocol and analysis used here were of high quality and there were no obvious threats to the external validity. The main concern about the clinical application of using zoledronate for osteopenia is the significantly higher rate of acute reaction to the first infusion seen in the zoledronate group. Cost is unlikely to be an issue as there is a generic version available that would cost about $200 every 18 months.
Focus Point: If your postmenopausal patients over age 65 with osteopenia can tolerate an infusion of zoledronate every 1.5 years, they are less likely to experience a fragility fracture.
For more information, see the topic Bisphosphonates for treatment and prevention of osteoporosis in DynaMed Plus. DynaMed users click here.
DynaMed Plus EBM Focus Editorial Team
This EBM Focus was written by Carina Brown, MD, Faculty Development and Information Mastery Fellow and Clinical Instructor at the University of Virginia. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed Plus and Associate Professor in Family Medicine at the University of Massachusetts Medical School and Katharine DeGeorge, MD, MS, Assistant Professor in Family Medicine at the University of Virginia and Clinical Editor at DynaMed Plus.