Defining Zoledronate’s Duration of Action and Optimal Dosing Interval for an Effective Therapy
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Grey A, Boland M, Wattie D, et al.: Prolonged antiresorptive activity of zoledronate: a randomized control trial. Gen Bone Miner Res 2010, 25:2251–2255.
Zoledronic acid (ZA) is a potent nitrogen-containing bisphosphonate with a long skeletal half-life that is administered annually by intravenous (IV) infusion. In the Horizon trial, ZA significantly reduced the risk of vertebral fracture by 70%, the risk of hip fracture by 40%, and the risk of nonvertebral fracture by 20% . ZA also reduced the risk of clinical fracture by 35% and decreased mortality by 28% after hip fracture in the Recurrent Fracture Trial . A combination of antifracture efficacy, low rate of adverse events, and infrequent dosing make it a desirable agent for the future.
Defining the duration of action of zoledronate and the optimal dosing interval may help reduce the cost of an effective therapy.
Andrew Grey performed a 3-year randomized placebo-controlled trial of the effects on bone turnover and bone mineral density (BMD) of a single infusion of 5 mg IV zoledronate. Fifty postmenopausal women with osteoporosis were randomized to either a single infusion of IV ZA or placebo. The primary end points were bone turnover markers such as β CTX (C telopeptide) and P1NP (procollagen type I N-terminal propeptide). Secondary end points were BMD of the lumbar spine, total hip, and total body. After 3 years, bone markers, serum β CTX, and P1NP were 44% and 40% lower in the zoledronate group (P < 0.001 vs placebo for each marker). BMD was higher in the zoledronate than in the placebo group by an average of 6.8% in the lumbar spine, 4.0% total hip, and 2.0% of total body (P < 0.001 for each skeletal site). Between-group differences in makers of bone turnover and BMD were stable from 12 to 36 months.
The data demonstrate the antiresorptive effects of a single 5-mg IV dose of zoledronate was sustained for 3 years and suggests we may wish to consider investigating the antifracture efficacy of ZA in dosing intervals longer than 1 year. However, it is important to note that the Horizon trial, which required IV once yearly for 3 years, is the only trial that has shown fracture efficacy as an end point in the treatment of patients at risk for osteoporotic fracture.
A recent report by Black et al.  at the 2010 American Society for Bone and Mineral Research Meeting in Toronto of a 3-year extension of the Horizon trial addresses another related issue, the possibility of a holiday after 3 years treatment. Black et al.  identified 1,233 patients in the Horizon trial at year 3 who were randomized to either continued infusions of IV ZA or placebo. BMD remained constant at all sites in the 6-year ZA group, whereas there was a slight drop in femoral neck BMD of about 1% in the group that received 3 years of placebo injection after 3 years of ZA but the BMD remained well above pretreatment levels.. Results for other sites of BMD were similar. Biochemical markers remained constant in the group receiving ZA for 6 years but rose slightly in the group receiving placebo for 3 years. New morphometric vertebral fractures were significantly lower in the group receiving six ZA injections (RR = 0.48, P = 0.04), whereas other categories of fractures including nonvertebral, hip, and clinical vertebral were not different between study groups.
The data demonstrate that the antiresorptive effect of IV ZA is sustained for 3 years. Future studies of different dosing intervals may be considered. However, for now we do know that once-yearly IV ZA for 3 years is effective in reducing fracture risk.
Conflicts of interest: S.L. Silverman: has received grant support from Novartis.
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