Zoledronic Acid Lowers Bone Turnover in Postmenopausal Women

Laurie Barclay, MD

September 06, 2011

September 6, 2011 — Compared with raloxifene, zoledronic acid is associated with significantly greater reductions in bone turnover markers among postmenopausal women with low bone mass, according to the results of a multicenter, double blind, randomized controlled trial reported in the August issue of Menopause.

"Zoledronic acid, a bisphosphonate administered via a single 15-minute intravenous infusion, is approved for the treatment and prevention of osteoporosis in postmenopausal women," write Gloria Bachmann, MD, from the Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey in New Brunswick, and colleagues. "...Raloxifene, a selective estrogen receptor modulator, belongs to a class of drugs known as estrogen agonists/antagonists. It is approved for the treatment and prevention of osteoporosis as well as for reducing the risk of invasive breast cancer."

The goal of the study was to compare the effects of zoledronic acid and raloxifene on bone turnover markers, which may predict changes in the risk for fractures.

Clinical Care Changes Not Likely

"The findings in this trial are not likely to have any impact on the clinical care of postmenopausal women with low bone mass, as the findings are essentially confirmatory based on data from previous studies, and as only surrogate markers of bone fracture risk reduction were used," Dale W. Stovall, MD, professor of obstetrics and gynecology at the University of Virginia in Charlottesville, told Medscape Medical News in an independent comment. "However, the lack of a significant reduction in the bone resorption marker, urine N-telopeptide of type I collagen (urine NTx), in women over age 65 is interesting. Still, the study was not adequately powered to assess effects on bone in this specific subpopulation."

In this trial, 110 postmenopausal women with low bone mineral density (BMD) were randomly allocated to treatment with either a single intravenous infusion of zoledronic acid (5 mg) or 6 months of daily oral raloxifene (60 mg). The main efficacy endpoint was change from baseline to 6 months in urine NTx levels, and the secondary efficacy endpoints were change from baseline to 2, 4, and 6 months in serum levels of bone-specific alkaline phosphatase (BSAP), a bone formation marker.

Benefits of the Study

"This study has several strengths," Dr. Stovall said. "It utilizes a randomized, double-blinded treatment allocation, a central laboratory, appropriate inclusion criteria, and has adequate statistical power to assess its primary outcome. Furthermore, this is the first head-to-head study between oral raloxifene and i.v. zoledronic acid in women with low bone mass."

Compared with raloxifene, zoledronic acid was associated with a significantly greater decrease in urine NTx levels at 6 months (the primary endpoint) as well as at 2 and 4 months (P < .001 for all comparisons). At all time points, zoledronic acid was also associated with significantly greater reductions in serum BSAP levels (P < .001 for all comparisons).

"The study demonstrated a possible differential effect of raloxifene in women over 65 years of age versus those under age 65," Dr. Stovall said. "More specifically, women over age 65 did not have a significant reduction in the marker of bone resorption utilized in this study, urine NTx. Of course, the study was not adequately powered to definitively assess this finding."

Although both treatments were well tolerated, there were more adverse events with zoledronic acid, mostly transient post-dose symptoms observed within 3 days after infusion.

"Zoledronic acid demonstrated significantly greater decreases in bone turnover markers than did raloxifene in postmenopausal women with low bone mass," the study authors write. "With the oral regimen, as expected, compliance decreased over the course of this study, an outcome which may negatively affect efficacy. However, for younger women with lower fracture risk but increased risk for breast cancer, raloxifene may be a preferred treatment option."

Study Limitations

Limitations of this study noted by Dr. Stovall include duration of only 6 months, which was insufficient to compare the effects of zoledronic acid and raloxifene on BMD, and use of bone turnover markers as a proxy for fracture risk.

"Clearly, the ideal outcome of interest would be fractures, [but] as the authors point out, answering that question would require a very large multi-year study," Dr. Stovall said. "Another important outcome of interest in osteoporosis treatment trials is BMD, and this trial did not assess BMD. The authors point out here as well, that the limited length of follow-up in this trial, 6 months, prevented the likelihood that any significant differences would be found."

"As head-to-head randomized clinical trials are the best method of comparison of the effects of 2 or more anti-resorptive or anabolic bone agents on fracture risk reduction, such a study utilizing fractures as the primary outcome would likely determine the superiority of one agent over another in regards to the prevention of fractures," Dr. Stovall concluded. "However, as raloxifene also has invasive breast cancer risk reduction as a second clinical indication, the overall clinical impact of these 2 agents might still be in question."

Novartis Pharmaceuticals supported this study and employs 3 of the study authors. Some of the other study authors have disclosed various financial relationships with Novartis, Ferring Pharmaceuticals, Novo Nordisk, Solvay Pharmaceuticals, Barr Laboratories, Bradley Pharmaceuticals, Eli Lilly & Co, Merck & Co Inc, Warner Chilcott, Wyeth, BioSante, Boehringer Ingelheim, FemmePharma, GlaxoSmithKline, Nanma/Tripharma/Trinity, Procter & Gamble, QuatRx Pharmaceuticals, Teva, Allergan, Amgen Inc, Ascend Therapeutics, Azur Pharma Inc, Bayer, Concert Pharmaceuticals, Corcept Therapeutics Inc, Depomed Inc, Graceway Pharmaceuticals, LLC, KV Pharmaceutical, Lipocine Inc, Meditrina Pharmaceuticals, Merrion Pharmaceuticals, NDA Partners, Novogyne Pharmaceuticals, Pear Tree Pharmaceuticals, Schering-Plough, Sciele, and/or Ther-Rx. Dr. Stovall has disclosed no relevant financial relationships.

Menopause. 2011:18:851-856.

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