Changes in Bone Density and Turnover Explain the Reductions in Incidence of Nonvertebral Fractures that Occur during Treatment with Antiresorptive Agents
Marc C. Hochberg,
Susan Greenspan,
Richard D. Wasnich,
Paul Miller,
Desmond E. Thompson and
Philip D. Ross
University of Maryland School of Medicine (M.C.H.), Baltimore, Maryland 21201; University of Pittsburgh School of Medicine (S.G.), Pittsburgh, Pennsylvania 15213; Hawaii Osteoporosis Center (R.D.W.), Honolulu, Hawaii 96814; Colorado Center for Bone Research (P.M.), Denver, Colorado 80227; and Merck \|[amp ]\| Co., Inc. (D.E.T., P.D.R.), Rahway, New Jersey 07065
Address all correspondence and requests for reprints to: Dr. Marc Hochberg, 10 South Pine Street, Medical School Teaching Facility 8-34, Baltimore, Maryland 21201. E-mail: . mhochber{at}umaryland.edu
Abstract
Some, but not all, antiresorptive agents have been shown toreduce the risk of nonvertebral fractures. Agents that significantlyreduced nonvertebral fracture risk also appear to produce largermean increases in bone mineral density (BMD) and reductionsin biochemical markers (BCM) of bone turnover, compared withother agents. To examine the extent to which increases in BMDand reductions in BCM during antiresorptive therapy are associatedwith reductions in risk of nonvertebral fractures, we performeda meta-analysis of all randomized, placebo-controlled trialsof antiresorptive agents conducted in postmenopausal women withosteoporosis (i.e. prior vertebral fracture or low BMD) withavailable relevant data. A total of 18 such trials with usabledata were identified, including a total of 2,415 women withincident nonvertebral fractures over 69,369 women-years of follow-up.Poisson regression was used to estimate the association betweenchanges in BMD or BCM during the first year and overall reductionsin risk of nonvertebral fractures (vs. the placebo group) acrossall trials. Larger increases in BMD and larger reductions inBCM were significantly associated with greater reductions innonvertebral fracture risk. For example, each 1% increase inspine BMD at 1 yr was associated with an 8% reduction in nonvertebralfracture risk (P = 0.02). Mean BMD changes at the hip were smallerthan at the spine, but the predicted net effect on fracturerisk was the same; an agent that increases spine BMD by 6% at1 yr reduces nonvertebral fracture risk by about 39%, and anagent that increases hip BMD by 3% at 1 yr reduces nonvertebralfracture risk by about 46%. The results also predict that a70% reduction in resorption BCM would reduce risk by 40%, anda 50% reduction in formation BCM would reduce risk by 44%. Itappears that either BMD or BCM changes are able to explain theeffect of treatment, because a separate variable for treatmentwas not independently significant in any models. These datademonstrate that larger increases in BMD at both the spine andhip and larger reductions in both formation and resorption BCMare associated with greater reductions in the risk of nonvertebralfractures. Antiresorptive agents that do not produce large increasesin BMD or large reductions in BCM do not appear to and wouldnot be expected to decrease the risk of nonvertebral fractures.
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