Highlights of the 28th Annual Meeting of the American Society for Bone and Mineral Research (ASBMR)

September 15-19, 2006; Philadelphia, Pennsylvania

Ego Seeman, MD


January 11, 2007

In This Article

What Else Is New in Osteoporosis Therapy?

Concerns have been raised about oversuppression of remodeling and potential adverse events with BPs; however, evidence for an increased fracture rate remodeling with bisphosphonates was not forthcoming at this meeting:

  • There was no increased incidence of osteonecrosis of the jaw reported in the Horizon-PFT study.[1]

  • In postmenopausal women receiving alendronate who were then randomized to receive 1 IV infusion of zoledronate 5 mg + 52 weeks of oral placebo (n = 113) or 1 IV infusion of placebo + 52 weeks of oral alendronate 70 mg (n =112), bone mineral density (BMD) values remained stable with both treatments. Urine N-telopeptide of type I collagen and bone-specific alkaline phosphatase biomarker levels remained at or close to baseline levels in the alendronate group during the study. Biomarker levels were reduced from baseline after 3 months in the zoledronate group, but returned to baseline after 6 months and increased thereafter, remaining within the premenopausal normal range.[4]

  • Results of a histomorphometric analysis of 10 subjects treated with ZA vs 13 treated with alendronate showed almost identical effects; the level of suppression of bone remodeling was no lower than in premenopausal women.[5]

  • Eighty-nine biopsies were examined in a 2-year study of the effects of IV ibandronate on bone histology; activation frequency (a measure of remodeling rate), and mineralizing surface (a measure of the surface extent of new bone formation and mineralization) were comparable to those found in healthy premenopausal women, and there was no evidence of adverse effects on bone mineralization.[6]

  • Biopsies obtained from 11 men given risedronate 35 mg once weekly for treatment of primary osteoporosis and 6 placebo-treated men -- all of whom were participating in a randomized, double-blind, placebo-controlled, multicenter, 2-year, phase 3 study -- were comparable; while activation frequency was reduced in risedronate-treated patients, bone remodeling continued with normal appositional rates, confirming normal osteoblast function.[7]

  • Iliac crest biopsies in 45 postmenopausal women with osteoporosis who received pamidronate, alendronate, or risedronate for at least 4 years showed that microcrack frequency was low (0.15 microcracks/mm2 per bone volume (BV) and 0.014 microcracks/mm2 per total tissue volume (TV) despite a marked reduction of bone turnover and no higher than controls (0.07 microcracks/mm2 per BV; 0.007 microcracks/mm2 per TV); 54% of treated women had no microcracks and there was no association between microcrack frequency and the duration of therapy or fracture prevalence.[8]

Comparator trials using antifracture efficacy as the endpoint are not available. Consequently, surrogate endpoints such as decrease in remodeling marker levels or increase in BMD are believed by some to be evidence that one drug is better than another. This notion is flawed.

An increase in BMD after administration of an antiresorptive agent is largely a function of initial differences in remodeling rather than any real difference in drug potency as inferred by some authors. The increase in BMD is a poor predictor of reduction in fracture risk.[9,10] Most of the change in BMD during 3-4 years of antiresorptive treatment occurs during the first 6-18 months. The initial increase in BMD is the result of filling of remodeling sites (excavated before treatment) with new bone, which then undergoes primary and secondary mineralization. The greater the numbers of excavated sites present before treatment, the greater will be the rise in BMD.[11] Early reduction in biochemical measures of bone remodeling predicts increases in BMD. Among 833 women who received weekly alendronate 70 mg or risedronate 35 mg, the tertile with the greatest decrease in markers at 3 or 6 months had the greatest mean increase in BMD at 24 months and the lowest number of 24-month BMD nonresponders.[12] The analysis of interest not provided was a comparison of the drugs after controlling for baseline differences in remodeling.

The Multiple Outcomes of Raloxifene Evaluation trial (MORE) enrolled 7705 patients with low BMD with or without baseline fractures and demonstrated that raloxifene reduced the risk of vertebral fractures.[13] A recent analysis of a subset of 2430 osteoporotic women suggested that after 3 years, the reduction in incident spine fractures with raloxifene treatment differed significantly by pretreatment levels of bone-specific alkaline phosphatase and osteocalcin.[14] These data differ from findings reported with bisphosphonates. We await publication of these results to explain these differences.


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