26 ENDOCRINOLOGY APRIL 15, 2010 • INTERNAL MEDICINE NEWS Lasofoxifene Cuts Fractures After Menopause ‘A significant effect … was not evident until 5 years, fractures also is similar to that observed treat 492 patients for 1 year to prevent a in women taking other antiresorptive single major coronary event,” she said. and absolute risk reductions were very small.’ therapies, and it stands in contrast to The PEARL investigators said that la- raloxifene’s inability to reduce this risk, sofoxifene raised the risk of venous BY MARY ANN MOON benefits over raloxifene for the skeleton, they said. thromboembolism to a similar degree as breast, heart, or reproductive tract. However, Dr. Becker noted in her ed- do raloxifene, tamoxifen, and oral estro- he investigational drug lasofox- “Given the plethora of drugs current- itorial that nearly all the reduction in gen therapies. Like these agents, laso- ifene decreases the risk of verte- ly available for osteoporosis, studies of risk for nonvertebral fractures could be foxifene also significantly increased the Tbral and nonvertebral fractures new agents should show clear benefits attributed to forearm and wrist frac- rate of hot flushes and leg cramps. It did in postmenopausal women with osteo- over existing agents,” she wrote. Results tures. “A significant effect in the overall not raise the risk of endometrial cancer porosis, according to a report. of the PEARL study do not do so, Dr. group was not evident until 5 years, and or endometrial hyperplasia. The nonsteroidal selective estrogen- Becker added. absolute risk reductions were very Dr. Becker countered that although receptor modulator (SERM) also reduces Dr. Cummings and his colleagues per- small. the increase in absolute risk of venous the risk of ER-positive breast cancer, formed the international, randomized, “On balance, lasofoxifene seems to of- thromboembolism was small, lasofox- major coronary heart disease events, and placebo-controlled PEARL study in 8,556 fer little, if any, advantage over raloxifene ifene more than doubled the relative stroke without raising the risk of en- women aged 59-80 years who had a bone as an agent against osteoporosis,” she risk. dometrial cancer or hyperplasia. mineral density T score of –2.5 or less at said (N. Engl. J. Med. 2010;362:752-4). In addition, rates of uterine polyps, en- Like other SERMs, lasofoxifene raises the lumbar spine or femoral neck. A to- Lasofoxifene also reduced the risk of dometrial hypertrophy, and vaginal can- the risk of venous thromboembolism tal of 28% already had at least one ver- ER-positive breast cancer by 85%, com- didiasis all were significantly higher than and increases the rate of hot flushes and tebral fracture at baseline. pared with placebo. Although this find- with placebo, she said. leg cramps, wrote Dr. Steven R. Cum- After 5 years of follow-up, women ing is “impressive,” it is similar to the risk Pfizer submitted a new drug applica- mings of California Pacific Medical Cen- who received 0.5 mg per day of lasofox- reduction reported for raloxifene, Dr. tion to the Food and Drug Administra- ter Research Institute, San Francisco, ifene showed a 42% reduction in relative Becker added. tion in 2007, and in 2008 an advisory pan- and his associates in the Postmenopausal risk for vertebral fractures and a 24% re- Lasofoxifene was associated with a el voted 9-3 that the benefits of the SERM Evaluation and Risk-Reduction with La- duction in relative risk for nonvertebral 32% reduction in relative risk of coro- outweighed this risk in postmenopausal sofoxifene (PEARL) study. fractures, compared with those who re- nary heart disease events (5.1 cases per women with osteoporosis. The FDA has Taken together, these findings seem to ceived placebo. 1,000 person-years) and a 36% reduction not yet issued a decision. ■ indicate that lasofoxifene performs Bone density at the lumbar spine, in relative risk of stroke (2.5 cases per somewhat better than do other SERMs femoral neck, and total hip improved by 1,000 person-years), compared with Disclosures: The PEARL study was such as raloxifene, and also has advan- about 3% with the active drug, the in- placebo (7.5 and 3.9 cases per 1,000 per- funded by Pfizer, manufacturer of tages over hormone therapy, tamoxifen, vestigators said (N. Engl. J. Med. son-years, respectively), Dr. Cummings lasofoxifene. Dr. Cummings reported and tibolone. 2010;362:686-96). and his associates said. receiving consulting fees from Amgen, Eli However, in an editorial accompany- This decrease in risk of vertebral frac- However, Dr. Becker noted that the Lilly, GlaxoSmithKline, and Organon, ing this report, Dr. Carolyn Becker of the tures is comparable with that reported number of these events was quite small, lecture fees from Eli Lilly and Novartis, and division of endocrinology, diabetes, and in women taking raloxifene, estrogen and there were no differences in rates of grant support from Amgen, Pfizer, and Eli hypertension at Brigham and Women’s therapy, oral bisphosphonates, and ti- fatal stroke. “Although the cardiovascu- Lilly. Dr. Becker’s financial disclosures are Hospital, Boston, argued that the drug bolone. lar benefits reported in the PEARL trial available with the text of the article at “offers no major clinically important The decrease in risk of nonvertebral seem impressive, one would need to NEJM.org. Role of Bisphosphonates in Atypical Fracture Downplayed BY SHARON WORCESTER Since radiographs in those with fractures were gen- While the current findings provide assurance that erally not available, atypical features—such as those as- these types of fractures are extremely rare, and that he risk of subtrochanteric and diaphyseal femur sociated with cortical thickness and fracture morphol- many more common and equally devastating hip frac- Tfractures is not significantly increased in women ogy—could not be assessed; if this information were tures are prevented than are caused by bisphosphonates, taking bisphosphonates, even among those treated for available, it is likely the femoral physicians should “reevaluate up to 10 years, a secondary analysis of data from three fracture rate would be even ‘Although we can confidently patients who are receiving large randomized bisphosphonate trials suggests. lower, they said. long-term bisphosphonate The findings follow several case reports that hinted at The findings support those conclude that absolute rates of therapy in the context of con- an increased risk of these atypical fractures in bisphos- from population base studied, such fractures are low, wide temporary guidelines for treat- phonate users. However, the current study, which in- including one that found evi- ment initiation, progress while cluded a review of 283 hip or femur fractures in 14,195 dence of an increased incidence confidence intervals ... preclude receiving therapy, current bone women with 51,287 patient-years of follow-up showed of hip and femur fractures with definitive conclusions regarding mineral density measurement, that only 12 subtrochanteric or diaphyseal femur frac- alendronate use, but which at- and risk factors for fracture,” tures occurred in 10 women, for a rate of 2.3 per 10,000 tributed that to the increased the relative risk of treatment.’ wrote Dr. Shane of Columbia patient-years, Dennis M. Black, Ph.D., of the University use of alendronate in high-risk University, New York (N. Engl. of California at San Francisco and his colleagues wrote. patients rather than to the use of alendronate. J. Med. 2010 March 24 [doi:10.1056/NEJMe1003064]). The data analyzed in the current study were from the “Although we can confidently conclude that absolute It is reasonable to consider drug holidays, particu- phase III Fracture Intervention Trial (FIT), the FIT rates of such fractures are low, wide confidence inter- larly in those with substantially reduced levels of Long-Term Extension (FLEX) trial, and the Health vals (resulting from the very low incidence of events) bone turnover markers, but again, the evidence of per- Outcomes and Reduced Incidence with Zoledronic preclude definitive conclusions regarding the relative sistent antifracture efficacy after discontinuation must Acid Once Yearly Pivotal Fracture Trial (HORIZON- risk of treatment,” the investigators wrote. be balanced with data showing that 10 vs. 5 years of PFT); the relative hazard ratios for subtrochanteric and However, based on data they analyzed, the investi- alendronate use is associated with significantly fewer diaphyseal femur fractures were 1.03 for alendronate vs. gators estimated that 3 years of bisphosphonate treat- new vertebral and nonvertebral fractures in those placebo in the FIT trial, 1.50 for zoledronic acid vs. ment in 1,000 women with osteoporosis would prevent with bone mineral density T scores of –2.5 or lower, placebo in the HORIZON-PFT trial, and 1.33 for con- about 100 fractures, including 71 vertebral fractures and she wrote. ■ tinued alendronate use vs. placebo in the FLEX trial, the 29 nonvertebral fractures, including 11 hip fractures. investigators reported (N. Engl. J. Med. 2010 March 24 Balanced against the annual rate of 2.3 subtrochanteric Disclosures: This study was supported by Merck and [doi:10.1056/NEJMoa1001086]). and diaphyseal femur fractures seen in the three trials, Novartis. The investigators reported receiving grants, Even in the FLEX trial, which included up to 10 years “the hypothetical risk is quite small,” they concluded. travel reimbursement, consulting fees, and lecture fees from of treatment with alendronate, the risk of femur frac- Additional research is needed to more fully address Merck, Novartis, and several other pharmaceutical ture and atypical femur fracture was very low, with no the matter of bisphosphonate use and the risk of sub- manufacturers, as well as the National Osteoporosis significantly increased risk of fracture among those who trochanteric and diaphyseal fractures, Dr. Elizabeth Foundation. Dr. Shane reported receiving grants from continued treatment for the full 10 years, they wrote.