A randomised, double-blinded, placebo-controlled, trial to determine the individual response in bone turnover markers to lasofoxifene therapy

Lasofoxifene is a novel selective estrogen receptor modulator that is being developed for the treatment of postmenopausal osteoporosis. Bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA) is currently used to diagnose osteoporosis. BMD response to therapy, however, is often not apparent until at least one year following start of treatment. Biochemical markers of bone turnover may provide an early indication of BMD response in individual patients.The aims of the study were: 1) to determine the variability in bone turnover markers (BTM) to estimate a value for least significant change (LSC); 2) to determine the number of subjects with a response to lasofoxifene greater than LSC; 3) to determine the number of subjects whose bone turnover is decreased to the lower half of the reference range and 4) to evaluate the use of bone turnover markers to predict the change in bone density in response to lasofoxifene.Fifty-one postmenopausal osteopenic women, ages 55 to 77 (mean 63.7) years, were recruited with 44 women completing the 2 year follow up. Participants received either lasofoxifene (0.25 mg/d) or placebo, in a 1:1 ratio. Duplicate measurements of BTM (bone alkaline phosphatase (bone ALP), N-terminal propeptide of type I collagen (PINP), serum β crosslinked C-telopeptides of type I collagen (sβ-CTX), urinary crosslinked N-telopeptides of type I collagen (U-NTX)) were made at baseline and 6 months with single measurements at 4, 8 and 12 weeks. Duplicate measurements of BMD at the lumbar spine (LS), total hip (TH) and distal forearm (DF) were made by DXA at baseline, one and two years in all subjects.Almost all women (92 to 96%), treated with lasofoxifene, had a reduction in serum-based bone turnover markers greater than LSC, and 52 to 80% had serum-based bone turnover markers in the lower half of the reference range, by six months of lasofoxifene therapy. The change in mean LSBMD from baseline, was significantly greater in the lasofoxifene group compared to placebo at 1 and 2 years (+ 2.5% and + 3.4%, respectively, P < 0.0001). Change in PINP and U-NTX at 6 months correlated inversely with change in LS and TH BMD at one and two years.The use of lasofoxifene therapy leads to significant decreases in bone turnover by 4 weeks of lasofoxifene therapy as a group, with a decrease in BTM greater than LSC occurring in almost all women taking lasofoxifene by 6 months. By this time, in over half of women taking lasofoxifene, BTM reached the lower half of the reference range. Our results suggest that bone turnover markers are useful for monitoring response to lasofoxifene. Changes occur early and relate to the BMD response.