Reductions In Turnover Markers Research Articles

Effect of fish oil supplementation on bone turnover markers in women on aromatase inhibitors: a pilot study

Aromatase inhibitors (AI) are adjunctive therapies for estrogen‐receptor positive breast cancer (BC); however, they exacerbate bone loss. We tested the effects of a non‐pharmacological treatment, fish oil, on bone measures in 37 postmenopausal BC survivors on AI. In addition to calcium (1,000 mg/d) and cholecalciferol (800 IU/d), women were randomly assigned to 4 g eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)/d via fish oil or placebo (safflower oil) capsules. Bone mineral density was low in 41% of women; none were osteoporotic. Average age was 61.8±9.7 and BMI 28.0±5.8. There were no between group differences in dietary intake of calories, protein, calcium, vitamin D, n‐3 or n‐6 fatty acids, or other nutrients. Resorption and formation markers (serum C‐terminal telopeptide [sCTX] and procollagen type 1 N‐terminal propeptide [P1NP], respectively) were measured at baseline and 3 months. Baseline sCTX and P1NP were similar between groups. sCTX was reduced by −7.8±20.8% and P1NP by −10.2±16.5% in the EPA+DHA group. The reductions in turnover markers in the EPA+DHA group were not statistically different compared to changes in placebo (sCTX 0.4±20.4; P1NP −3.3±15.9). In this high risk group, nutritional supplementation was not enough to overcome the effects of AI on bone turnover. Project supported by the CT Breast Health Initiative and University of Connecticut Health Center Clinical Research Center.

How to Interpret Surrogate Markers of Efficacy in Osteoporosis

dence of the effectiveness of treatment. (6) The first issue raised is that changes in bone turnover are at least as informative as changes in BMD. We concur, and that is why changes in biochemical markers of bone turnover were an important secondary efficacy endpoint. Whereas the primary efficacy endpoint was the change in trochanter BMD at 12 months (for reasons noted in the paper), changes in four different biochemical markers of bone turnover measured at three different time-points (3, 6, and 12 months) were reported as secondary efficacy endpoints and discussed with equal prominence to the BMD changes. For all four markers, at all time-points measured, the reduction in the level of the marker from baseline was statistically greater with alendronate than with risedronate. The second point raised is that the relationship between changes in BMD and markers and fracture risk reduction may be nonlinear. Eastell et al. (7) reported that reductions in turnover during treatment with risedronate were associated with reductions in the risk of vertebral fractures, but appeared to reach a plateau beyond which fracture risk did not further decline. Data from a much larger study with alendronate reported no evidence of such a plateau over a wider range of reductions in turnover markers. (8) Moreover, in both publications, there was no evidence of a plateau or nonlinearity in the relationship between reduction in turnover markers and reduction in risk of nonvertebral fractures. It was also suggested that we did not evaluate cut-points for changes in bone turnover markers. These results are presented in a separate publication. (9) Analyses of data from the FIT and VERT studies are not comparable in design and did not reach the same conclusion as suggested by Drs Eastell and Delmas. (3,10) Although both studies addressed the issue of the relationship between incidence of spine fracture and changes in spine BMD on treatment, neither addressed the relationship between nonspine or hip fracture risk and changes in BMD. Thus, whereas we have acquired new information about the correlates of fracture reduction with antiresorptive treatments, the exact nature of those relationships are not yet clearly understood. fractures, it is important to recall that fractures were captured as adverse events. The fractures were self-reported, included any fracture (fingers, toes, face, etc.) regardless of location or cause, and were not verified by review of radiographic reports. In addition, this represents the total number of fractures, not the number of patients with fracture. As stated in the paper, there was no significant difference in the percent of patients reporting fractures as adverse events between treatment groups. We are certain that Drs Delmas and Eastell would agree that it is not prudent to make inferences from unadjudicated and underpowered fracture studies. Furthermore, in the recently completed FACTsInternational study of identical design, 18 fractures occurred in the alendronate treatment group and 20 fractures occurred in the risedronate treatment group. These results will be presented later this year, but serve to underscore the difficulty in interpreting fracture data from clinical trials not