COMPARISON OF NEW BIOCHEMICAL MARKERS OF BONE TURNOVER IN LATE POSTMENOPAUSAL OSTEOPOROTIC WOMEN IN RESPONSE TO ALENDRONATE TREATMENT

To evaluate the clinical utility of recently developed biochemical mar kers of bone turnover to monitor the response of osteoporotic patients to antiresorptive therapy, we compared the results of three advanced assays for markers of bone resorption and four of bone formation to hi gh pressure liquid chromatography (HPLC)-fluorometric assays for urina ry pyridinoline and deoxypyridinoline. These assays were also used to resolve the uncertainties concerning the rate of bone turnover in late postmenopausal (late-PMP) osteoporotic women The rate of bone turnove r in 85 women (mean +/- so age, 63 +/- 6 yr) with low bone mass and al l more than 5 yr postmenopausal (mean +/- SD yr PMP, 16 +/- 7 yr) was compared to that in 46 premenopausal women (mean +/- SD age, 40 +/- 5 yr) randomly selected from a large cohort and all having a normal spin e bone mineral density (BMD). The late-PMP osteoporotic patients were a subset of patients enrolled in a double blind, placebo-controlled, r andomized study comparing the effects of several doses of oral alendro nate, a potent and specific inhibitor of bone resorption. Periodically during the 2-yr study, the women's spinal BMD and the level of severa l markers of bone turnover were measured. Serum total and intact osteo calcin, bone-specific alkaline phosphatase, and carboxy-terminal prope ptide of type I collagen measured by RIA were used to assess bone form ation. To assess bone resorption, we measured the urinary excretion of total pyridinoline (HPLC Pyr) and deoxypyridinoline (HPLC D-Pyr) by H PLC, type I collagen cross-linked N-telopeptide and urinary free PYR ( F-Pyr) by enzyme-linked immunosorbent assay, and the serum concentrati on of type I collagen crosslinked C-telopeptide (ICTP) by RIA. All bon e formation markers, except carboxy-terminal propeptide of type I, col lagen, and all bone resorption markers, except ICTP, were significantl y increased above normal (33-171%; P < 0.001), in late-PMP osteoporoti c women. The long term within-patient variability assessed over a 15-m onth period in the placebo group was low and was somewhat lower for se rum markers (12.5-17.4%) than for urinary markers (24-29%). Under trea tment with alendronate, resorption markers decreased earlier than mark ers of bone formation, consistent with a direct action of the drug to inhibit osteoclastic bone resorption. With the exception of F-Pyr and ICTP, the levels of bone markers were reduced to the normal premenopau sal range, and this steady state was maintained from 6-15 months. The marked decrease in bone turnover was associated with a significant inc rease in spinal BMD, and highly significant correlations were observed between percent change in bone markers at 3 months and percent change in BMD after 24 months of treatment for all bone formation markers (r = -0.63-0.67), HPLC D-Pyr (r = -0.48), and type I collagen cross-link ed N-telopeptide (r = -0.53; all P < 0.0001). The correlation with BMD change was modest for HPLC Pyr (r = -0.31; P < 0.01) and was not sign ificant for F-Pyr (r = -0.21) or ICTP (r = -0.20). This study, using n ew biochemical markers of bone turnover, demonstrates that bone turnov er is increased in late-PMP osteoporotic women, a pattern that provide s a mechanistic basis for the beneficial effect of alendronate on bone mass. Alendronate treatment decreased bone turnover to the normal pre menopausal range, with a steady state level reached after 1 month of t herapy with 10 mg for resorption markers and after 3-6 months of thera py for markers of bone formation. The highly significant correlation b etween early changes in biochemical markers and the later change in bo ne mass suggests that some markers of bone turnover have clinical util ity for monitoring the effects of antiresorptive treatment of osteopor osis.