UNDERCARBOXYLATED OSTEOCALCIN MEASURED WITH A SPECIFIC IMMUNOASSAY PREDICTS HIP FRACTURE IN ELDERLY WOMEN - THE EPIDOS STUDY

Increased levels of circulating undercarboxylated osteocalcin (ucOC), measured indirectly with the hydroxyapatite (HAP) binding assay, have been shown to predict hip fracture risk in a small group of elderly in stitutionalized women. The aim of this study was to confirm these find ings in a prospective cohort study (EPIDOS prospective study) of 7598 healthy, independently living women over 75 yr of age. One hundred and four women who sustained a hip fracture during a 22-month follow-up p eriod were age matched with 255 controls who did not fracture. Baselin e samples were collected before hip fracture for measurement of total OC and ucOC, assessed either with the HAP binding assay or directly wi th a new enzyme-linked immunosorbent assay (ELISA). This direct ELISA uses human recombinant noncarboxylated OC as a standard and two monocl onal antibodies, one of which was raised against the 14-30 Glu synthet ic peptide. We found that the intra- and interassay variations are les s than 11%, and this assay exhibits a 5% crossreactivity with purified human bone OC, used as a source of carboxylated OC. ucOC levels measu red with this ELISA correlated well with the HAP binding assay in the population of 359 elderly women (r = 0.82; P < 0.0001). We estimated t he risk of hip fracture for women with levels of ucOC in the highest q uartile of values for the 255 controls. We found that increased levels of ucOC measured by ELISA were associated with increased hip fracture risk with an odds ratio (OR) of 1.9 (95% confidence interval, 1.2-3.0 ), and the ELISA had a greater sensitivity than the HAP assay. In cont rast, total OC was not associated with hip fracture risk. After adjust ment for femoral neck bone mineral density (BMD) and mobility status a ssessed by gait speed, ucOC still predicted hip fracture with an OR of 1.8 (1.0-3.0). Women with both femoral neck BMD in the lowest quartil e and ucOC in the highest quartile were at higher risk of hip fracture , with an OR of 5.5 (2.7-11.2), than those with only low BMD or high u cOC levels. In conclusion, we have developed a new specific ELISA for serum ucOC, with low cross-reactivity with carboxylated OC and increas ed specificity and sensitivity over the HAP assay. Using this new ELIS A, we found that ucOC, but not total OC, predicts hip fracture risk in dependently of femoral neck. BMD in elderly women drawn from the gener al population. Thus, ucOC measurement could be combined with bone mass determination to improve the assessment of hip fracture risk in elder ly women.