Vergnaud P, Garnero P, Meunier P J, Bréart G, Kamihagi K, Delmas P D
INSERM U-403, Hôpital E. Herriot, Lyon, France.
J Clin Endocrinol Metab. 1997 Mar;82(3):719-24. doi: 10.1210/jcem.82.3.3805.
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 institutionalized women. The aim of this study was to confirm these findings 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 period were age matched with 255 controls who did not fracture. Baseline samples were collected before hip fracture for measurement of total OC and ucOC, assessed either with the HAP binding assay or directly with a new enzyme-linked immunosorbent assay (ELISA). This direct ELISA uses human recombinant noncarboxylated OC as a standard and two monoclonal antibodies, one of which was raised against the 14-30 Glu synthetic peptide. We found that the intra- and interassay variations are less than 11%, and this assay exhibits a 5% cross-reactivity with purified human bone OC, used as a source of carboxylated OC. ucOC levels measured 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 the risk of hip fracture for women with levels of ucOC in the highest quartile 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 contrast, total OC was not associated with hip fracture risk. After adjustment for femoral neck bone mineral density (BMD) and mobility status assessed 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 quartile 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 ucOC levels. In conclusion, we have developed a new specific ELISA for serum ucOC, with low cross-reactivity with carboxylated OC and increased specificity and sensitivity over the HAP assay. Using this new ELISA, we found that ucOC, but not total OC, predicts hip fracture risk independently of femoral neck BMD in elderly women drawn from the general population. Thus, ucOC measurement could be combined with bone mass determination to improve the assessment of hip fracture risk in elderly women.
采用羟基磷灰石（HAP）结合试验间接测定发现，循环中未羧化骨钙素（ucOC）水平升高可预测一小部分老年住院女性的髋部骨折风险。本研究旨在通过对7598名75岁以上健康、独立生活的女性进行前瞻性队列研究（EPIDOS前瞻性研究）来证实这些发现。在22个月的随访期内发生髋部骨折的104名女性与255名未发生骨折的对照者进行年龄匹配。在髋部骨折前采集基线样本，用于测定总OC和ucOC，采用HAP结合试验或直接用一种新的酶联免疫吸附测定（ELISA）进行评估。这种直接ELISA使用重组人未羧化OC作为标准品和两种单克隆抗体，其中一种是针对14 - 30 Glu合成肽产生的。我们发现该测定法的批内和批间变异小于11%，并且该测定法与用作羧化OC来源的纯化人骨OC的交叉反应率为5%。在359名老年女性群体中，用这种ELISA测定的ucOC水平与HAP结合试验结果相关性良好（r = 0.82；P < 0.0001）。我们评估了255名对照者中ucOC水平处于最高四分位数的女性发生髋部骨折的风险。我们发现，ELISA测定的ucOC水平升高与髋部骨折风险增加相关，比值比（OR）为1.9（95%置信区间，1.2 - 3.0），并且ELISA的敏感性高于HAP试验。相比之下，总OC与髋部骨折风险无关。在对股骨颈骨密度（BMD）和通过步速评估的活动状态进行校正后，ucOC仍能以OR为1.8（1.0 - 3.0）预测髋部骨折。股骨颈BMD处于最低四分位数且ucOC处于最高四分位数的女性发生髋部骨折的风险高于仅BMD低或ucOC水平高的女性，OR为5.5（2.7 - 11.2）。总之，我们开发了一种新的血清ucOC特异性ELISA，与羧化OC的交叉反应性低，且比HAP试验具有更高的特异性和敏感性。使用这种新的ELISA，我们发现ucOC而非总OC可独立于股骨颈BMD预测来自普通人群的老年女性的髋部骨折风险。因此，ucOC测量可与骨量测定相结合，以改善老年女性髋部骨折风险的评估。
