Editorial: Serum Undercarboxylated Osteocalcin and the Risk of Hip Fracture

The discovery of osteocalcin (boneGla protein, BGP) in the mid-seventies by Price and coworkers (1) ushered in a period of unprecedented interest in markers of bone metabolism that continues to this day. A product almost exclusively of mature, active osteoblasts, the protein containing 49 amino acids is a secretory cleavage product of a larger intracellular precursor molecule. Transcription of the osteocalcin gene, located on chromosome 1, is regulated by 1,25-dihydroxyvitamin D, estrogens, glucocorticoids, and other molecules. Posttranslational modification of osteocalcin occurs through the vitamin K-dependent gamma-carboxylation of three glutamate molecules in positions 17, 21, and 24 of the human protein. Vitamin D may also have a role in this posttranslational process (2). Gamma-carboxylation of the nascent protein is largely responsible for its calcium binding properties. In the course of its secretion into the milieu of bone, osteocalcin also gains access to the circulation where it can be measured. Although the exact role of osteocalcin in bone metabolism remains obscure, this circulating protein is a focus of great interest as a marker of bone formation and turnover (3). The relevance of vitamin K deficiency to possible abnormalities in osteocalcin function, by virtue of undercarboxylation, was highlighted by Price et al. (4), who demonstrated that the skeleton was sensitive to deficiency in this vitamin. Clinical studies showed subsequently that vitamin K deficiency, and other factors such as aging, may in fact lead to an impairment in the carboxylation of osteocalcin, resulting in a disproportionate increase in the undercarboxylated form of osteocalcin (ucOC) in the circulation (5, 6). Vitamin K2 levels have been shown by Hodges et al. (7) to be lower in women with osteoporotic fractures than in healthy individuals. Szulc et al. showed that in elderly, institutionalized women followed for 18–36 months, increased serum levels of ucOC were predictive of hip fracture (8–9). These latter results, however, might have been indicative merely of an association between poor nutritional status and hip fracture risk among institutionalized subjects and not necessarily a general biological mechanism that could be relevant to a more representative sampling of the population. In this issue of The Journal of Clinical Endocrinology and Metabolism, Vergnaud et al. (10) address this important question. In a nested case control study based upon a large population of healthy elderly women from the EPIDOS study of 7598 women, increased serum levels of immunoreactive ucOC, but not of total osteocalcin, were shown to be predictive of hip fracture risk (odds-ratio: 2.0, 95% confidence interval: 1.2–3.2). Although serum levels of ucOC showed a significant negative correlation with bone mineral density (BMD), adjustment for BMD did not change the odds ratios significantly. Adjustment for a factor related to risk of falling, namely gait speed, also did not change the predictive value of ucOC. Thus, ucOC appears to be an independent predictor of hip fracture risk. When BMD (lowest quartile) and serum ucOC (highest quartile) were considered together, the oddsratio increased to 5.5 (confidence interval: 2.7–11.2). It is important to note that the mean baseline levels of both total and undercarboxylated osteocalcin were indistinguishable among the fracture and the control groups. The article of Vergnaud et al. (10) supports previous investigations that have suggested that measurements of bone markers are useful predictors of fracture risk. Previously published studies have shown that the combined analysis of severalmarkers of bone formation and resorption can predict a major proportion of the variability in bone loss. These studies have included relatively small, preselected study populations (11), but also larger prospective studies such as the European Vertebral Osteoporosis Study (EVOS; 12) and, subsequently, the EPIDOS study (13). Although the data would tend to favor markers of bone resorption over those of bone formation as more useful predictors, further analysis of the EVOS study did reveal that low serum osteocalcin concentrations were associated with increased risk of hip fracture (odds ratio: 3.1; 95% confidence interval: 1.0–9.2; HA Pols, personal communications). In another prospective study, low serum levels of another bone formation marker, carboxyterminal propeptide of type I collagen, were associated with increased risk of hip fracture (14). Although measurement of ucOC may be useful in providing an integrated assessment of the factors that are responsible for gamma carboxylation of osteocalcin, such as vitamins K and D, underlying biochemical mechanisms by which ucOC could be associated with impaired bone metabolism are not known. Analyses of osteocalcin in bone samples from a relatively small number of patients with osteoporosis have shown negligible differences in the proportion of undercarboxylated residues compared with bone specimens from healthy controls (15). The lower affinity of the undercarboxylated protein for bone mineral may also serve to diminish its relative importance in influencing bone metabolism. On the other hand, in transgenic mice engineered to be deficient in osteocalcin, bone formation is actually enhanced (16), suggesting an inhibitory function of osteocalcin on osteoblast activity. It is conceivable that ucOC, a direct product of the osteoblast, is more inhibitory on osteoblast function than the posttranslational, carboxylated form. Further studies of the functional properties of carboxylated and noncarboxylated osteocalcin on bone metabolism are clearly needed. Received January 2, 1997. Accepted January 2, 1997. Address all correspondence and requests for reprints to: Markus J. Seibel, M.D., Department of Medicine, University of Heidelberg, Bergheimerstrasse 58, 69115 Heidelberg, Germany. 0021-972X/97/$03.00/0 Vol. 82, No. 3 Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1997 by The Endocrine Society