Abstract
The most abundant non-collagenous protein in bone matrix is osteocalcin, which is a key biochemical marker of osteoblastic activity and bone formation. The 1,25-dihydroxyvitamin D₃-induced regulation of osteocalcin gene expression via the vitamin D responsive element (VDRE) provides a molecular connection between vitamin D status and the production of osteocalcin. This review is a comprehensive overview of the impact of vitamin D supplementation on serum osteocalcin levels in various populations, based on molecular biology, clinical trials and meta-analyses. The vitamin D receptor (VDR) complexed with its ligand is able to associate with the vitamin D receptor element (VDRE) at nucleotide positions -466 to -437 of the rat osteocalcin gene promoter and consequently stimulate transcription in a cooperative manner with other basal elements of the promoter such as the TATA box and the CCAAT box. But, when translated into the clinic, this molecular relationship is quite complex. Meta-analytical evidence shows that, in women, vitamin D supplementation is associated with a significant decrease in serum osteocalcin (mean difference -0.610; high heterogeneity between studies, likely due to different age, baseline vitamin D status, supplementation dosage and duration, calcium supplementation given concurrently, and menopausal status). In particular, increased levels of vitamin D and/or higher baseline levels of 25-hydroxyvitamin D are associated with improvements in circulating osteocalcin, possibly due to increased carboxylation and improved bone matrix incorporation along with reduced bone turnover. A further twist on the vitamin D status-vitamin K aspect is that vitamin K is required for γ-carboxylating osteocalcin, which otherwise cannot bind to hydroxyapatite. Administration of antiresorptive therapy, calcium, and exercise also modulate the osteocalcin response to vitamin D, with differential osteocalcin response by age group(postmenopausal women versus premenopausal women and men), and with unique pathophysiological considerations in some populations, such as chronic kidney disease, obesity, and diabetes. Interpretation of serum measurements is complicated by methodological issues such as assay standardization, diurnal variation and the presence of osteocalcin fragments. This review aims to present the current knowledge on vitamin D supplementation and serum osteocalcin in an integrated fashion and to identify gaps and unanswered questions. This discrepancy in the effects of vitamin D on osteocalcin serves as yet another reminder that tailored approaches to vitamin D supplementation are necessary and that osteocalcin should be interpreted with other bone turnover markers, not as a stand-alone marker. In the future, the potential research directions are: thorough dose-response studies taking into account vitamin K status; the study of the undercarboxylated versus carboxylated fraction of the osteocalcin; the incorporation of the measurement of osteocalcin in the comprehensive fracture risk assessment algorithms