The study findings indicate that alterations in γ–carboxylation of OC, in connection to weight status and androgen hormones excess may depict PCOS. Participation of serum free testosterone as independent predictor of ucOC, determining about half of ucOC variability when corroborated to bone resorption rate, suggests regulatory interrelationships between androgens and OC metabolism in women, implying potential involvement of the skeleton as an endocrine organ in the pathogenesis of PCOS. In addition to that, the positive association of ucOC with serum insulin observed in lean study participants is a finding which is in agreement to the key effect of ucOC to directly augment pancreatic insulin production and delivery. In turn, within the bone-pancreas regulatory loop, hyperinsulinemia, a feature of PCOS, may promote bone matrix OC decarboxylation and ucOC release via the OPG/RANKL pathway [5, 21].
Nonetheless, the underlying mechanism linking ucOC to androgen excess in PCOS is less clear. Human visceral adipose cells also express the OC gene, which appears to be up-regulated in vitro by dihydrotestosterone, an effect which in men may be reflected by the positive correlation of serum free testosterone with circulating ucOC levels and the ucOC/OC ratio . In male mouse Leydig cells, the ability of osteoblastic ucOC to promote testosterone gene expression at the transcriptional level was recently acknowledged by Oury et al.  as an effect accomplished via a G-protein coupled orphan receptor which belongs to the C family of GCPRs expressed in mice Leydig cells. Thus, a molecular basis was provided to the positive association between serum OC and free testosterone levels observed in adult men or paralleling skeletal growth in boys of pubertal age [24, 25]. However, mouse ovarian follicle cells appear not to express the OC signaling pathway identified in Leydig cells and regulation of sex steroids synthesis in the ovary by ucOC is not yet demonstrated . Notwithstanding, it has to be kept in mind that in the study of Oury et al. testosterone regulation by osteoblast-derived OC was tested in healthy mice ovary explants, an experimental model not superposable to the physiopathological mechanisms governing androgen regulation in PCOS.
Consistent with previous reports , both body mass and body fat exerted a strong lowering effect on ucOC, independently of the study subgroup. In fact, obvious weight-dependent relationships of ucOC with several endocrine and metabolic PCOS parameters became apparent in the present study. While ucOC was positively related to both hyperandrogenemia and insulin concentration in lean women, significant associations of ucOC to PCOS traits lacked in the overweight and obese subgroup pointing out to potential implication of additional metabolic players affecting the relationship between ucOC and endocrine parameters in PCOS. There is strong evidence that leptin, one fat tissue-derived adipocytokine, impairs OC production and bioactivity in the skeleton by a central serotonin-mediated activation of the sympathetic nervous system . In mice, leptin up-regulates osteoblastic ESP (Embryonic Stem cell specific Phosphatase) gene expression via adrenergic β2 and ATF4 receptors, an effect associated with accelerated γ-carboxylation of OC, low ucOC and low insulin secretion and sensitivity . Although not assessed in the present study, one may assume hyperleptinemia associated to increased fat mass contributed to the lower OC and ucOC levels observed in overweight and obese participants. In rats fed a high-fat diet, obesity resulted in activation of PPAR (peroxisome proliferator-activated receptor)-gamma and suppression of Wnt/β-catenin pathways both associated with stimulation of bone marrow adipogenesis and decreased osteoblast differentiation, as a substrate to diminished OC concentration . Nevertheless, the relationship between OC and fat mass appears to be reciprocal, since a decrease in serum ucOC concentration induced by anti-catabolic bone agents was able to predict long-term accumulation of fat mass .
Likewise, in a population-based sample of healthy children, ucOC was related to metabolic parameters in a weight-dependent manner. Higher relative circulating ucOC levels were associated to higher HOMA-IR in leaner but not heavier subjects and to higher high molecular weight (HMW)-adiponectin concentration, an association more apparent in heavier children , presumably in order to compensate for the low adiponectin state in heavy subjects. Expression of adiponectin receptors in osteoblasts and regulation of bone metabolism by adiponectin both in vitro
 and in vivo
[31, 32] in addition to increased adiponectin gene expression induced by ucOC could support the concept of an adiponectin-OC loop [3, 29] and the increased ucOC delivery in response to hypoadiponectinemia.
As shown here, serum OC assayed as both 1–49 OC and the more stable N-mid (1–43) fragment rather poorly reflects bone-energy metabolism axis status. In part, this may be attributable to factors such as specificity of the assay used, differences in pre-analytical sample stability or large intra-individual variations .
As a conclusion, in a weight-dependent manner, the ucOC secretion pattern is related to PCOS status. In lean women, high ucOC levels are strongly predicted by testosterone excess and in turn, may contribute to increased insulin secretion to compensate for altered insulin sensitivity. Future studies are warranted to investigate possible pathogenetic implications of ucOC in the development of PCOS metabolic traits and its potential usefulness as a clinical tool.