Grand Challenges in Bone Endocrinology

This article gives a personal view of some of the major unanswered research questions at the interface between bone and endocrinology. One of the most compelling challenges relates to the emerging relationship between bone and energy metabolism. On a clinical level, it is well established that obesity exerts a protective effect on bone mass and risk of osteoporosis, an influence which appears to be established in childhood (Tobias, 2010). In terms of explaining this relationship between fat and bone, a series of studies by Karsenty and colleagues based on transgenic mice identified an intriguing pathway linking bone turnover and energy metabolism involving decarboxylated oste-ocalcin and insulin (Ferron et al., 2010). This finding is consistent with an inverse association between osteocalcin and insulin levels observed in elderly men (Kindblom et al., 2009). However, extraskeletal receptors for osteocalcin responsible for mediating such a pathway are yet to be identified. Moreover, there may be fundamental differences in the regulation of energy metabolism between man and rodent models, and in the absence of prospective clinical data linking changes in bone turnover to alterations in glucose tolerance and/or fat mass, the relevance of this mechanism to humans remains unclear. A related question is whether bone metabolism is related to energy metabolism not only as a consequence of interactions with insulin, but also whether there is significant interplay with endocrine pathways originating from the intestine. It has been recognized for some time that feeding causes rapid suppression of bone markers such as beta CTX (Clowes et al., 2002), presumably reflecting an influence of gut-derived hormones on bone turnover. Intriguingly, further recent work by Karsenty and colleagues suggests that gut-derived hormones also exert a profound influence on bone mass, based on their findings in transgenic mice which suggest that reduced production of serotonin by the gut underlies familial high bone mass in patients with mutations of the LRP5 gene (Yadav et al., 2008), which in turn suggests that serotonin antagonists represent a novel approach to treating oste-oporosis (Yadav et al., 2010). However, the role of reduced serotonin levels in mediating this phenotype remains controversial, not the least because patients with carci-noid syndrome, in whom circulating levels of serotonin are greatly increased, are not known to develop osteoporosis. Dissecting out the mechanism of action of PTH, the major endocrine regulator of calcium metabolism, is a further important challenge. Continuous and intermittent exposure to PTH have diverse effects on …