We sought to determine whether the allelic variation in seven monogenic bone disease genes (CLCN7, TCIRGI, SOST, CA2, CSTK, TGFB1 and SLC26A2) contributes to osteoporosis/bone mineral density (BMD) variation in the normal Chinese population.
Further studies are required to delineate the differences between GC regulation of sclerostin in mice and humans and assess whether sclerostin mediates GC-induced osteoporosis in humans.
Our study showed a strong association between bone mineral density and polymorphisms in the FDPS gene, and a borderline association with LRP5 and SOST polymorphisms in postmenopausal Romanian women with osteoporosis.No association was found for VKORC1.
Identification of the disease causing genes, increased the knowledge on the regulation of BMD and highlighted important signaling pathways and novel therapeutic targets such as sclerostin, RANKL and cathepsin K. Genetic variation in genes involved in these pathways are often also involved in the regulation of normal variation in BMD and osteoporosis susceptibility.
As loss-of-function mutations in the SOST gene are associated with Sclerosteosis, another disorder of excessive bone growth, our study suggests that the SOST-LRP5 antagonistic interaction plays a central role in bone mass regulation and may represent a nodal point for therapeutic intervention for osteoporosis and other bone diseases.
A highly specific expression pattern and the exclusive bone phenotype have made Sclerostin an attractive target for therapeutic intervention in treating metabolic bone diseases such as osteoporosis and in facilitating fracture repair.
As loss-of-function mutations in the SOST gene are associated with Sclerosteosis, another disorder of excessive bone growth, our study suggests that the SOST-LRP5 antagonistic interaction plays a central role in bone mass regulation and may represent a nodal point for therapeutic intervention for osteoporosis and other bone diseases.
We have reviewed the currently available evidences that support the use of sclerostin antibody in treating osteoporosis and compare its efficacy and mechanism of action with the currently available anabolic drug, human PTH.
Sclerostin neutralizing antibodies are being tested in ongoing clinical trials to target osteoporosis and osteogenesis imperfecta but their interaction with mechanical stimuli on bone formation remains unclear.
Sclerostin-neutralizing antibodies (Scl-Ab), romosozumab, human parathyroid hormone (hPTH, 1-34), and hPTH/hPTHrP analogues (e.g. teriparatide and abaloparatide) stimulate bone formation and have been studied in clinical trials for severe osteoporosis.
Together, these results demonstrate that inhibition of sclerostin by Scl-Ab increased bone formation, and decreased bone resorption, leading to improved bone structure, bone mass and bone strength while maintaining bone quality in multiple animal models of osteoporosis.
This finding suggests that the production and/or activity of sclerostin can be titrated in vivo, leading to variable increases in bone mass without any unwanted skeletal effects, a hypothesis of obvious significance for the development of new therapeutics for osteoporosis.
In conclusion, by showing a direct correlation between T and sclerostin, both in vivo and in vitro, this study adds further support to the emerging clinical and experimental studies focusing on sclerostin as a therapeutic target for osteoporosis treatment.