Le modificazini dei regolatori di WNT in corso di diverse terapie osteometaboliche

Osteoblast differentiation is predominantly regulated by the WNT/b-catenin signaling (canonical WNT pathway), which acts as the master regulator of osteogenesis together with bone morphogenetic proteins. WNT pathway can also reduce osteoclastogenesis and bone resorption by promoting the osteoblast expression of osteoprotegerin. The regulation of canonical WNT pathway in bone is driven by the production of receptor inhibitors such as Sclerostin and Dickkopf-related protein 1 (DKK1). Bone active agents used for the treatment of postmenopausal and male osteoporosis include a number of inhibitors of bone resorption and a unique anabolic agent, recombinant human PTH (1–34) (teriparatide). Some of their effects on bone turnover seem to be related with changes in WNT/b-catenin signaling . Objective of this thesis was to determine whether treatment with different bone active agents is associated with relevant changes of serum levels of either sclerostin or DKK1. The results of these studies are: - Long-term treatment with teriparatide is associated with an increase in serum levels of DKK1 that might be associated with the appearance of declining effect on bone formation markers. - Decreased bone formation after several months of continuous bisphosphonate therapy (neridronic and clodronic acid administered weekly intramuscularly) is associated with increased serum levels of sclerostin. - Intermittent bisphosphonate therapy (zoledronate yearly) is associated with no change in sclerostin levels but with a significant and quick increase in DKK1 that seem to disappear within 12 months - The changes in bone turnover markers associated with Denosumab treatment of postmenopausal osteoporosis are associated with significant increase in sclerostin similar to those seen after long term treatment with continuous bisphosphonates, and with significant decrease in DKK1. This latter observation might explain the continuous increase over 5 years in BMD observed during treatment with Denosumab. These results show that WNT/b-catenin pathway is strongly involved in the bone turnover changes induced by bone active agents and may provide a possible explanation for the observed different duration of the therapeutic window for teriparatide, denosumab and bisphosphonates.