LA RISPOSTA DI ADATTAMENTO DEI SISTEMI DI CONTROLLO DEL REMODELING OSSEO A DIVERSE INTENSITA’ DI SOPPRESSIONE DELL’ATTIVITA’ OSTEOCLASTICA

INTRODUCTION: Sclerostin and the pathway Wnt/DKK-1 are key regulators of bone remodelling, in particular they are secreted by the osteocytes and they are able to influence the activity of osteoclasts and osteoblasts. Moreover recent studies have demonstrated the ability of bisphosphonates to modulate the serum levels of sclerostin in a dose dependent manner. AIM OF THE STUDY: to evaluate the effect of different doses and different administration schedule of zoledronic acid, a nitrogen containing bisphosphonate, on serum levels of sclerostin and DKK-1. MATERIALS AND METHODS: We have analysed two groups of women: the AI Group (25 women with breast cancer without bone metastases) and the AI+META Group (25 women with breast cancer with bone metastases). The first group has been treated with zoledronic acid 4 mg once a year for the treatment of osteoporosis whereas the second one has been treated with zoledronic acid 4 mg monthly for the prevention of skeletal related events. Blood samples for the analysis of CTX, DKK-1 and sclerostin serum levels were collected before the first infusion and at 28 days, 3,6 and 12 months after the first infusion. RESULTS: At basal there were no difference between the two groups in CTX, DKK-1 and sclerostin serum levels. 28 days after treatment we observed in both groups a significant decrease in CTX serum levels reaching the same nadir. Then in the AI+META group the inhibitions of bone turnover was stable throughout the study whereas in the AI group CTX serum levels began to raise at 3 months with a significant increase (+30%) at 6 and 12 months. In the AI group slcerostin serum levels were stable throughout the study with only a transient but not significant increase at 3 months. In the AI+META Group we observed a stable increase in sclerostin serum levels which became significant at 6 months with a percent increase of 30% at 12 months (p=0,03). Sclerostin serum levels were significantly different between the two groups at 6 months (AI+META 28,41±6,71 pmol/L vs AI 23,81±6,69 pmol/L, p=0,03) and the difference remains stable at 12 months (p=0,03). We have not observed any significant variation in DKK1 serum levels within or between the two groups. CONCLUSIONS: the persistent inhibition of bone turnover due to the high doses of zoledronic acid causes an uncoupling between bone resorption and bone formation. Osteocytes react to this uncoupling secreting sclerostin trying to counterbalance the osteoclastic inhibition and to normalize the bone remodelling process.