Altered mechanosensitivity can explain the substantially increased bone mass in hypoparathyroidism

摘要

Hypoparathyroidism (HypoPTH) is characterized by low or absent parathyroid hormone (PTH). It is mainly associated with a drastic suppression of bone turnover by around 80% (Rubin et al., 2008) and a substantial increase in bone mass in the range of 10-32%(Rubin et al., 2008; Abugassa et al., 1993).It is known that PTH can affect bone cells, but how it would lead to such a high net formation in HypoPTH is unclear. In hyperparathyroidism studies it was found that elevated PTH up regulates RANK production in osteoblasts causing increased bone resorption via binding to RANKL expressed on osteoclasts. This suggests that during HypoPTH, RANK would be down regulated thus reducing turnover, which is in agreement with clinical measurements (Rubin et al., 2008). As a result of this reduced turnover, an increase inbone mass would be expected due to filling of the resorption space. However, given that the resorption space accounts only for approx. 5% of the total volume, this effect cannot fully explain the substantial gain in bone mass during HypoPTHAs an additional effect of PTH on bone cells, we hypothesize that the sensitivity of the cells to mechanical loading is altered, as already proposed by Frost (Frost, 1987). Support for this hypothesis came later from experiments in which it was shown that osteoblast-like cells are more sensitive to mechanical stimulation in vitro (Ryder and Duncan, 2000; Carvalho et al, 1994) and in vivo (Chow et al., 1998) when PTH is added.To investigate if this hypothesis can explain the marked increase in bone mass seen with HypoPTH, we simulated the proposed effects of HypoPTH using a well established computer model for the simulation of bone remodeling. Simulations were performed formodels representing bone biopsies obtained from the iliac of HypoPTH patients at different time points and compared to experimental data.