Study of the bisphosphonates impact on the chemical and physical conditions of human jaw bone by means of SR at ID21

Orateur : Bernhard HESSE (ESRF)

Under healthy conditions bone tissue is consistently remodeled, which enables both, tissue repair and optimal adaptation of the organ architecture to the governing loading condition. Osteocytes are involved in bone remodeling and mineralization by orchestrating the delicate equilibrium between bone resorption and formation by osteoclasts and osteoblasts, respectively. Osteocytes encapsulated in the mineralized tissue matrix during the formation of the osteons are connected to adjacent cells and the vasculature through a complex canalicular network. Bisphosphonates (BPs) are powerful drugs that reduce remodeling through inhibition of osteoclast activity. However, it is known that BP has a dose-dependent cytotoxicity and prolonged exposure to high BP doses may induce a necrosis. Osteonecrosis of the jaw in association with bisphosphonates (BRONJ) is a serious and most often irreversible side effect of BP treatment. The underlying pathophysiological mechanisms are still poorly understood and there are no satisfactory treatment options for patients suffering from BRONJ or evidence based recommendations to prevent the disease. In previous experiments using phase-nano CT we could report alterations of the osteocyte network and alterations of the mass density adjacent to the cell-network after BP treatment. Moreover, distinct differences in mass density and lacunar volume distributions between jaw bones and bones from the peripheral skeleton support the hypothesis that higher concentrations of BP-loaded mineral can be deposited in the jaw, not only in the extracellular organic matrix, but also in empty pores. To date, the deposition/release mechanisms of BP in bone are not well understood, except that BP has a high chemical affinity to hydroxyapatite (HA) and that the latter can be dissolved by decreasing the pH level. Therefore, the biological action has been suggested to be tightly linked to the concentration of unbound BP and hence, to the precipitation/dissolution kinetics of BP-loaded mineral from extracellular matrix surfaces and micro-pores. Different precipitation/dissolution kinetics of BP-HA from the organic matrix and collagen-free pores may therefore be key factors for the development of a necrosis. To test this hypothesis and further investigate BP impact on the chemical and physical conditions of human bone I propose to investigate the chemical properties of different bones constituents (extracellular organic matrix, BP-HA filled pores) by means of XANES, FTIR and XRF. Additionally, I expect to correlate the finding that will be obtained at ID21 with 3D structural information previously obtained at ID19 and ID22 and to mechanical properties that we could assess through acoustic microscopy.

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