Abstract
Osteonecrosis of the jaw, in association with bisphosphonates (BRONJ) used for treating osteoporosis or cancer, is a severe and most often irreversible side effect whose underlying pathophysiological mechanisms remain largely unknown. Osteocytes are involved in bone remodeling and mineralization where they orchestrate the delicate equilibrium between osteoclast and osteoblast activity and through the active process called osteocytic osteolysis. Here, we hypothesized that (i) changes of the mineralized tissue matrix play a substantial role in the pathogenesis of BRONJ, and (ii) the osteocyte lacunar morphology is altered in BRONJ. Synchrotron µCT with phase contrast is an appropriate tool for assessing both the 3D morphology of the osteocyte lacunae and the bone matrix mass density. Here, we used this technique to investigate the mass density distribution and 3D osteocyte lacunar properties at the sub-micrometer scale in human bone samples from the jaw, femur and tibia. First, we compared healthy human jaw bone to human tibia and femur in order to assess the specific differences and address potential explanations of why the jaw bone is exclusively targeted by the necrosis as a side effect of BP treatment. Second, we investigated the differences between BRONJ and control jaw bone samples to detect potential differences which could aid an improved understanding of the course of BRONJ. We found that the apparent mass density of jaw bone was significantly smaller compared to that of tibia, consistent with a higher bone turnover in the jaw bone. The variance of the lacunar volume distribution was significantly different depending on the anatomical site. The comparison between BRONJ and control jaw specimens revealed no significant increase in mineralization after BP. We found a significant decrease in osteocyte-lacunar density in the BRONJ group compared to the control jaw. Interestingly, the osteocyte-lacunar volume distribution was not altered after BP treatment.
Highlights
Under healthy conditions bone undergoes continuous remodeling to adapt to spatially and temporarily variable demands, through a delicate equilibrium between resorption and formation, which is performed by osteoclast and osteoblast cells, respectively.Bisphosphonates (BP), which are commonly prescribed in the treatment of osteoporosis and bone metastasis, have been shown to reduce significantly the risk of fracture [1,2]
We investigated the differences in lacunar morphology and peri-lacunar tissue properties at the submicrometer length scale in human jaw bone tissue samples obtained from both healthy subjects and patients suffering from bisphosphonate-related osteonecrosis of the jaw (BRONJ)
We hypothesized that (i) the bone turnover of the healthy human jaw bone, assessed by analyzing the mass density distribution, would be increased in comparison to the other anatomical sites and (ii) that extracellular matrix density and lacunar volumes of samples originating from patients suffering from BRONJ would be altered in order to compensate for the mineral homeostasis disturbed by the inhibited osteoclast activity
Summary
Under healthy conditions bone undergoes continuous remodeling to adapt to spatially and temporarily variable demands, through a delicate equilibrium between resorption and formation, which is performed by osteoclast and osteoblast cells, respectively. The LCN has been reported to be essential for micro-crack repair by triggering bone remodeling [32] In addition to their mechanical function, it is hypothesized that osteocytes regulate mineral metabolism, e.g. bone phosphate metabolism [33,34]. We hypothesized that (i) the bone turnover of the healthy human jaw bone, assessed by analyzing the mass density distribution, would be increased in comparison to the other anatomical sites and (ii) that extracellular matrix density and lacunar volumes of samples originating from patients suffering from BRONJ would be altered in order to compensate for the mineral homeostasis disturbed by the inhibited osteoclast activity. We reported and compared the osteocyte lacunae volume distribution and the spatial arrangement of lacunae, as well as descriptors for the mass density distribution of the perilacunar tissue
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