Abstract
Denosumab has been shown to increase bone mineral density (BMD) and reduce the fracture risk in patients with post-menopausal osteoporosis (PMO). Increase in BMD is linked with an increase in bone matrix mineralisation due to suppression of bone remodelling. However, denosumab anti-resorptive action also leads to an increase in fatigue microdamage, which may ultimately lead to an increased fracture risk. A novel mechanobiological model of bone remodelling was developed to investigate how these counter-acting mechanisms are affected both by exercise and long-term denosumab treatment. This model incorporates Frost's mechanostat feedback, a bone mineralisation algorithm and an evolution law for microdamage accumulation. Mechanical disuse and microdamage were assumed to stimulate RANKL production, which modulates activation frequency of basic multicellular units in bone remodelling. This mechanical feedback mechanism controls removal of excess bone mass and microdamage. Furthermore, a novel measure of bone local failure due to instantaneous overloading was developed. Numerical simulations indicate that trabecular bone volume fraction and bone matrix damage are determined by the respective bone turnover and homeostatic loading conditions. PMO patients treated with the currently WHO-approved dose of denosumab (60 mg administrated every 6 months) exhibit increased BMD, increased bone ash fraction and damage. In untreated patients, BMD will significantly decrease, as will ash fraction; while damage will increase. The model predicted that, depending on the time elapsed between the onset of PMO and the beginning of treatment, BMD slowly converges to the same steady-state value, while damage is low in patients treated soon after the onset of the disease and high in patients having PMO for a longer period. The simulations show that late treatment PMO patients have a significantly higher risk of local failure compared to patients that are treated soon after the onset of the disease. Furthermore, overloading resulted in an increase of BMD, but also in a faster increase of damage, which may consequently promote the risk of fracture, specially in late treatment scenarios. In case of mechanical disuse, the model predicted reduced BMD gains due to denosumab, while no significant change in damage occurred, thus leading to an increased risk of local failure compared to habitual loading.
Highlights
Denosumab treatment of patients with post-menopausal osteoporosis (PMO) has been shown to increase bone mineral density (BMD) as assessed by dual-energy X-ray absorptiometry (DXA) and it was observed that denosumab reduced the risk of new radiographic vertebral fractures by 68%, with the risk of hip fractures and non-vertebral fractures decreasing by 40 and 20%, respectively (Cummings et al, 2009)
Based on the above described mechanisms observed for action of denosumab treatment of PMO, we have developed a comprehensive model of bone remodelling incorporating the effect of bone mineralisation, microdamage, and mechanobiological feedback
Hernandez et al (2001b) developed a computational model of bone remodelling to compare the contributions of focal bone balance and mineralisation on BMD by simulating alendronate treatment using a bone balance method and a mineralisation method
Summary
Denosumab treatment of patients with post-menopausal osteoporosis (PMO) has been shown to increase bone mineral density (BMD) as assessed by dual-energy X-ray absorptiometry (DXA) and it was observed that denosumab reduced the risk of new radiographic vertebral fractures by 68%, with the risk of hip fractures and non-vertebral fractures decreasing by 40 and 20%, respectively (Cummings et al, 2009). Mineral is removed from the bone matrix by osteoclastic action, which dissolves it, returning it to the bloodstream In this manner, the model predicts that bone sites undergoing high turnover are characterised by a lower BTM (and BMD) based on the fact that continuous remodelling prevents excessive secondary mineralisation. The mechanobiological link between microdamage and remodelling was established via discovery of increased remodelling around apoptotic osteocytes in rat ulnar fatigueloading experiments (Verborgt et al, 2000) In the latter case, inhibition of osteocyte apoptosis prevents the intra-cortical resorption that occurs in response to microcracks (Cardoso et al, 2009), suggesting that osteocyte apoptosis controls osteoclast recruitment to the damaged area. We investigate a variety of treatment scenarios with emphasis on combined effects of mechanical loading (including overuse and disuse) together with denosumab treatment in PMO
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