ORCID Profile
0000-0002-3407-1582
Current Organisation
Universidad de Sevilla
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Publisher: Wiley
Date: 09-12-2021
DOI: 10.1002/CNM.3419
Publisher: Frontiers Media SA
Date: 17-06-2022
DOI: 10.3389/FBIOE.2022.886579
Abstract: Denosumab (Dmab) treatment against postmenopausal osteoporosis (PMO) has proven very efficient in increasing bone mineral density (BMD) and reducing the risk of bone fractures. However, concerns have been recently raised regarding safety when drug treatment is discontinued. Mechanistic pharmacokinetic-pharmacodynamic (PK-PD) models are the most sophisticated tools to develop patient specific drug treatments of PMO to restore bone mass. However, only a few PK-PD models have addressed the effect of Dmab drug holidays on changes in BMD. We showed that using a standard bone cell population model (BCPM) of bone remodelling it is not possible to account for the spike in osteoclast numbers observed after Dmab discontinuation. We show that inclusion of a variable osteoclast precursor pool in BCPMs is essential to predict the experimentally observed rapid rise in osteoclast numbers and the associated increases in bone resorption. This new model also showed that Dmab withdrawal leads to a rapid increase of damage in the bone matrix, which in turn decreases the local safety factor for fatigue failure. Our simulation results show that changes in BMD strongly depend on Dmab concentration in the central compartment. Consequently, bone weight (BW) might play an important factor in calculating effective Dmab doses. The currently clinically prescribed constant Dmab dose of 60 mg injected every 6 months is less effective in increasing BMD for patients with high BW (2.5% for 80 kg in contrast to 8% for 60 kg after 6 years of treatment). However, bone loss observed 24 months after Dmab withdrawal is less pronounced in patients with high BW (3.5% for 80kg and 8.5% for 60 kg). Finally, we studied how to safely discontinue Dmab treatment by exploring several transitional and combined drug treatment strategies. Our simulation results indicate that using transitional reduced Dmab doses are not effective in reducing rapid bone loss. However, we identify that use of a bisphosphonate (BP) is highly effective in avoiding rapid bone loss and increase in bone tissue damage compared to abrupt withdrawal of Dmab. Furthermore, the final values of BMD and damage were not sensitive to the time of administration of the BP.
Publisher: Elsevier BV
Date: 2021
Publisher: Frontiers Media SA
Date: 17-08-2022
DOI: 10.3389/FBIOE.2022.940620
Abstract: Alendronate is the most widely used drug for postmenopausal osteoporosis (PMO). It inhibits bone resorption, affecting osteoclasts. Pharmacokinetics (PK) and pharmacodynamics (PD) of alendronate have been widely studied, but few mathematical models exist to simulate its effect. In this work, we have developed a PK model for alendronate, valid for short- and long-term treatments, and a mechanistic PK-PD model for the treatment of PMO to predict bone density gain (BDG) at the hip and lumbar spine. According to our results, at least three compartments are required in the PK model to predict the effect of alendronate in both the short and long terms. Clinical data of a 2-year treatment of alendronate, reproduced by our PK-PD model, demonstrate that bone response is site specific (hip: 7% BDG, lumbar spine: 4% BDG). We identified that this BDG is mainly due to an increase in tissue mineralization and a decrease in porosity. The difference in BDG between sites is linked to the different loading and dependence of the released alendronate on the bone-specific surface and porosity. Osteoclast population diminishes quickly within the first month of alendronate treatment. Osteoblast population lags behind but also falls due to coupling of resorption and formation. Two dosing regimens were studied (70 mg weekly and 10 mg daily), and both showed very similar BDG evolution, indicating that alendronate accumulates quickly in bone and saturates. The proposed PK-PD model could provide a valuable tool to analyze the effect of alendronate and to design patient-specific treatments, including drug combinations.
Publisher: Frontiers Media SA
Date: 04-06-2021
DOI: 10.3389/FBIOE.2021.635056
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.
No related grants have been discovered for Jose Luis Calvo Gallego.