Optimisation of romosozumab plus denosumab sequential treatments against postmenopausal osteoporosis. Insights from in silico simulations.

Drug treatments against osteoporosis are commonly divided into anti-catabolic and anabolic. Anti-catabolic drugs reduce bone turnover and increase bone mass mainly through mineralization of the existing bone matrix. Anabolic drugs, on the other hand, enhance osteoblastic activity, resulting in new bone formation. Treatments are often limited to a few years due to reported side effects, which increases fracture risk upon discontinuation. Switching to a different drug is a common strategy. However, it is not clear what is the best combination of a dual-drug therapy, the lapse between treatments and other parameters defining the combination. In this study, we conducted in silico trials to assess the efficacy of two drugs: denosumab (anti-catabolic) and romosozumab (anabolic and anti-catabolic). Our simulations indicate that starting treatment with romosozumab leads to greater bone mass gain. This is because anti-catabolic treatments reduce bone rate and, due to osteoblast-osteoclast coupling, the number of osteoblast precursors. Romosozumab increases the proliferation of these precursors, so their population should be maximised for optimal efficacy. Therefore, prior administration of an anti-catabolic drug may be counterproductive to the effectiveness of romosozumab. We also found that a rest period between treatments does not benefit bone mass gain. Furthermore, concurrent administration of romosozumab and denosumab results in greater bone mass gain and might be worth investigating in future clinical trials. Finally, we showed that reduction of fracture risk in patients undergoing sequential treatments is dose dependent and consequently, dosage could be optimised in a patient-specific manner.