Oral Presentation ANZBMS-MEPSA-ANZORS 2022

Assessment of strategies for safe drug discontinuation and transition of denosumab treatment in PMO - insights from a mechanistic PK/PD model of bone turnover (#120)

Javier Dr Martinez-Reina 1 , Jose L. Dr Calvo-Gallego 1 , Madge Dr Martin 2 , Peter Dr Pivonka 3
  1. Department of Mechanical Engineering and Manufacturing, University of Seville, Seville, Spain
  2. Multiscale Modeling and Simulation, University of Paris-Est Creteil, Paris, Creteil, France
  3. Queensland University of Technology, Brisbane, QLD, Australia

Denosumab (Dmab) treatment against postmenopausal osteoporosis (PMO) has proven very efficient in increasing bone mineral density (BMD) and reducing the risk of bone fractures1. However, concerns have been recently raised regarding safety when drug treatment is discontinued2. 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 BMD3.

Here, we show 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 discontinuation4. We demonstrate 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.

Furthermore, 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. Also, the final BMD and damage values were not sensitive to the time of administration of the BP.

  1. Cummings S, San Martin J, McClung M, Siris E, Eastell R, Reid I, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361(8):756{65. doi:10.1056/NEJMoa0809493.
  2. Anastasilakis A, Makras P, Yavropoulou M, Tabacco G, Naciu A, Palermo A. Denosumab discontinuation and the rebound phenomenon: A narrative review. J Clin Med 2021, 10(1):152. doi:10.3390/jcm10010152.
  3. Martinez-Reina J., Calvo-Gallego J.L., Pivonka P. Are drug holidays a safe option in treatment of osteoporosis? - Insights from an in silico mechanistic PK-PD model of denosumab treatment of postmenopausal osteoporosis. J Mech Behav Biomed Mater, 2021, 113:104140. doi:10.1016/j.jmbbm.2020.104140.
  4. Martinez-Reina J., Calvo-Gallego J.L., Martin M., Pivonka P. Assessment of strategies for safe drug discontinuation and transition of denosumab treatment in PMO - Insights from a mechanistic PK/PD model of bone turnover, Frontiers in Bioengineering and Biotechnology, 2022. (In Print)