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Clinical trials are an essential tool for evaluating new treatments and may provide further mechanistic understanding of their effects in vivo. However, the histomorphometry from clinical trials is limited to 2D images and reflects single time points. Biochemical markers of bone turnover give global insight into a drug's action, but not the local dynamics of the bone remodeling process and the cells involved. Additionally, comparative trials necessitate separate treatment groups, meaning only aggregated measures can be compared. In this study, in silico modeling based on histomorphometry and pharmacokinetic data was used to assess the effects of treatment versus control on \u03bcCT scans of the same biopsy samples over time, matching the changes in bone volume fraction observed in biopsies from denosumab and placebo groups through year 10 of the FREEDOM Extension trial. In the simulation, treatment decreased osteoclast number, which led to a modest increase in trabecular thickness and osteocyte stress shielding. Long\u2010term bone turnover suppression led to increased RANKL production, followed by a small increase in osteoclast number at the end of the 6\u2010month\u2013dosing interval, especially at the end of the Extension study. Lack of treatment led to a significant loss of bone mass and structure. The study's results show how in silico models can generate predictions of denosumab cellular action over a 10\u2010year period, matching static and dynamic morphometric measures assessed in clinical biopsies. The use of in silico models with clinical trial data can be a method to gain further insight into fundamental bone biology and how treatments can perturb this. With rigorous validation, such models could be used for informing the design of clinical trials, such that the number of participants could be reduced to a minimum to show efficacy. \u00a9 2021 The Authors. <jats:italic>JBMR Plus<\/jats:italic> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.<\/jats:p>","DOI":"10.1002\/jbm4.10494","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T18:02:39Z","timestamp":1616608959000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Ten\u2010Year Simulation of the Effects of Denosumab on Bone Remodeling in Human Biopsies"],"prefix":"10.1093","volume":"5","author":[{"given":"Duncan C","family":"Tourolle","sequence":"first","affiliation":[{"name":"Institute for Biomechanics ETH Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2262-4039","authenticated-orcid":false,"given":"David W","family":"Dempster","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology College of Physicians and Surgeons of Columbia University  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0344-1608","authenticated-orcid":false,"given":"Charles","family":"Ledoux","sequence":"additional","affiliation":[{"name":"Institute for Biomechanics ETH Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8411-7465","authenticated-orcid":false,"given":"Daniele","family":"Boaretti","sequence":"additional","affiliation":[{"name":"Institute for Biomechanics ETH Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio","family":"Aguilera","sequence":"additional","affiliation":[{"name":"Amgen Inc  Mexico City Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Najma","family":"Saleem","sequence":"additional","affiliation":[{"name":"Amgen Inc  Thousand Oaks CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5811-7725","authenticated-orcid":false,"given":"Ralph","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institute for Biomechanics ETH Zurich  Zurich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,4,5]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"International Osteoporosis Foundation. 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