@article{f9528c17b6be4fd8bda19c906b79a5fa,
title = "Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Antiresorptive Drugs: Proportion of Treatment Effect Explained",
abstract = "Few analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction seeking to estimate the proportion of treatment effect explained (PTE) by BTMs. Pooling such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from up to 62,000 participants enrolled in 12 bisphosphonate (BP) and four selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and one bone resorption marker (C-terminal telopeptide of type I collagen [CTX]) and incident fracture outcome data, we estimated the PTE using two different models. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 5 years of follow-up. For vertebral fracture, the results showed that changes in all three BTMs at 6 months explained a large proportion of the treatment effect of ARs (57 to >100%), but not for and non-vertebral or hip fracture. We conclude that short-term AR treatment-related changes in bone ALP, PINP, and CTX account for a large proportion of the treatment effect for vertebral fracture. Change in BTMs is a useful surrogate marker to study the anti-fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs.",
keywords = "BIOCHEMICAL MARKERS OF BONE TURNOVER, BONE MODELING AND REMODELING, DISEASES AND DISORDERS OF/RELATED TO BONE, EPIDEMIOLOGY, OSTEOPOROSIS",
author = "{for the Foundation for the National Institutes of Health (FNIH) Bone Quality Project} and Richard Eastell and Black, {Dennis M.} and Lui, {Li Yung} and Arkadi Chines and Fernando Marin and Sundeep Khosla and {de Papp}, {Anne E.} and Cauley, {Jane A.} and Bruce Mitlak and McCulloch, {Charles E.} and Eric Vittinghoff and Bauer, {Douglas C.}",
note = "Funding Information: Scientific and financial support for the FNIH Bone Quality Project are made possible through direct contributions to FNIH by AgNovos Healthcare, American Society for Bone and Mineral Research, Amgen Inc., Daiichi Sankyo, Inc., Dairy Research Institute, Eli Lilly and Company, Merck Sharp & Dohme Corp., Inc., and Roche Diagnostics Corporation. In‐kind data to support the project was provided by Actavis, Amgen Inc., Bayer Schering Pharma Oy, Eli Lilly and Company, GlaxoSmithKline, Merck Sharp & Dohme Corp., National Institute of Arthritis and Musculoskeletal and Skin Diseases & National Heart, Lung, and Blood Institute, Novartis, Pfizer, Inc., Roche Diagnostics Corporation, and Sermonix. The authors acknowledge Lucy Wu, MPH (UCSF), for her assistance throughout the project and in preparation of the manuscript, and Lisa Palermo, MS (UCSF), for her work in programming and managing compilation harmonization of received data. Funding Information: RE reports grants from Amgen, grants and personal fees from Immunodiagnostic Systems, grants from Alexion, grants and personal fees from Roche, personal fees from Eli Lilly, personal fees from GSK Nutrition, personal fees from Mereo, personal fees from Sandoz, grants and personal fees from Nittobo, personal fees from AbbVie, personal fees from Samsung, personal fees from Haoma Medica, personal fees from Elsevier, personal fees from CL Bio, personal fees from FNIH, and personal fees from Viking outside the submitted work. DMB reports personal fees from Merck, personal fees from Amgen, personal fees from Asahi‐Kasei, and personal fees from Effx during the conduct of the study; personal fees from Eli Lilly and personal fees from University of Pittsburgh outside the submitted work. L‐YL has nothing to disclose. AC reports being an Amgen Inc. employee during the time of data collection and analysis. FM reports personal fees from Eli Lilly and Company outside the submitted work. SK has nothing to disclose. AEdP is a full‐time employee and stock holder in Merck & Co. Inc., Kenilworth, NJ. JAC has nothing to disclose. BM is an employee and shareholder of Radius Health and a retiree and shareholder of Eli Lilly and Company. CEM has received grant support from Foundation for the NIH during the conduct of the study. EV reports salary support from FNIH during the conduct of the study. DCB has nothing to disclose. Funding Information: Scientific and financial support for the FNIH Bone Quality Project are made possible through direct contributions to FNIH by AgNovos Healthcare, American Society for Bone and Mineral Research, Amgen Inc., Daiichi Sankyo, Inc., Dairy Research Institute, Eli Lilly and Company, Merck Sharp & Dohme Corp., Inc., and Roche Diagnostics Corporation. In-kind data to support the project was provided by Actavis, Amgen Inc., Bayer Schering Pharma Oy, Eli Lilly and Company, GlaxoSmithKline, Merck Sharp & Dohme Corp., National Institute of Arthritis and Musculoskeletal and Skin Diseases & National Heart, Lung, and Blood Institute, Novartis, Pfizer, Inc., Roche Diagnostics Corporation, and Sermonix. The authors acknowledge Lucy Wu, MPH (UCSF), for her assistance throughout the project and in preparation of the manuscript, and Lisa Palermo, MS (UCSF), for her work in programming and managing compilation harmonization of received data. All study data were acquired by requesting individual patient data from study sponsors. An overarching data use agreement was created between all parties and individual data use agreements were created between individual study sponsors, FNIH, and UCSF. Per the data sharing agreements that we have with each sponsor, the data can be used for surrogate marker analyses including any surrogate qualification processes with regulatory authorities. However, other uses of the data are restricted by this agreement and UCSF is not allowed to share the data. Authors' roles: RE: study design, drafting, interpretation and revision of manuscript, review of manuscript. DMB: study design, data compilation, drafting, interpretation and revision of manuscript, review of manuscript. L-YL: statistical analysis and interpretation, creation of figures and tables, and revision and review of manuscript. AC, FM, SK, AEdP, JAC, and BM: revision and review of manuscript. CEM: statistical analysis and interpretation and review of manuscript. EV: statistical analysis and interpretation, creation of figures, and revision of manuscript. DCB: study design, drafting, interpretation and revision of manuscript, and review of manuscript. Publisher Copyright: {\textcopyright} 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research",
year = "2021",
month = feb,
doi = "10.1002/jbmr.4178",
language = "English (US)",
volume = "36",
pages = "236--243",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "2",
}