Treatment‐related changes in bone turnover and fracture risk reduction in clinical trials of antiresorptive drugs:​ proportion of treatment effect explained

Eastell, Richard<sup>1</sup>; Black, Dennis M.<sup>2</sup>; Lui, Li‐Yung<sup>3</sup>; Chines, Arkadi<sup>4</sup>; Marin, Fernando<sup>5</sup>; Khosla, Sundeep<sup>6</sup>; de Papp, Anne E.<sup>7</sup>; Cauley, Jane A.<sup>8</sup>; Mitlak, Bruce<sup>9</sup>; McCulloch, Charles E.<sup>2</sup>; Vittinghoff, Eric<sup>2</sup>; Bauer, Douglas C.<sup>2,10</sup>

Affiliations

¹Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK

²Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA

³California Pacific Medical Center, San Francisco, CA, USA

⁴Amgen Inc., Thousand Oaks, CA, USA

⁵Eli Lilly and Company, Lilly Research Centre, Windlesham, UK

⁶Mayo Clinic College of Medicine, Rochester, MN, USA

⁷Merck & Co., Inc., Kenilworth, NJ, USA

⁸Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

⁹Radius Health, Waltham, MA, USA

¹⁰Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

Abstract and keywords

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

Links

DOI: 10.1002/jbmr.4178

PubMed: 32916023

WoS: 000574217000001

History

Received: 2019-12-23

Revised: 2020-08-14

Accepted: 2020-09-3

Online: 2020-10-2

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