The relationship between baseline BMD and fracture incidence in the placebo groups of RCTs using individual patient data from the FNIH-ASBMR-SABRE Project

Marian Schini; Li-Yung Lui; Tatiane Vilaca; Susan K Ewing; Austin Thompson; Douglas C Bauer; Mary L Bouxsein; Dennis M Black; Richard Eastell

doi:10.1093/jbmr/zjae201

The relationship between baseline BMD and fracture incidence in the placebo groups of RCTs using individual patient data from the FNIH-ASBMR-SABRE Project

J Bone Miner Res. 2024 Dec 16:zjae201. doi: 10.1093/jbmr/zjae201. Online ahead of print.

Authors

Marian Schini¹, Li-Yung Lui², Tatiane Vilaca¹, Susan K Ewing³, Austin Thompson³, Douglas C Bauer^{3

4}, Mary L Bouxsein⁵, Dennis M Black³, Richard Eastell¹

Affiliations

¹ Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, United Kingdom.
² Research Institute, California Pacific Medical Center, San Francisco, CA, United States.
³ Department of Epidemiology & Biostatistics, University of California, San Francisco, CA, United States.
⁴ Department of Medicine, University of California, San Francisco, CA, United States.
⁵ Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center and Department of Orthopedic Surgery, Harvard Medical School, Boston, MA, United States.

PMID: 39680674
DOI: 10.1093/jbmr/zjae201

Abstract

We have proposed to the Food and Drug Administration (FDA) that treatment-related increases in total hip bone mineral density (TH BMD) at two years could be a surrogate endpoint for fracture risk reduction in clinical trials. The qualification of a surrogate includes a strong association of the surrogate with the clinical outcome. We compiled a large database of individual patient data (IPD) through the FNIH-ASBMR-SABRE project, and this analysis aimed to assess the relationship between baseline BMD and fracture risk in the placebo groups. We estimated the association of baseline TH, femoral neck (FN) and lumbar spine (LS) BMD with fracture risk using IPD from the combined placebo groups which included data from 46 666 placebo participants in 25 randomised controlled trials (RCTs). We estimated the relative risk (RR) of fracture per standard deviation (SD) decrease in baseline BMD using logistic regression models for radiographic vertebral fractures and proportional hazards models for hip, non-vertebral, "all" and "all clinical" fractures. Total person-years in the combined placebo groups was 250 662 (mean baseline age 70.2 ± 7.2 years, mean TH BMD T-score -1.97 ± 0.90). We observed significant relationships between baseline TH BMD and vertebral (RR = 1.55/SD), hip (RR = 2.27), non-vertebral (RR = 1.31), all (RR = 1.43) and all clinical (RR = 1.35) fracture risk. Fracture risk estimates were similar for FN BMD and after adjustment for age, race and study. Fracture incidence increased with decreasing TH BMD quintile, confirming the strong graded association between TH BMD and fracture risk. There was a strong relationship between LS BMD and vertebral fracture risk (RR = 1.56/SD), but only a weak association with non-vertebral (RR = 1.07) and no association with hip (RR = 1.01) fracture risk. These data support the very strong relationship between hip BMD and fracture risk and provide supporting rationale for change in TH BMD as a surrogate for fracture risk reduction in future RCTs.

Keywords: Analysis/quantitation of bone; Clinical trials; Diseases and disorders of/related to bone; Dxa; Epidemiology; Fracture risk assessment; General population studies; Osteoporosis; Practice/policy-related issues.

Plain language summary

Bone mineral density (BMD) is the standard of care for the diagnosis of osteoporosis. In this study, we analysed data from more than 40 000 placebo participants in 25 randomised controlled trials of medications used for osteoporosis. We showed that there is a strong relationship between low total hip BMD and high risk of fractures.