Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs: A Meta-Regression

Douglas C. Bauer, Dennis M. Black, Mary L. Bouxsein, Li Yung Lui, Jane A. Cauley, Anne E. de Papp, Andreas Grauer, Sundeep Khosla, Charles E. Mcculloch, Richard Eastell

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Few pooled analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction. 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 28,000 participants enrolled in 11 bisphosphonate (BP) and three 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 two bone resorption markers (N-terminal and C-terminal telopeptide of type I collagen) and incident fracture outcome data, we performed a meta-regression relating the mean net effect of treatment on change in bone turnover (active minus placebo % difference after 3 to 12 months) to the log of study-wide fracture risk reduction, and used linear regression to plot the best fitting line. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 4 years of follow-up. Change in bone ALP and PINP were available for over 16,000 and 10,000 participants, respectively. For vertebral fracture, the results showed a strong relationship between treatment-related bone ALP or PINP changes and vertebral fracture risk reduction (r2=0.82 [p<0.001] and r2=0.75 [p=0.011], respectively) Relationships were weaker and no longer statistically significant for nonvertebral (r2=0.33 [p=0.053] and r2=0.53 [p=0.065], respectively) and hip fracture (r2=0.17 [p=0.24] and r2=0.43 [p=0.11], respectively) outcomes. Analyses limited to BP trials gave similar results. For all fracture types, relationships were weaker and nonsignificant for bone resorption markers. We conclude that short-term AR treatment-related changes in bone ALP and PINP strongly predict vertebral fracture treatment efficacy, but not nonvertebral or hip fracture treatment efficacy. Change in bone formation markers might be useful to predict the anti-vertebral fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Fracture Fixation
Bone Remodeling
Bone Fractures
Risk Reduction Behavior
Clinical Trials
Alkaline Phosphatase
Hip Fractures
Bone and Bones
Pharmaceutical Preparations
Diphosphonates
Bone Resorption
Osteogenesis
Placebos
Bone Density Conservation Agents
Selective Estrogen Receptor Modulators
Therapeutics
National Institutes of Health (U.S.)
Linear Models
N-propeptide type I collagen

Keywords

  • BIOCHEMICAL MARKERS OF BONE TURNOVER
  • BONE MODELING AND REMODELING
  • DISEASES AND DISORDERS OF/RELATED TO BONE
  • EPIDEMIOLOGY
  • OSTEOPOROSIS

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs : A Meta-Regression. / Bauer, Douglas C.; Black, Dennis M.; Bouxsein, Mary L.; Lui, Li Yung; Cauley, Jane A.; de Papp, Anne E.; Grauer, Andreas; Khosla, Sundeep; Mcculloch, Charles E.; Eastell, Richard.

In: Journal of Bone and Mineral Research, 01.01.2018.

Research output: Contribution to journalArticle

Bauer, Douglas C. ; Black, Dennis M. ; Bouxsein, Mary L. ; Lui, Li Yung ; Cauley, Jane A. ; de Papp, Anne E. ; Grauer, Andreas ; Khosla, Sundeep ; Mcculloch, Charles E. ; Eastell, Richard. / Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs : A Meta-Regression. In: Journal of Bone and Mineral Research. 2018.
@article{424121d9a4284256bc00bc40d5945a5a,
title = "Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs: A Meta-Regression",
abstract = "Few pooled analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction. 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 28,000 participants enrolled in 11 bisphosphonate (BP) and three 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 two bone resorption markers (N-terminal and C-terminal telopeptide of type I collagen) and incident fracture outcome data, we performed a meta-regression relating the mean net effect of treatment on change in bone turnover (active minus placebo {\%} difference after 3 to 12 months) to the log of study-wide fracture risk reduction, and used linear regression to plot the best fitting line. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 4 years of follow-up. Change in bone ALP and PINP were available for over 16,000 and 10,000 participants, respectively. For vertebral fracture, the results showed a strong relationship between treatment-related bone ALP or PINP changes and vertebral fracture risk reduction (r2=0.82 [p<0.001] and r2=0.75 [p=0.011], respectively) Relationships were weaker and no longer statistically significant for nonvertebral (r2=0.33 [p=0.053] and r2=0.53 [p=0.065], respectively) and hip fracture (r2=0.17 [p=0.24] and r2=0.43 [p=0.11], respectively) outcomes. Analyses limited to BP trials gave similar results. For all fracture types, relationships were weaker and nonsignificant for bone resorption markers. We conclude that short-term AR treatment-related changes in bone ALP and PINP strongly predict vertebral fracture treatment efficacy, but not nonvertebral or hip fracture treatment efficacy. Change in bone formation markers might be useful to predict the anti-vertebral 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 = "Bauer, {Douglas C.} and Black, {Dennis M.} and Bouxsein, {Mary L.} and Lui, {Li Yung} and Cauley, {Jane A.} and {de Papp}, {Anne E.} and Andreas Grauer and Sundeep Khosla and Mcculloch, {Charles E.} and Richard Eastell",
year = "2018",
month = "1",
day = "1",
doi = "10.1002/jbmr.3355",
language = "English (US)",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs

T2 - A Meta-Regression

AU - Bauer, Douglas C.

AU - Black, Dennis M.

AU - Bouxsein, Mary L.

AU - Lui, Li Yung

AU - Cauley, Jane A.

AU - de Papp, Anne E.

AU - Grauer, Andreas

AU - Khosla, Sundeep

AU - Mcculloch, Charles E.

AU - Eastell, Richard

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Few pooled analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction. 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 28,000 participants enrolled in 11 bisphosphonate (BP) and three 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 two bone resorption markers (N-terminal and C-terminal telopeptide of type I collagen) and incident fracture outcome data, we performed a meta-regression relating the mean net effect of treatment on change in bone turnover (active minus placebo % difference after 3 to 12 months) to the log of study-wide fracture risk reduction, and used linear regression to plot the best fitting line. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 4 years of follow-up. Change in bone ALP and PINP were available for over 16,000 and 10,000 participants, respectively. For vertebral fracture, the results showed a strong relationship between treatment-related bone ALP or PINP changes and vertebral fracture risk reduction (r2=0.82 [p<0.001] and r2=0.75 [p=0.011], respectively) Relationships were weaker and no longer statistically significant for nonvertebral (r2=0.33 [p=0.053] and r2=0.53 [p=0.065], respectively) and hip fracture (r2=0.17 [p=0.24] and r2=0.43 [p=0.11], respectively) outcomes. Analyses limited to BP trials gave similar results. For all fracture types, relationships were weaker and nonsignificant for bone resorption markers. We conclude that short-term AR treatment-related changes in bone ALP and PINP strongly predict vertebral fracture treatment efficacy, but not nonvertebral or hip fracture treatment efficacy. Change in bone formation markers might be useful to predict the anti-vertebral fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs.

AB - Few pooled analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction. 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 28,000 participants enrolled in 11 bisphosphonate (BP) and three 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 two bone resorption markers (N-terminal and C-terminal telopeptide of type I collagen) and incident fracture outcome data, we performed a meta-regression relating the mean net effect of treatment on change in bone turnover (active minus placebo % difference after 3 to 12 months) to the log of study-wide fracture risk reduction, and used linear regression to plot the best fitting line. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 4 years of follow-up. Change in bone ALP and PINP were available for over 16,000 and 10,000 participants, respectively. For vertebral fracture, the results showed a strong relationship between treatment-related bone ALP or PINP changes and vertebral fracture risk reduction (r2=0.82 [p<0.001] and r2=0.75 [p=0.011], respectively) Relationships were weaker and no longer statistically significant for nonvertebral (r2=0.33 [p=0.053] and r2=0.53 [p=0.065], respectively) and hip fracture (r2=0.17 [p=0.24] and r2=0.43 [p=0.11], respectively) outcomes. Analyses limited to BP trials gave similar results. For all fracture types, relationships were weaker and nonsignificant for bone resorption markers. We conclude that short-term AR treatment-related changes in bone ALP and PINP strongly predict vertebral fracture treatment efficacy, but not nonvertebral or hip fracture treatment efficacy. Change in bone formation markers might be useful to predict the anti-vertebral fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs.

KW - BIOCHEMICAL MARKERS OF BONE TURNOVER

KW - BONE MODELING AND REMODELING

KW - DISEASES AND DISORDERS OF/RELATED TO BONE

KW - EPIDEMIOLOGY

KW - OSTEOPOROSIS

UR - http://www.scopus.com/inward/record.url?scp=85040179407&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040179407&partnerID=8YFLogxK

U2 - 10.1002/jbmr.3355

DO - 10.1002/jbmr.3355

M3 - Article

C2 - 29318649

AN - SCOPUS:85040179407

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

ER -