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In premenopausal women with idiopathic osteoporosis, lower bone formation rate is associated with higher body fat and higher IGF-1

Abstract

Summary

We examined serum IGF-1 in premenopausal IOP, finding relationships that were opposite to those expected: higher IGF-1 was associated with lower bone formation and higher body fat, and lower BMD response to teriparatide. These paradoxical relationships between serum IGF-1, bone, and fat may contribute to the mechanism of idiopathic osteoporosis in premenopausal women.

Introduction

Premenopausal women with idiopathic osteoporosis (IOP) have marked deficits in bone microarchitecture but variable bone remodeling. We previously reported that those with low tissue-level bone formation rate (BFR) are less responsive to teriparatide and have higher serum IGF-1, a hormone anabolic for osteoblasts and other tissues. The IGF-1 data were unexpected because IGF-1 is low in other forms of low turnover osteoporosis—leading us to hypothesize that IGF-1 relationships are paradoxical in IOP. This study aimed to determine whether IOP women with low BFR have higher IGF-1 and paradoxical IGF-1 relationships in skeletal and non-skeletal tissues, and whether IGF-1 and the related measures predict teriparatide response.

Methods

This research is an ancillary study to a 24 month clinical trial of teriparatide for IOP. Baseline assessments were related to trial outcomes: BMD, bone remodeling. Subjects: Premenopausal women with IOP(n = 34); bone remodeling status was defined by baseline cancellous BFR/BS on bone biopsy. Measures: Serum IGF-1 parameters, compartmental adiposity (DXA, CT, MRI), serum hormones, and cardiovascular-risk-markers related to fat distribution.

Results

As seen in other populations, lower BFR was associated with higher body fat and poorer teriparatide response. However, in contrast to observations in other populations, low BFR, higher body fat, and poorer teriparatide response were all related to higher IGF-1: IGF-1 Z-score was inversely related to BFR at all bone surfaces (r =  − 0.39 to − 0.46; p < 0.05), directly related to central fat (p = 0.05) and leptin (p = 0.03). IGF-1 inversely related to 24 month hip BMD %change (r =  − 0.46; p = 0.01).

Conclusions

Paradoxical IGF-1 relationships suggest that abnormal or atypical regulation of bone and fat may contribute to osteoporosis mechanisms in premenopausal IOP.

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Data availability

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Code availability

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Funding

The study was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R03 AR064016), the United States Food and Drug Administration (FDA) Orphan Products Clinical Trials Grants Program (R01 FD003902), the National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK26687), the Simon-Strauss Foundation, and the Thomas L. Kempner, Jr. and Katheryn C. Patterson Foundation. Eli Lilly, USA, supplied teriparatide and identical placebo.

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Corresponding author

Correspondence to A. Cohen.

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Ethics approval

Institutional Review Boards at both Columbia University, New York, NY and Creighton University, Omaha, NE approved the parent and ancillary studies.

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All participants provided their written informed consent.

Conflict of interest

AC, ES, RRR, and JML receive research support from Amgen and Eli Lilly. DWD receives research support and consulting fees from Amgen, Eli Lilly, and Radius Health.

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Supplementary Information

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198_2021_6196_MOESM1_ESM.docx

Supplemental Table: Comparison of GH and IGF-1, and non-skeletal measures of IGF-1 action (fat distribution and cardiovascular risk markers) between subjects with Low vs. High BFR on biopsy (median (IQR)). Groups are compared via Mann-Whitney U (Wilcoxan Rank Sum) Test

Supplementary file1 (DOCX 17 KB)

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Goetz, T., Nair, N., Shiau, S. et al. In premenopausal women with idiopathic osteoporosis, lower bone formation rate is associated with higher body fat and higher IGF-1. Osteoporos Int (2021). https://doi.org/10.1007/s00198-021-06196-8

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Keywords

  • Body composition
  • Bone biopsy
  • Bone turnover markers
  • Marrow adiposity
  • Premenopausal osteoporosis
  • Teriparatide