Adi Cohen, Stavroula Kousteni, Brygida Bisikirska, Jayesh G Shah, J Sanil Manavalan, Robert R Recker, Joan Lappe, David W Dempster, Hua Zhou, Donald J McMahon, Mariana Bucovsky, Mafo Kamanda‐Kosseh, Julie Stubby, Elizabeth Shane

We have previously reported that premenopausal women with idiopathic osteoporosis (IOP) have profound microarchitectural deficiencies and heterogeneous bone remodeling. Those with the lowest bone formation rate have higher baseline serum IGF-1 levels and less robust response to teriparatide. Because IGF-1 stimulates bone formation and is critical for teriparatide action on osteoblasts, these findings suggest a state of IGF-1 resistance in some IOP women. To further investigate the hypothesis that osteoblast and IGF-1 related mechanisms mediate differential responsiveness to teriparatide in IOP, we studied circulating osteoblast progenitor (COP) cells and their IGF-1 receptor (IGF-1R) expression. In premenopausal women with IOP, peripheral blood mononuclear cells (PBMCs) were obtained at baseline (n = 25) and over 24 months of teriparatide treatment (n = 11). Flow cytometry was used to identify and quantify COPs (non-hematopoetic lineage cells expressing osteocalcin and Runx2) and to quantify IGF-1R expression levels. At baseline, both the percent of PBMCs that were COPs (%COP) and COP cell-surface IGF-1R expression correlated directly with several histomorphometric indices of bone formation in tetracycline-labeled transiliac biopsies. In treated subjects, both %COP and IGF-1R expression increased promptly after teriparatide, returning toward baseline by 18 months. While neither baseline %COP nor increase in %COP after three months predicted the BMD response to teriparatide, the percent increase in IGF-1R expression on COPs at 3 months correlated directly with the BMD response to teriparatide. Additionally, lower IGF-1R expression after teriparatide was associated with higher body fat, suggesting links between teriparatide resistance, body composition and the GH/IGF-1 axis. In conclusion, these assays may be useful to characterize bone remodeling noninvasively, and may serve to predict early response to teriparatide, and possibly other bone formation stimulating medications. These new tools may also have utility in the mechanistic investigation of teriparatide resistance in premenopausal IOP, and perhaps in other populations. This article is protected by copyright. All rights reserved.