title: IGF-1 Receptor Expression on Circulating Osteoblast Progenitor Cells Predicts Tissue-Based Bone Formation Rate and Response to Teriparatide in Premenopausal Women With Idiopathic Osteoporosis.
abstract: 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 insulin-like growth factor-1 (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. Although neither baseline %COP nor increase in %COP after 3 months predicted the bone mineral density (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. © 2017 American Society for Bone and Mineral Research.
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Adi
authors.identifier: http://orcid.org/0000-0002-0641-5747
authors.initials: A
authors.lastname: Cohen
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Kousteni
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Brygida
authors.initials: B
authors.lastname: Bisikirska
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Jayesh G
authors.initials: JG
authors.lastname: Shah
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: J Sanil
authors.initials: JS
authors.lastname: Manavalan
authors.affiliation: Creighton University, Omaha, NE, USA.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Recker
authors.affiliation: Creighton University, Omaha, NE, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Lappe
authors.affiliation: Helen Hayes Hospital, West Haverstraw, NY, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Dempster
authors.affiliation: Helen Hayes Hospital, West Haverstraw, NY, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: McMahon
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Bucovsky
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Mafo
authors.initials: M
authors.lastname: Kamanda-Kosseh
authors.affiliation: Creighton University, Omaha, NE, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Stubby
authors.affiliation: Columbia University, New York, NY, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Shane
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000293:Adolescent; D000328:Adult; D001706:Biopsy; D001823:Body Composition / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008875:Middle Aged; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D010024:Osteoporosis / Q000188:drug therapy* / Q000503:physiopathology*; D017697:Premenopause / Q000187:drug effects / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D019379:Teriparatide / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D019379:Teriparatide; D017526:Receptor, IGF Type 1
keywords: BONE HISTOMORPHOMETRY; DXA; IGF-1; OSTEOBLASTS; PREMENOPAUSAL OSTEOPOROSIS