MON-739 Overexpression of Preosteoclast-Derived PDGF-BB Prevents Glucocorticoid-Induced Osteoporosis in Young Mice in a Sex-Specific Manner

Abstract Disclosure: E. Zhang: None. S. Barik: None. A. Otte: None. J.L. Crane: Ultragenyx. Glucocorticoid-induced osteoporosis (GIO) is the leading cause of secondary osteoporosis, affecting 30-50% of people taking chronic glucocorticoids (GC). We have previously demonstrated that GIO in young mice is partially due to reduced platelet-derived growth factor-BB (PDGF-BB) secretion by preosteoclasts (POC), decreasing type-H blood vessels in trabecular bone and periosteum. Others have shown a sex-specific GC impact with males on chronic GCs having greater declines in trabecular bone score relative to females. We tested the hypothesis that PDGF-BB overexpression could prevent the GIO bone phenotype by analyzing trabecular and cortical bone parameters based on sex. We generated transgenic mice overexpressing PDGF-BB (PdgfbcTG) driven by tartrate-resistant acid phosphatase promoter in POCs, comparing their bone phenotype to sex matched wild-type (WT) mice injected intraperitoneally with either vehicle (Veh) or methylprednisolone (MPS) daily from 2-6 weeks of age. Bone parameters were analyzed using femoral µCT scans (Bruker Skyscan 1275) and CTan software (v1.23). Trabecular and cortical regions of interest were defined as 5% of total femoral length from the distal growth plate and 35% from the epiphysis, respectively, with 3D analysis threshold of 130–255 AU. WT MPS mice had significantly decreased bone volume over tissue volume (BV/TV) and cortical thickness relative to WT Veh mice, regardless of sex. Further bone morphometry analyses showed sex-specific GC sensitivity in types of bone with greater changes in trabecular bone parameters in male mice versus cortical bone parameters in female mice. Specifically in males, WT MPS mice had a significantly decreased trabecular number (Tb.N) and increased trabecular separation (Tb.Sp) relative to controls. Overexpression of PDGF-BB resulted in increased BV/TV and Tb.N and decreased Tb.Sp while protecting the trabecular bone from the detrimental effects of MPS relative to WT Veh mice. PdgfbcTG MPS-treated males maintained significantly increased Tb.N and decreased Tb.Sp relative to WT Veh mice, suggesting not only resistance to GIO but also potential improvement in male trabecular bone phenotype. In contrast, female mice showed significant differences in cortical bone morphometry in relation to MPS and PDGF-BB. WT MPS female mice had a significantly decreased cortical bone area, total cross-sectional area, and cortical area fraction relative to WT Veh mice. PDGF-BB overexpression did not change any of these parameters but did protect the cortical bone from the detrimental MPS effects relative to WT female mice. The effect of MPS was isolated to the periosteal surface; the decreased periosteal perimeter in WT MPS female mice was abrogated by overexpression of PDGF-BB. Overall, overexpressing PDGF-BB prevented the GIO phenotype predominantly protecting trabecular bone in male and cortical bone in female mice. Presentation: Monday, July 14, 2025