Skeletal and osteocyte transcriptomic responses to abaloparatide and teriparatide: A comparative study in estrogen-depleted mice

Osteocytes express parathyroid hormone (PTH)/PTH-related protein (PTHrP) receptors (PTH1R) and respond to the PTHrP analog abaloparatide (ABL) and to the 1-34 PTH fragment teriparatide (TPTD), used to treat osteoporosis. Several studies indicate overlapping but distinct skeletal responses to ABL or TPTD, in particular, the effects of TPTD and ABL on cortical bone appear to differ. Furthermore, little is known about their differential effects on osteocytes. We therefore compared the cortical osteocyte and skeletal responses to ABL and TPTD in sham and ovariectomized (OVX) mice. As expected, administered 7-weeks post OVX for 4 weeks at a dose of 40 ug/kg/day, TPTD and ABL had similar effects on trabecular bone, but ABL showed stronger effects in cortical bone. At the level of the cortical osteocyte, both treatments decreased osteocyte lacunar area, reflecting altered peri-lacunar remodeling in favor of matrix accumulation. Osteocyte RNA-sequencing revealed that several genes and signaling pathways were altered by OVX and affected similarly by TPTD and ABL. Notwithstanding, several signaling pathways were also uniquely regulated by ABL. Thus, in mice, TPTD and ABL induce a positive osteocyte peri-lacunar remodeling balance, but ABL induced stronger cortical responses and affected differently the osteocyte transcriptome. Thus, we conclude that ABL affects the cortical osteocyte transcriptome in a manner subtly different than TPTD, resulting in more beneficial changes in remodeling/modeling and homeostasis of the cortex.