Abaloparatide exhibits greater osteoanabolic response and higher cAMP stimulation andβ‐arrestin recruitment than teriparatide

Abstract

Teriparatide and abaloparatide are parathyroid hormone receptor 1 (PTHR1) analogs with unexplained differential efficacy for the treatment of osteoporosis. Therefore, we compared the effects of abaloparatide and teriparatide on bone structure, turnover, and levels of receptor activator of nuclear factor‐kappa B ligand (RANKL) and osteoprotegerin (OPG). Wild‐type (WT) female mice were injected daily with vehicle or 20–80 µg/kg/day of teriparatide or abaloparatide for 30 days. Femurs and spines were examined by microcomputed tomography scanning and serum levels of bone turnover markers, RANKL, and OPG, were measured by ELISA. Both analogs similarly increased the distal femoral fractional trabecular bone volume, connectivity, and number, and reduced the structure model index (SMI) at 20–80 µg/kg/day doses. However, only abaloparatide exhibited a significant increase (13%) in trabecular thickness at 20 µg/kg/day dose. Femoral cortical evaluation showed that abaloparatide caused a greater dose‐dependent increase in cortical thickness than teriparatide. Both teriparatide and abaloparatide increased lumbar 5 vertebral trabecular connectivity but had no or modest effect on other indices. Biochemical analysis demonstrated that abaloparatide promoted greater elevation of procollagen type 1 intact N‐terminal propeptide, a bone formation marker, and tartrate‐resistant acid phosphatase 5b levels, a bone resorption marker, and lowered the RANKL/OPG ratio. Furthermore, PTHR1 signaling was compared in cells treated with 0–100 nmol/L analog. Interestingly, abaloparatide had a markedly lower EC50 for cAMP formation (2.3‐fold) and β‐arrestin recruitment (1.6‐fold) than teriparatide. Therefore, abaloparatide‐improved efficacy can be attributed to enhanced bone formation and cortical structure, reduced RANKL/OPG ratio, and amplified Gs‐cAMP and β‐arrestin signaling.

The Efficacy of PTH and Abaloparatide to Counteract Immobilization-Induced Osteopenia Is in General Similar

“…Another recent report from Sahbani et al. also showed similar effect of ABL and PTH at doses comparable to those used in the present investigation ( 43 ). In contrast to these pre-clinical findings, clinical studies have reported greater aBMD response rates in osteoporotic patients treated with ABL compared with patients treated with PTH ( 23 , 54 ).…”

“…This is consistent with the present study, which found that PTH and ABL lead to similar amounts of osteoclast covered surfaces at the proximal tibial metaphysis. This finding is further corroborated by a very recent study, which showed that the same dose of PTH and ABL resulted in similar serum CTX values in intact female mice ( 43 ). Therefore, despite the overall anabolic effect of PTH and ABL, the elevated bone turnover increases the likelihood of perforating trabeculae.…”

“…and Sahbani et al. ( 42 , 43 ). It seems tempting to measure biochemical markers of bone formation or resorptions in serum.…”

“…In contrast to treatment with PTH, no studies have previously investigated the effect of ABL in relation to disuse-induced bone loss in rats. However, ABL has previously been studied in intact ( 42 , 43 ), ovariectomized ( 44 , 45 ), and orchiectomized animals ( 46 , 47 ), as well as during fracture healing in mice ( 26 ) and rats ( 48 ). These studies have demonstrated bone anabolic properties of ABL in accordance with those established in the present study.…”

Spinal Cord Injury as a Model of Bone-Muscle Interactions: Therapeutic Implications From in vitro and in vivo Studies

“…Recently, abaloparatide, a parathyroid hormone-related protein (PTHrP), was approved by Food and Drug Administration (FDA) for the treatment of severe post-menopausal osteoporosis (26). A recent study performed by Sahbani et al compared abaloparatide to teriparatide on bone structure, turnover, and levels of RANKL and OPG on wild-type female mice (27). The authors showed that 20-80 µg/kg/day of abaloparatide for 30 days resulted in a significant increase (13%) in trabecular bone thickness and lowered the RANKL/OPG ratio.…”