THU346 Repairing Skeletal Deterioration In Diabetes With Bone Anabolic Therapies
Authors: Marino Silvia , Akel Nisreen , Li Shenyang , Cregor Meloney , Perez Betiana , Troncoso Gaston , Meeks Jomeeka , Stuart Scott , Sato Amy , Nookaew Intawat , Bellido Teresita 
Published: October 2023

Abstract
Disclosure: S. Marino: None. N. Akel: None. S. Li: None. M. Cregor: None. B. Perez: None. G. Troncoso: None. J. Meeks: None. S. Stuart: None. A. Sato: None. I. Nookaew: None. T. Bellido: None.
Treatments for skeletal fragility in diabetes are sorely needed as antiresorptive agents, the current standard of care, stop bone loss but do not rebuild bone nor restore the deteriorated bone microarchitecture. Herein, we demonstrate bone restoration in a preclinical model of established diabetes by two bone anabolic pathways: activation of the PTH1 receptor, with equimolar doses of either PTH (1-34) or Abaloparatide/ABL (100/95 µg/kg/day), and neutralization of the osteocyte-derived inhibitor of bone formation sclerostin with romosozumab/Scl-Ab (100mg/kg/w). Type 2 diabetes (T2D) was induced in skeletally mature male C57BL/6J mice by high fat diet combined with streptozotocin; and, after established diabetes, mice were treated for 4 weeks with the bone anabolic agents. At the end of the study, T2D mice exhibited decreased total (−5%), femoral (−7%) and spinal (−11%) BMD vs nondiabetic mice. PTH/ABL restored the bone lost and increased BMD to a similar extent: total 8%, femoral 11% and spinal 9% vs vehicle-treated T2D mice. Scl-Ab also increased BMD at all sites, but the effects were superior: total 24%, femoral 26%, and spinal 40%. T2D mice exhibited low bone formation (BF) and high bone resorption (BR) circulating markers throughout the disease progression. However, at the tissue level BF and BR were suppressed as evidenced by histomorphometric indexes (BFR −70%; Oc.S/BS -34%) and bone transcriptome GO profiles. PTH/ABL increased BF (BFR ∼700% and P1NP 130/244%) as well as BR (Oc.S/BS unchanged/34%; TRAP5b ∼200%) and corrected the diabetic low bone remodeling signature towards high bone remodeling with bone gain. In contrast, Scl-Ab increased formation (BFR 500% and P1NP 50%) but drastically decreased resorption (TRAP5b −190% and Oc.S/BS −500%). T2D mice exhibited damaged bone microarchitecture. The reduced femoral and spinal cancellous bone BV/TV (−22 and −10%) was corrected by ABL (40 and 42%), Scl-Ab (130 and 83%), and PTH only in the spine (43%). Further, femoral and spinal trabecular thickness were increased equally by PTH/ABL (35 and 24%) and also by Scl-Ab (60 and 66%). Moreover, the decreased cortical thickness (−7%) and BA/TA (−5%) at the femoral mid-diaphysis of T2D mice were corrected and further increased by PTH/ABL (10 and 11%) and Scl-Ab (23 and 19%). Yet, whereas PTH reduced marrow area, ABL increased tissue area TA, and Scl-Ab exerted both effects, resulting in advantageous bone distribution by ABL and Scl-Ab leading to increased energy to ultimate load (60 and 90%) and toughness (50 and 82%). Nevertheless, all agents corrected the low stiffness of T2D bone (-19%) and also increased ultimate load. These findings demonstrate the therapeutic value of bone anabolic agents to treat diabetes-induced bone disease by increasing bone formation and improving bone microarchitecture and show the benefit of simultaneously inhibiting resorption to achieve superior bone gain and strength.
Presentation: Thursday, June 15, 2023