Low Dose of Bisphosphonate Enhances Sclerostin Antibody-Induced Trabecular Bone Mass Gains in Brtl/+ Osteogenesis Imperfecta Mouse Model

Abstract

Osteogenesis imperfecta (OI) is a genetic disorder characterized by altered bone quality and imbalanced bone remodeling, leading to skeletal fractures that are most prominent during childhood. Treatments for OI have focused on restoring pediatric bone density and architecture to recover functional strength and consequently reduce fragility. Though antiresorptive agents like bisphosphonates (BPs) are currently the most common intervention for the treatment of OI, a number of studies have shown efficacy of sclerostin antibody (SclAb) in inducing gains in bone mass and reducing fragility in OI mouse models. In this study, the effects of the concurrent use of BP and SclAb were evaluated during bone growth in a mouse harboring an OI-causing Gly→Cys mutation on col1a1. A single dose of antiresorptive BP facilitated the anabolic action of SclAb by increasing availability of surfaces for new bone formation via retention of primary trabeculae that would otherwise be remodeled. Chronic effects of concurrent administration of BP and SclAb revealed that accumulating cycles conferred synergistic gains in trabecular mass and vertebral stiffness, suggesting a distinct advantage of both therapies combined. Cortical gains in mass and strength occurred through SclAb alone, independent of presence of BP. In conclusion, these preclinical results support the scientific hypothesis that minimal antiresorptive treatment can amplify the effects of SclAb during early stages of skeletal growth to further improve bone structure and rigidity, a beneficial outcome for children with OI. © 2018 American Society for Bone and Mineral Research.

Sclerostin Antibody–Induced Changes in Bone Mass Are Site Specific in Developing Crania

“…In the present study, these findings were limited to some vascular foramen occlusion, whereas intracranial volumes and shapes remained unchanged. The present findings demonstrate outcomes after a high dose for an extreme duration and suggest need for additional studies to better understand how this finding could be mitigated through a less severe treatment regimen or when Scl‐Ab is combined with an antiresorptive, possibly facilitating reduced drug exposure from both medications.…”

Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone

“…We can reason that bone sites with high expression levels of osteoblast markers and osteoblast progenitors have "little room" for further formation where further minimal upregulation was observed. Second, there is a finite bone surface area in which SclAb can induce bone formation (eg, without the use of cotreatment with bisphosphonate) (66,67) and perhaps a maximization of bone-forming surfaces in the sample had already occurred, further limiting bone response. Future work should evaluate these potential factors, including evaluating bone turnover markers (P1NP, TNSAP) and their role in determining the magnitude of treatment response.…”

Osteogenesis Imperfecta: New Perspectives From Clinical and Translational Research

“…It might also be advantageous to give bisphosphonates concomitant with sclerostin antibody, at least during growth. Studies in both G610C and Brtl mice have shown that the metaphyseal trabecula of growing mice were retained through the antiresorptive action of bisphosphonates and could serve as templates for the formation of new bone that was stimulated by sclerostin inhibition …”

“…Studies in both G610C and Brtl mice have shown that the metaphyseal trabecula of growing mice were retained through the antiresorptive action of bisphosphonates and could serve as templates for the formation of new bone that was stimulated by sclerostin inhibition. (115,116) Transforming growth factor beta (TGFb) plays an important role in determining bone mass and quality. (117) Mice overexpressing TGFb in bone have osteoporosis, (118) whereas mice with genetic TGFb inhibition have stronger bones.…”