High- and low-dose OPG–Fc cause osteopetrosis-like changes in infant mice

Abstract

Background Receptor Activator of Nuclear Factor-κB ligand (RANKL) inhibitors are being considered for use in children with osteogenesis imperfecta (OI). We sought to assess efficacy of two doses of a RANKL inhibitor, OPG-Fc, in a growing animal model of OI, the col1α2-deficient mouse (oim/oim) and its wildtype controls (+/+). Methods Treated mice showed runting and radiographic evidence of osteopetrosis with either high (20 mg/kg twice weekly) or low dose (1 mg/kg/week) OPG-Fc. Because of this adverse event, OPG-Fc treatment was halted and the mice were euthanized or monitored for recovery with monthly radiographs and assessment of serum osteoclast activity (TRACP-5b) until 25 weeks of age. Results Twelve weeks of OPG-Fc treatment resulted in radiographic and histologic osteopetrosis with no evidence of bone modeling and negative Tartrate-resistant acid phosphatase (TRAP) staining, root dentin abnormalities, and TRACP-5b activity suppression. Signs of recovery appeared four to eight weeks post-treatment cessation. Conclusion Both high and low dose OPG-Fc treatment resulted in osteopetrotic changes in infant mice, an outcome not seen in studies with the RANKL inhibitor RANK – Immunoglobulin Fc segment complex (RANK-Fc), or in studies with older animals. Further investigations of RANKL inhibitors prior to their consideration for use in children are necessary.

Bone quality changes associated with aging and disease: a review

“…Similar to most of the conditions mentioned in this review, these abnormalities result in altered bone quality and increased fracture risk. The condition may be caused by genetic abnormalities in regulators of osteoclast activity or by excessive suppression of bone turnover . Bone quality in osteopetrosis was characterized in the toothless rat and the osteopetrotic mouse by X‐ray diffraction and FTIRI; the latter showing microhardness was increased in osteopetrotic bone, the former demonstrated the persistence of small crystals.…”

RANKL Inhibitors Induce Osteonecrosis of the Jaw in Mice With Periapical Disease

“…Denosumab recognizes human and monkey, but not mouse or rat RANKL, so other recombinant RANKL inhibitors such as RANK‐Fc and OPG‐Fc have been used to inhibit RANKL in animal models . In this study, RANKL was inhibited by RANK‐Fc or OPG‐Fc, using dosing regimens intended to maximally inhibit osteoclasts throughout the 12‐week treatment period.…”

Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent?

“…Treatment ended 12 weeks after the transition time point. Doses of RANK-Fc and ALN were based on results of previous studies that showed increased bone mineral density without side effects using the same dose [1][2][3]. Weaning was carried out between 3 and 4 weeks.…”

“…The oim/oim mice, as a result of an inappropriate stop codon in the collagen I alpha 2 chain's gene, have a aI(I) 3 triple helix instead of the expected aI(1) 2 aI(2) helix [11] and provide a reproducible model with a moderate-to-severe (Type III) form of OI [34], including the presence of spontaneous fractures. Both alendronate (a bisphosphonate) and RANKFc, an inhibitory antibody to RANKL (receptor activator of nuclear factor-jB ligand), tested in short-term (8-week) studies showed a comparable reduction in the number of fractures relative to saline-treated oim/oim mice [2]. The bone composition assessed by Fourier transform infrared (FTIR) imaging after short-term alendronate treatment of the oim/oim mouse, however, was unchanged relative to saline-treated mice [8].…”

“…The bone composition assessed by Fourier transform infrared (FTIR) imaging after short-term alendronate treatment of the oim/oim mouse, however, was unchanged relative to saline-treated mice [8]. RANK-Fc blocks the formation, activation, and survival of osteoclasts [2,3,13]. Because RANKL inhibitors have a shorter half-life in bone than do bisphosphonates, they are being investigated as an alternative therapy.…”