Single dose of bisphosphonate preserves gains in bone mass following cessation of sclerostin antibody in Brtl/+ osteogenesis imperfecta model

Abstract

Sclerostin antibody has demonstrated a bone-forming effect in pre-clinical models of osteogenesis imperfecta, where mutations in collagen or collagen-associated proteins often result in high bone fragility in pediatric patients. Cessation studies in osteoporotic patients have demonstrated that sclerostin antibody, like intermittent PTH treatment, requires sequential anti-resorptive therapy to preserve the anabolic effects in adult populations. However, the persistence of anabolic gains from either drug has not been explored clinically in OI, or in any animal model. To determine whether cessation of sclerostin antibody therapy in a growing OI skeleton requires sequential anti-resorptive treatment to preserve anabolic gains in bone mass, we treated 3 week old Brtl/+ and wild type mice for 5 weeks with SclAb, and then withdrew treatment for an additional 6 weeks. Trabecular bone loss was evident following cessation, but was preserved in a dose-dependent manner with single administration of pamidronate at the time of cessation. In vivo longitudinal near-infrared optical imaging of cathepsin K activation in the proximal tibia suggests an anti-resorptive effect of both SclAb and pamidronate which is reversed after three weeks of cessation. Cortical bone was considerably less susceptible to cessation effects, and showed no structural or functional deficits in the absence of pamidronate during this cessation period. In conclusion, while SclAb induces a considerable anabolic gain in the rapidly growing Brtl/+ murine model of OI, a single sequential dose of antiresorptive drug is required to maintain bone mass at trabecular sites for 6 weeks following cessation.

Splenomegaly, myeloid lineage expansion and increased osteoclastogenesis in osteogenesis imperfecta murine

“…The sexual dimorphism in the OIM phenotype is therefore more prevalent during early adulthood, but some differences are already evident by 5 weeks of age prior to sexual maturation. Some studies in OIM have pooled mice of both genders for evaluation of treatment approaches [42], and many have used animals of one gender only [24, 26, 43–45]. As noted in other recent studies, there are indications of sex-related differences in OI that may affect response to treatment that should be taken into account in future studies, particularly those targeting adolescents and adults [41, 46].…”

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

“…Doses were administered subcutaneously biweekly, from age 3 to 14 weeks. Previously, we have demonstrated that biweekly administration of 25 mg/kg Scl‐Ab induced significant therapeutic benefits in femora of Brtl/+ between 3 and 8 weeks of age . In the present study, we chose Scl‐Ab dose and durations to double our prior treatment exposure to better understand the outcomes of a maximal, sustained effect of treatment throughout growth.…”

Osteogenesis imperfecta

“…Although 4 week old Col1a1 Jrt/+ mice, carrying an exon 9 splice donor site defect in one allele, showed 60% increase in distal fem oral trabecular bone mass and nearly 20% increase in cortical thickness when treated for 4 weeks with a dis tinct, but similar, anti sclerostin antibody as described above, the treatment did not translate to a structural benefit in the lumbar vertebrae or to a biomechani cal benefit in the long bone, and 5 month old mice showed no structural or biomechanical benefit at these sites 231 . Importantly, anti sclerostin treatment will prob ably require sequential anti resorptive intervention to preserve trabecular gains following cessation of anabolic therapy, although at levels that are lower than those used for primary intervention 232 .…”