Sclerostin antibody (Scl-Ab) improves osteomalacia phenotype in dentin matrix protein 1(Dmp1) knockout mice with little impact on serum levels of phosphorus and FGF23

Abstract

Unlike treatments for most rickets, the treatment using 1,25-(OH)2 vitamin D3 has little efficacy on patients with hypophosphatemic rickets, a set of rare genetic diseases. Thus, understanding the local cause for osteomalacia in hypophosphatemic rickets and developing an effective treatment to restore mineralization in this rare disease has been a longstanding goal in medicine. Here, we used Dmp1 knockout (KO) mice (whose mutations led to the same type of autosomal recessive hypophosphatemic rickets in humans) as the model in which the monoclonal antibody of sclerostin (Scl-Ab) was tested in two age groups for 8 weeks: the prevention group (starting at age 4 weeks) and the treatment group (starting at age 12 weeks). Applications of Scl-Ab greatly improved the osteomalacia phenotype (>15%) and the biomechanical properties (3-point bending, ~60%) in the treated long-bone group. Our studies not only showed improvement of the osteomalacia in the alveolar bone, which has the highest bone metabolism rate, as well as the long bone phenotypes in treated mice. All these improvements attributed to the use of Scl-Ab are independent of the change in serum levels of phosphorus and FGF23, since Scl-Ab had little efficacy on those parameters. Finally, we propose a model to explain how Scl-Ab can improve the Dmp1 KO osteomalacia phenotype, in which the sclerostin level is already low.

Sclerostin Antibody Treatment Increases Bone Mass and Normalizes Circulating Phosphate Levels in Growing Hyp Mice

“…(13) Scl-Ab treatment increases bone mass and, subsequently, bone strength in several preclinical animal models, including postmenopausal osteoporosis, (34) osteogenesis imperfecta, (16,35) and autosomal recessive hypophosphatemic rickets. (17) Consistent with this, we find that Scl-Ab induces gains in bone mass in Hyp animals with the largest gains in the cortical compartment. Previous studies have demonstrated that Scl-Ab activates bone lining cells on existing bone surfaces and sustains osteoprogenitor cell recruitment to increase bone mass.…”

“…The Scl-Ab dosing strategy was chosen based on previous publications testing the efficacy of Scl-Ab in preclinical rodent models. (7,(15)(16)(17) Treatment was initiated at weaning (4 weeks of age) and continued for 4 weeks until euthanization at 8 weeks of age. All animal studies were approved by the Rush University Institutional Animal Care and Use Committee.…”

Application of anti-Sclerostin therapy in non-osteoporosis disease models

“…This is a mouse model of hypophosphatemic rickets manifested by osteomalacia in the setting of low serum phosphorus levels and elevated FGF-23 levels. (82) Interestingly, Sclerostin antibody treatment for 8 weeks in both 1 month and 3-month-old animals significantly improved (but did not completely restore) alveolar bone morphology and volume. (82) Sclerostin antibody also increased long bone volume and strength suggesting there may be a role for Sclerostin inhibition in the treatment of hypophosphatemic rickets.…”

“…(82) Interestingly, Sclerostin antibody treatment for 8 weeks in both 1 month and 3-month-old animals significantly improved (but did not completely restore) alveolar bone morphology and volume. (82) Sclerostin antibody also increased long bone volume and strength suggesting there may be a role for Sclerostin inhibition in the treatment of hypophosphatemic rickets. (82) Together these studies suggest a role for systemic Sclerostin antibody therapy in the treatment of alveolar bone loss due to periodontitis and hypophosphatemic rickets induced osteomalacia.…”

“…(82) Sclerostin antibody also increased long bone volume and strength suggesting there may be a role for Sclerostin inhibition in the treatment of hypophosphatemic rickets. (82) Together these studies suggest a role for systemic Sclerostin antibody therapy in the treatment of alveolar bone loss due to periodontitis and hypophosphatemic rickets induced osteomalacia.…”