Sclerostin antibody treatment enhances bone strength but does not prevent growth retardation in young mice treated with dexamethasone

Abstract

Objective. Exposure to supraphysiologic levels of glucocorticoid drugs is known to have detrimental effects on bone formation and linear growth. Patients with sclerosteosis lack the bone regulatory protein sclerostin, have excessive bone formation, and are typically above average in height. This study was undertaken to characterize the effects of a monoclonal antibody to sclerostin (Scl-AbI) in mice exposed to dexamethasone (DEX).Methods. Young mice were concomitantly treated with DEX (or vehicle control) and Scl-AbI antibody (or isotype-matched control antibody [Ctrl-Ab]) in 2 independent studies. Linear growth, the volume and strength of the bones, and the levels of bone turnover markers were analyzed.Results. In DEX-treated mice, Scl-AbI had no significant effect on linear growth when compared to control treatment (Ctrl-Ab). However, in mice treated with DEX and Scl-ABI, a significant increase in trabecular bone at the femoral metaphysis (bone volume/total volume ؉117% versus Ctrl-Ab-treated mice) and in the width and volume of the cortical bone at the femoral diaphysis (؉24% and ؉20%, respectively, versus CtrlAb-treated mice) was noted. Scl-AbI treatment also improved mechanical strength (as assessed by 4-point bending studies) at the femoral diaphysis in DEXtreated mice (maximum load ؉60% and ultimate strength ؉47% in Scl-AbI-treated mice versus Ctrl-Abtreated mice). Elevated osteocalcin levels were not detected in DEX-treated mice that received Scl-AbI, although levels of type 5b tartrate-resistant acid phosphatase were significantly lower than those observed in mice receiving DEX and Ctrl-Ab.Conclusion. Scl-AbI treatment does not prevent the detrimental effects of DEX on linear growth, but the antibody does increase both cortical and trabecular bone and improves bone mechanical properties in DEX-treated mice.Glucocorticoid (GC)-based drugs have potent immunosuppressive and antiinflammatory properties and have assumed an important role in the treatment of many types of inflammatory and autoimmune conditions. However, drugs of this type are associated with a range of well-known side effects (1). One of the most serious problems associated with GC exposure is a deleterious effect on bone, which leads to a high proportion of patients who, after receiving long-term GC therapy, develop GC-induced osteoporosis and are susceptible to bone fractures (2). The detrimental effect of GCs on bone strength has been reported to involve many different mechanisms, including inhibition of osteoblastic bone formation, increased osteoclastic bone resorption, changes in calcium balance, and inhibition of the osteoanabolic action of sex steroids (3). More recently, it has also been proposed that GC exposure not only may cause changes to bone mass and bone architecture, but also may alter the localized material properties of bone (4).When administered to children or to growing

Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin

“…(10) Consistent with our current findings in skeletally mature Sost/ sclerostin-deficient mice, previous studies showed that pharmacologic inhibition of sclerostin with a neutralizing antibody opposed the lack of bone gain and the loss of strength induced by glucocorticoids in growing mice. (51,52) Although it was proposed that these effects were due to preservation of Journal of Bone and Mineral Research osteoblast activity, (52) mice treated with glucocorticoids and the anti-sclerostin antibody in these earlier studies exhibited lower circulating TRAP5b (51) or CTX-1, (52) but still markedly reduced bone formation markers osteocalcin and P1NP, (51) compared to the corresponding mice treated with glucocorticoids alone. Likewise, our in vivo studies show that sustained activation of the Wnt/b-catenin signaling in Sost-deficient mice abolishes the increase in resorption induced by glucocorticoids but not the decreased bone formation.…”

Distinct effects of pioglitazone and metformin on circulating sclerostin and biochemical markers of bone turnover in men with type 2 diabetes mellitus

“…Although sclerostin is a well-established inhibitor of bone formation, recent evidence indicates that it can also promote osteoclastogenesis by stimulating RANKL produced by osteocytes (40). Moreover, inhibition of sclerostin in animals and humans by a specific antibody does not only lead to increased bone formation but also to decreased bone resorption (41,42). Taken together, these data suggest that PIO stimulates the production of sclerostin, which would in turn increase RANKL production by osteocytes, thus resulting in a dual effect on bone metabolism, reducing bone formation and increasing bone resorption, which could explain the adverse effect of PIO on bone quality.…”

Quantitative analysis of bone and soft tissue by micro-computed tomography: applications to ex vivo and in vivo studies

“…10 However, scans starting at a distance of up to 0.29 mm from the growth plate have been reported. 11 It is recommended to minimise the scanning of the growth plate itself to avoid the Quantitative analysis of bone and soft tissue by micro-CT GM Campbell and A Sophocleous effects of radiation. The size of the scan in the axial direction typically ranges from 1 to 2 mm for mice [10][11][12] and from 2 to 3 mm for rats.…”