Serum Sclerostin Levels in Adults With Osteogenesis Imperfecta: Comparison With Normal Individuals and Response to Teriparatide Therapy

Abstract

Sclerostin (SOST), a glycoprotein primarily derived from osteocytes, is an important regulator of bone remodeling. Osteogenesis imperfecta (OI) is a heritable disorder of bone characterized by low bone mass, bone fragility, recurrent fractures, and bone deformities. Altered SOST-mediated signaling may have a role in pathogenesis of type I collagen-related OI; however, this has not been evaluated in humans. We measured serum SOST levels in adults with OI who were enrolled in a randomized, placebo-controlled clinical trial that evaluated the effects of osteoanabolic therapy with teriparatide. Compared with age- and sex-matched control participants, mean SOST levels were lower in those with type I or types III/VI OI (p < 0.0001). Receiver operating curve analysis revealed that sclerostin alone or sclerostin plus bone mineral content discriminated patients with OI from controls (area under the curve 0.80 and 0.87, respectively). SOST levels increased in the group of patients with type I OI during therapy with teriparatide (compared with placebo, p = 0.01). The increase was significant at 6, 12, and 24 months of therapy (p ≤ 0.02) and was apparent as early as 3 months (p = 0.06). The magnitude of increases in SOST levels during therapy was inversely correlated with increases in vertebral volumetric bone mineral density (vBMD). Overall, these results suggest that: 1) SOST regulation is fundamentally altered in osteogenesis imperfecta; 2) serum SOST levels could be a biomarker of OI in adults; and 3) alterations in SOST may help predict the response to anabolic therapies in OI. © 2017 American Society for Bone and Mineral Research.

Changes in the intra- and peri-cellular sclerostin distribution in lacuno-canalicular system induced by mechanical unloading

“…Sclerostin (Scl, SOST) is a protein encoded by the SOST gene that is primarily secreted by osteocytes and is known to be a negative regulator of the bone mass [8,9]. Scl binds to lowdensity lipoprotein receptor-related proteins (LRP) 5, LRP 6, and frizzled receptors to antagonize Wnt/ catenin signaling [10][11][12][13]. Wnt/ catenin signaling is crucial for osteoblast differentiation.…”

Impact of Intrinsic Muscle Weakness on Muscle–Bone Crosstalk in Osteogenesis Imperfecta

“…Finally, there is no clear consensus on whether or not the levels of sclerostin are altered in OI patients, although there is evidence of improved bone properties in several mouse models of OI ( oim/oim [ 27 ], +/G610C , Brtl −/− [ 122 ], Col1a1 +/Jrt [ 123 ], and Crtap −/− [ 124 ]) subjected to sclerostin inhibition. Patient clinical trials utilizing anti-sclerostin antibodies are currently ongoing with initial results showing increased markers of bone formation and reduced markers of bone resorption [ 2 , 15 , 18 , 125 , 126 ].…”

Increased Osteocyte Lacunae Density in the Hypermineralized Bone Matrix of Children with Osteogenesis Imperfecta Type I

“…It was recently shown that serum levels of DKK1 are indeed elevated in children with OI [ 32 ]. While sclerostin serum levels were found normal or even decreased in OI patients [ 33 , 34 , 35 ], treatment with sclerostin antibody increased bone mass and improved bone mechanical strength in diverse mouse models and in patients [ 36 , 37 , 38 ]. In addition, the profoundly perturbed osteoblasts in OI might also sense and react differently to sclerostin or other local factors.…”