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? 2014 American Society for Bone and Mineral Research ""High bone mass in animals and humans with sclerostin deficiency is associated with increased bone strength, which is not the case for all disorders with high bone mineral density, some of which are even associated with fragility fractures owing to unfavorable bone composition. In the current study we investigated whether alterations in bone composition may contribute to the bone strength characteristics associated with lack of sclerostin. We examined cortical bone of Sost-knockout (KO) mice (n?=?9, 16 weeks old) and sclerosteosis patients (young [4 to 14 years], n?=?4 and adults [24 and 43 years], n?=?2) by quantitative backscattered electron imaging and Raman microspectroscopy and compared it to bone from wild-type mice and healthy subjects, respectively. In Sost-KO mice endocortical bone exhibited altered bone composition, whereas subperiosteal bone was unchanged. When comparing endocortical bone tissue of identical tissue age as defined by sequential dual fluorochrome labeling the average bone matrix mineralization was reduced ?1.9% (p? age), and the relative proteoglycan content was significantly increased. Similarly, bone matrix mineralization density distribution was also shifted toward lower matrix mineralization in surgical samples of compact bone of sclerosteosis patients. This was associated with an increase in mineralization heterogeneity in the young population. In addition, and consistently, the relative proteoglycan content was increased. In conclusion, we observed decreased matrix mineralization and increased relative proteoglycan content in bone subcompartments of Sost-KO mice��a finding that translated into sclerosteosis patients. We hypothesize that the altered bone composition contributes to the increased bone strength of patients with sclerostin deficiency. ? 2014 American Society for Bone and Mineral Research. Sclerostin, the product of the SOST gene, is a glycoprotein produced in bone by osteocytes that inhibits bone formation by antagonizing canonical WNT signaling in cells of the osteoblastic lineage.[1] Sclerostin deficiency resulting from loss-of-function mutations of SOST causes sclerosteosis, a rare bone dysplasia characterized by high bone mass due to increased bone formation.[1-4] Patients with sclerosteosis do not report fractures, even after major trauma,[5] indicating increased bone strength. Animal studies conform to the observations in humans. Deletion of the Sost gene in mice increases bone formation associated with marked increases in bone mass and bone strength of both trabecular and cortical bone.