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Submitted on June 1, 2005
Accepted on September 21, 2005
Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, South Africa (J.C.G., P.B.); 210 Medical Center, Cape Town, South Africa (B.M.), Flora Clinic, Roodepoort, South Africa (H.H.); Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden The Netherlands (R.L.v.B., N.A.T.H., C.W.G.M.L., S.E.P.); Department of Molecular Cell Biology, Leiden University Medical Center, Leiden The Netherlands (R.L.v.B.)
* To whom correspondence should be addressed. E-mail: M.V.Iken{at}lumc.nl.
Background: Sclerosteosis is an autosomal recessive sclerosing bone disorder due to deficiency of sclerostin, a protein secreted by the osteocytes that inhibits bone formation. In the present study we assessed the effect of variable expression of the genetic defect on Bone Mineral Density (BMD) in patients and carriers of the determinant gene.
Methods: We studied 25 individuals (7 patients and 18 phenotypically normal heterozygotes). BMD was measured by Dual x-ray Absorptiometry (DXA) at the lumbar spine, total hip and distal forearm and lateral radiographs of the skull were obtained.
Results: Individuals with sclerosteosis had markedly increased BMD at all skeletal sites (Z-score ranges: lumbar spine +7.73 to +14.43, total hip +7.84 to +11.51 and forearm +4.44 to +9.53). In heterozygotes, BMD was above the mean value of healthy age-matched individuals at all skeletal sites and had a wide range of normal and clearly increased values. Skull radiographs showed the typical hyperostotic changes in affected individuals and mild or no changes in heterozygotes.
Conclusions: Heterozygous carriers of sclerosteosis have BMD values consistently higher than the mean of healthy subjects without any of the bone complications encountered in homozygotes. This finding suggests that the production and/or activity of sclerostin can be titrated in vivo leading to variable increases in bone mass without any unwanted skeletal effects, a hypothesis of obvious significance for the development of new therapeutics for osteoporosis.
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