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Bone Mineral Density in Sclerosteosis; Affected Individuals and Gene Carriers

Division of Human Genetics, Faculty of Health Sciences, University of Cape Town (J.C.G., P.B., B.M.), Observatory 7925, Cape Town, South Africa; Flora Clinic (H.H.), Roodepoort, Gauteng 1709, South Africa; and Departments of Endocrinology and Metabolic Diseases (R.L.v.B., N.A.T.H., C.W.G.M.L., S.E.P.) and Molecular Cell Biology (R.L.v.B.), Leiden University Medical Center, 2333 ZA, Leiden, The Netherlands

Address all correspondence and requests for reprints to: Dr. Socrates E. Papapoulos, Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail: m.v.iken{at}lumc.nl.

	Abstract

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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 (seven patients and 18 phenotypically normal heterozygotes). BMD was measured by dual x-ray absorptiometry 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; 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.

	Introduction

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SCLEROSTEOSIS IS A rare skeletal dysplasia characterized by progressive bone thickening and sclerosis of the skeleton, especially of the skull, resulting in enlargement of the jaw, facial distortion, raised intracranial pressure, and entrapment of cranial nerves with consequent facial palsy, hearing loss, and loss of smell (1, 2, 3, 4). Sudden death may result from impaction of the brainstem in the foramen magnum. The condition occurs mainly in Afrikaners, the white farmers who separated from the Dutch East India Co. and moved into the backcountry of South Africa. In this population, the estimated carrier rate of the determinant gene is approximately one in 100 individuals (5). A few affected individuals and families in other parts of the world have also been reported (4). Sclerosteosis is due to loss of function mutations of the SOST gene, which is located on chromosome 17q12–21 and encodes sclerostin, a protein produced by osteocytes that inhibits bone formation (6, 7, 8, 9, 10). In patients with sclerosteosis and sclerostin deficiency, the bone phenotype is probably due to increased bone formation that is not associated with increased bone resorption, leading to a positive bone balance and increased bone mass (11). Bone specimens from affected individuals have a lamellar structure with predominance of cuboidal, active-appearing osteoblasts, increased double-tetracycline label spacing, and increased osteoid that mineralizes normally (9, 12, 13). There are no reports of fractures in patients with sclerosteosis (5).

Sclerosteosis is inherited as an autosomal recessive trait, and heterozygous carriers of the disorder are clinically normal, although some may show age-related radiographic evidence of calvarial thickening (14). Despite recent progress in understanding the molecular basis of the condition, there has been no systematic evaluation of bone mineral density (BMD) in such patients and, in particular, in phenotypically normal heterozygotes. Such information can provide additional insight into the bone changes associated with the genetic defect that may lead to the development of novel therapies for patients with diseases characterized by low bone mass, such as osteoporosis. In the present study we addressed the question of whether one copy of the defective SOST gene, as present in asymptomatic carriers of the disease, has an effect on bone mass.

	Subjects and Methods

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We studied 25 individuals from six families with sclerosteosis. Seven individuals had the condition, and 18 were clinically normal relatives (parents, siblings, or children). None of the studied subjects had ever experienced a clinical fracture. Homozygosity and heterozygosity were documented by genotyping, which was performed by Dr. M. E. Brunkow (Celltech, Inc., Bothell, WA), as previously described (15).

Lateral radiographs of the skull were obtained from all subjects. BMD of the lumbar spine, hip, and left forearm were measured by dual x-ray absorptiometry (DXA; Hologic QDR-1000, Waltham, MA). We used reference values for Caucasians provided by the manufacturer, because the Afrikaner population is of western European origin, whereas for the hip we used the National Health and Nutrition Examination Surveys III database. Results are expressed as grams per square centimeter or as Z-scores, i.e. the difference in SD from the mean of healthy subjects of the same age.

Written informed consent was obtained from all adults, and parental consent was obtained for the children. The study was approved by the medical ethics committee of University of Cape Town.

	Results

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Radiology

Representative lateral skull radiographs of a child and an adult patient with sclerosteosis and of a carrier of the disease are shown in Fig. 1. Radiographic features of the disease were already present at the age of 7 yr (Fig. 1A) and progressed to the characteristic changes of the condition in adulthood (Fig. 1B). The radiographs of the heterozygotes showed evidence of cranium thickening, with some loss of the diploid space (Fig. 1C). However, carriers could not always be clearly distinguished from healthy subjects. and no radiographic changes could be detected in younger carrier individuals.

View larger version (65K): [in this window] [in a new window]   FIG. 1. Lateral skull radiographs of a child (A) and an adult (B) with sclerosteosis and a heterozygote carrier (C) of the determinant gene.

Affected individuals had markedly increased BMD at all skeletal sites (Table 1). The Z-scores ranged between +7.73 and +14.43 at the lumbar spine, between +7.84 and +11.51 at the total hip, and between +4.44 and +9.53 at the forearm.

The relation between BMD and age at the lumbar spine for patients and carriers is shown separately for males and females in Fig. 2. BMD values appear to follow a normal pattern, with increases in childhood and stabilization in young adults, but at a level higher than that in healthy subjects. Whether there is also a decline with ageing cannot be concluded due to the small number of individuals older than 50 yr.

View larger version (17K): [in this window] [in a new window]   FIG. 2. Lumbar spine BMD in male and female homozygous and heterozygous individuals with sclerosteosis. Lines depict normal ranges. •, Homozygotes; , heterozygotes.

	Discussion

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This is the first systematic evaluation of BMD in families with sclerosteosis, and we cannot, therefore, compare our findings with those from other studies of this disease. However, BMD measurements have been reported by other investigators in patients with van Buchem disease (hyperostosis corticalis generalisata familiaris), which closely resembles sclerosteosis (16, 17). Patients with van Buchem disease have radiological features similar to those of sclerosteosis, but the disorder runs a more benign course, and syndactyly, a typical feature of sclerosteosis, is absent. The condition is due to a 52-kb deletion downstream of the SOST gene that is thought to down-regulate SOST expression, leading to defective sclerostin production (11, 15, 18). BMD measured in hand radiographs of four patients with van Buchem disease and nine carriers showed increased values in the patients, but not in the heterozygotes, leading to the conclusion that carriers are not affected by the genetic defect (17). This observation in carriers of van Buchem disease is different from our findings in the sclerosteosis carriers. Whether this difference is due to the methodology used to measure BMD in our study (DXA) and in the van Buchem study (radiogammometry) or to different expression of the molecular defect is currently unclear.

Our results may have more general implications in understanding the role of sclerostin in bone formation and the modulation of its production and/or its activity for therapeutic purposes. Sclerostin is a secreted protein that is produced by osteocytes and inhibits bone formation (9, 10). It has been suggested that the restricted expression pattern of sclerostin and the exclusive good quality bone phenotype of patients with sclerosteosis may provide the basis for the design of therapeutics that specifically stimulate bone formation (11). One approach to achieve this is to develop antibodies capable of inhibiting the biological activity of sclerostin; this approach was shown in a preliminary report to be successful in rats (19). However, there have been concerns about such attempts to stimulate bone formation. Whyte and colleagues (20, 21), discussing the phenotypes of subjects with various bone-sclerosing disorders, including the high bone mass phenotype, suggested caution, because the use of such therapeutics may lead to unwanted skeletal effects. These are autosomal dominant disorders, phenotypically similar to sclerosteosis, caused by gain of function mutations of the low-density lipoprotein receptor-related protein 5, which is mapped to chromosome 11q12–13 and is required for stimulation of the canonical Wnt signaling pathway in osteoblasts (22, 23, 24). This pathway is important for the bone-forming function of osteoblasts, and increased Wnt signaling resulting from lipoprotein receptor-related protein 5 mutations is responsible for the bone phenotype of these patients. Sclerostin was shown recently to antagonize Wnt signaling explaining, at least in part, its action as a negative regulator of bone formation (25, 26) (our unpublished observation).

In our study, carriers of sclerosteosis with one defective copy of the SOST gene showed variable increases in bone mass without evidence of any of the skeletal complications encountered in homozygotes. These results suggest that inhibition of the production and/or activity of sclerostin can be titrated, leading to increases in bone mass without any unwanted skeletal effects. However, this hypothesis warrants additional testing in vivo.

	Acknowledgments

 
We thank Sr. Lecia Bartmann for her valuable assistance with the affected families.

	Footnotes

 
This work was supported by grants from Celltech, Inc., the Harry Crossley Foundation, the Mauerberger Foundation, the University of Cape Town Staff Research Fund, the South African Orthopedic Association (to P.B.), The Netherlands Organization for Health Research (NWO 916.046.017), and the European Commission (LSHM-CT-2003-503020) (both to R.L.v.B.).

First Published Online September 27, 2005

Abbreviations: BMD, Bone mineral density; DXA, dual x-ray absorptiometry.

Received June 1, 2005.

Accepted September 21, 2005.

	References

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gardner, J. C. Articles by Papapoulos, S. E. Search for Related Content PubMed PubMed Citation Articles by Gardner, J. C. Articles by Papapoulos, S. E. Related Collections Calcium and Bone Metabolism