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High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K

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Abstract

Introduction

Pycnodysostosis is typically associated with short stature, multiple fractures without adequate trauma and high bone density on x-ray. The increased bone density is due to a genetic defect of cathepsin K, leading to dysfunctional osteoclastic bone resorption and bone remodeling. We wanted to know how this defect influences the trabecular and cortical volumetric bone mineral density of long bones as measured quantitatively by pQCT.

Methods

Three siblings of a consanguineous family were admitted to our hospital because of multiple fractures. Pycnodysostosis was diagnosed based on the clinical presentation with the characteristic dense appearance of their bones on x-ray. The distal and proximal radius of the patients and of control subjects was scanned using a Stratec XCT-2000 pQCT scanner and data were processed using the software provided by the manufacturer. Genomic DNA was extracted from blood samples of all three patients and their parents. The coding exons of the cathepsin K gene (CTSK) were amplified and sequenced.

Results

The patients displayed the typical features of pycnodysostosis: Short stature, delay of closure of the fontanelles, hypoplasia of the maxilla, spondylolysis of the lumbar spine, stubby hands and feet and a history of multiple fractures. Volumetric bone density was much higher in pycnodysostotic bone than in the control bones 686 ± 28 mg/cm3 in patients vs. 290 ± 6 mg/cm3 in controls; p = 0.001), especially in the trabecular compartment (733 ± 26 mg/cm3 in patients vs. 195 ± 8 mg/cm3 in controls; p < 0.001), but also in the cortical bone (1108 ± 22 in patients vs. 1020 ± 17 in controls; p < 0.01). In contrast to this finding, the patients displayed an elevation of alkaline phosphatase in the serum and free deoxypyridinoline-crosslinks (DPD) in the urine, suggesting osteomalacia. Sequencing of the cathepsin K gene revealed homozygosity for a novel missense mutation in all three patients predicting the amino acid exchange from arginine to tryptophan at position 46 (R46W).

Conclusion

We present here for the first time quantitative data on the mineral density of bones of pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. The elevated bone mineral density in the cortex and the changes in the serum markers suggest an effect of cathepsin K not only on bone volume, but also on bone mineralization. This might in part explain the increased susceptibility to fractures of patients with pycnodysostosis.

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Acknowledgements

The authors thank the patients for their participation. MA was supported by a grant of the Deutsche Forschungsgemeinschaft (AM 103/9–1).

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Authors and Affiliations

  1. Department of Trauma, Hand, and Reconstructive Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    A. F. Schilling, W. Lehmann, T. Schinke, J. M. Rueger & M. Amling

  2. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    C. Mülhausen & R. Santer

  3. Center for Biomechanics and Skeletal Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    A. F. Schilling, W. Lehmann, T. Schinke, J. M. Rueger & M. Amling

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  1. A. F. Schilling
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  2. C. Mülhausen
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Correspondence to M. Amling.

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AFS and CM contributed equally and therefore share first authorship.

Funding MA was supported by a grant of the Deutsche Forschungsgemeinschaft (AM 103/9-1).

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Schilling, A.F., Mülhausen, C., Lehmann, W. et al. High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. Osteoporos Int 18, 659–669 (2007). https://doi.org/10.1007/s00198-006-0311-y

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  • DOI: https://doi.org/10.1007/s00198-006-0311-y

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