Osteopetrosis: genetics, treatment and new insights into osteoclast function

Cristina Sobacchi, Ansgar Schulz, Fraser P. Coxon, Anna Villa, Miep H. Helfrich

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428 Citations (Scopus)


Osteopetrosis is a genetic condition of increased bone mass, which is caused by defects in osteoclast formation and function. Both autosomal recessive and autosomal dominant forms exist, but this Review focuses on autosomal recessive osteopetrosis (ARO), also known as malignant infantile osteopetrosis. The genetic basis of this disease is now largely uncovered: mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO (in which osteoclasts are abundant but have severely impaired resorptive function), whereas mutations in TNFSF11 and TNFRSF11A lead to osteoclast-poor ARO. In osteoclast-rich ARO, impaired endosomal and lysosomal vesicle trafficking results in defective osteoclast ruffled-border formation and, hence, the inability to resorb bone and mineralized cartilage. ARO presents soon after birth and can be fatal if left untreated. However, the disease is heterogeneous in clinical presentation and often misdiagnosed. This article describes the genetics of ARO and discusses the diagnostic role of next-generation sequencing methods. The management of affected patients, including guidelines for the indication of haematopoietic stem cell transplantation (which can provide a cure for many types of ARO), are outlined. Finally, novel treatments, including preclinical data on in utero stem cell treatment, RANKL replacement therapy and denosumab therapy for hypercalcaemia are also discussed.

Original languageEnglish
Pages (from-to)522-536
Number of pages15
JournalNature Reviews Endocrinology
Early online date23 Jul 2013
Publication statusPublished - Sept 2013

Bibliographical note

The authors acknowledge grant support from the following sources: Ministero della Salute grants GR-2008-1134,625 to C. Sobacchi and RF-2009-1499,542 to A. Villa; Telethon Foundation grant GGP12178 to C. Sobacchi; Research Projects of National Interest (PRIN) Project grant 20122M7T8X_003 by the National Research Program-National Research Council (PNR-CNR) Aging Program 2012–2014 to A. Villa; Arthritis Research UK grants 17285 and 19379 to F. P. Coxon and M. H. Helfrich, respectively. The authors wish to thank: D. Mellis and J. Crockett (University of Aberdeen) for contributing Figure 4 panels a and d, and discussion regarding RANK and RANKL mutants; M. Hoenig (University Medical Centre, Ulm) for critical comments on the manuscript.


  • Animals
  • Humans
  • Osteopetrosis
  • RANK Ligand
  • Signal Transduction


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