Osteoprotegerin deficiency and juvenile Paget's disease

Michael P. Whyte, Sara E. Obrecht, Patrick M. Finnegan, Jonathan L. Jones, Michelle N. Podgornik, William H. McAlister, Steven Mumm

Research output: Contribution to journalArticlepeer-review

384 Scopus citations


Background: Juvenile Paget's disease, an autosomal recessive osteopathy, is characterized by rapidly remodeling woven bone, osteopenia, fractures, and progressive skeletal deformity. The molecular basis is not known. Osteoprotegerin deficiency could explain juvenile Paget's disease because osteoprotegerin suppresses bone turnover by functioning as a decoy receptor for osteoclast differentiation factor (also called RANK ligand). Methods: We evaluated two apparently unrelated Navajo patients with juvenile Paget's disease for defects in the gene encoding osteoprotegerin (TNFRSF11B) using polymerase-chain-reaction (PCR) amplification followed by direct sequencing and Southern blotting of genomic DNA. Genetic markers near TNFRSF11B were evaluated by both a PCR method that involved sequence-tagged site-content mapping of a deletion of TNFRSF11B and PCR spanning the DNA break points. Results: Both patients had a homozygous deletion of TNFRSF11B, with identical break points, on chromosome 8q24.2. The defect spans approximately 100 kb, but neighboring genes are intact. We found that serum levels of osteoprotegerin and soluble osteoclast differentiation factor were undetectable and markedly increased, respectively. Conclusions: Juvenile Paget's disease can result from osteoprotegerin deficiency caused by homozygous deletion of TNFRSF11B.

Original languageEnglish
Pages (from-to)175-184
Number of pages10
JournalNew England Journal of Medicine
Issue number3
StatePublished - Jul 18 2002


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