Bone Abstracts

Shwachman Diamond syndrome (SDS; MIM 260400) is a monogenic, autosomal recessive, pancreatic condition often accompanied by low bone mass and fracture. In SDS, as in cystic fibrosis, a low bone mass may be secondary to poor nutrition or chronic low-grade infection, but it has also been suggested there may be a primary bone phenotype. Paradoxically, recent studies in cell lines and in a mouse knockout for the SBDS gene, have suggested changes in important osteoclast growth factors and impairment of osteoclast formation and migration. Here we evaluated whether there were osteoclast abnormalities in bone biopsies of seven patients with SDS and assessed bone histology (but not histomorphometry) using trephine biopsies. We also studied whether previously reported abnormalities in signalling through the osteoclast receptor RANK (receptor activator of nuclear factor κB) in the mouse SBDS knockout, was seen in osteoclasts carrying mutant SBDS generated in vitro from patient monocytes (in five patients). Bone histology was variable: osteoclast function was evident in all patients and evidence of bone formation, but also osteoid accumulation was seen in some. Osteoclast ultrastructure revealed no gross anatomical abnormalities. In vitro studies did not reveal defects in osteoclast formation and RANK signalling, both in osteoclast precursors and in mature osteoclasts, was not impaired. Our data suggest that in SBDS patients, osteoclast formation is normal and that osteoclast activity may be increased, rather than reduced, in keeping with the increased fracture risk in patients. Our findings suggest that the SBDS mouse knockout model does not reproduce the phenotype seen in patients harbouring mutated SBDS alleles. Further studies using histomorphometry with dynamic bone markers are indicated to fully understand the basis of the increased fracture risk in these patients. Bone mass in SBDS patients should be monitored, including by non-invasive procedures.