Bone Abstracts

Gaucher disease (GD) is a lysosomal storage disorder due to deficiency of glucocerebrosidase, leading to glucocerebroside storage mainly in macrophages, but also in other cells (lymphocytes, osteoblasts, and neurons).

Clinically important bone manifestations of GD include severe acute ‘bone crisis’ (acute avascular osteonecrosis), medullary infarction, osteopenia or osteoporosis, osteolytic lesions, pathologic fractures, defective bone remodelling (Erlenmeyer flask deformity) and growth failure in children. At diagnosis nearly 100% of patients exhibit symptomatic or imaging evidence of at least one of these skeletal manifestations.

Decreased bone mineral density has generally been attributed to increased bone resorption, possibly due to osteoclastogenesis mediated by T cell via TNF-α or by macrophages via other cytokines. However biomarkers of osteoclast function are inconsistently increased in GD patients and no significant clinical response arises from inhibition of bone resorption with biphosphonates. Recently osteoblast dysfunction mediated by accumulating glycolipid through inhibition of protein kinase C has been demonstrated in GD. Nonetheless poor osteoclast-osteoblast signalling from osteoclasts via reduced sphingosine 1 phosphate production may also play a causal role.

Avascular necrosis and medullary infarction are generally related to bone marrow infiltration by macrophages, causing vascular occlusion, compression and increased intraosseous pressure. However the inflammatory mediators secreted by macrophages may also play a causal role. The biomarkers PARC/CCL18 and chitotriosidase, which are directly related to burden of storage in macrophages, are associated with prevalent osteonecrosis, and, in particular, with osteonecrosis occurring despite treatment.

The golden standard of treatment in GD is enzyme replacement therapy with macrophage targeted recombinat glucocerebrosidase. Enzyme replacement therapy reverses haematological and visceral complications, but bone improvement occurs slowly and incompletely. In particular the achievement of age- and sex-adjusted normal bone mineral density takes a longer period of time and require higher doses of ERT than other complications of GD. Other GD therapies, like substrate inhibitors, which are not macrophage targeted seems to have better efficacy to bone mineral density.

Declaration of interest: M Di Rocco has an advisory role in genzyme, Shire and has received honoraria from Genzyme, Shire, Actelion and Biomarin.