Gaucher disease (GD) is a lysosomal storage disease characterized by a genetic disruption in the metabolic breakdown of glucocerebroside caused by a lack of the enzyme beta-glucocerebrosidase. Bone complications are common in the non-neuronopathic form of GD (formerly type I) and lead to considerable pain, limitations in mobility and negative impact on the quality of life. Skeletal manifestations of GD include osteopenia and osteoporosis, bone loss, Erlenmeyer flask deformity and osteonecrosis. Low bone mineral density (BMD) is thought to arise from enhanced bone resorption mediated through macrophage-derived factors, such as the C-C motif ligand 3 (CCL3) chemokine. The aim of this study was to evaluate the clinical and biochemical characteristics of bone involvement in patients with the non-neuronopathic form of GD.
We studied 27 adult patients (15M/12F, median age 44.5 years, range: 18–71 years) with non-neuronopathic GD. Three patients were evaluated at diagnosis, while the others after a 6-month discontinuation of replacement therapy with imiglucerase due to temporary shortage of the drug supply in Greece. BMD of the lumbar spine and femoral neck was determined in all patients, using dual energy X-ray absorptiometry (DXA). Furthermore, magnetic resonance imaging (MRI) of the femoral bones was also performed in all patients. The MRI protocol included T1-weighted spin echo and turbo echo sequences, short time inversion recovery (STIR) sequences and T2-weighted spin echo, turbo spin echo (TSE) sequences. Based on the severity of abnormal MRI findings and the decreased fat content in the bone marrow, patients were categorized in 4 grades: I-IV. On the day of MRI, we evaluated also the circulating levels of CCL3 along with two sensitive serum markers of bone resorption: C-telopeptide of collagen type-1 (CTX) and tartrate resistant acid phosphatase isoform type-B (TRACP-5b), which is produced mainly by activated osteoclasts. Bone markers were also evaluated in 25 healthy, gender- and age- matched controls, as well as in all patients, 6 months post re-initiation of replacement therapy (when the drug became available again).
Twelve patients (46%) had bone pain, while 3 patients had restrictions in free movement and 2 patients experienced difficulty in walking at the time of study initiation. The majority of the patients (91%) had elevated chitotriosidase levels (median: 1647 nmol/ml/hr, range: 147–18880 nmol/ml/hr; UNL: 150 nmol/ml/hr) indicating active disease, while 25% of the patients had abnormally high levels of acid phosphatase. Six (22%) patients had osteoporosis at least in one of the studied sites, 18 (66%) patients had osteopenia and 3 patients had normal DXA scan. All but one patient had abnormal MRI findings: 3 (11%) had grade I MRI abnormalities, 18 (66%) had grade II, 3 (11%) grade III and 2 (7%) grade IV. Erlenmeyer flask sign was observed in 23 (85%) patients.
At study initiation, GD patients had elevated serum levels of TRACP-5b (mean±SD: 7.6±5.3 IU/L) compared to controls (1.3±0.6 IU/L; p<0.001) and high circulating CCL3 (71±31 pg/ml) versus controls (16±11 pg/ml, p<0.001). There was a positive correlation between serum TRACP-5b and chitotriosidase levels (r=0.493, p=0.017) as well as between TRACP-5b and CCL3 levels (r=0.512, p=0.01). Patients with osteopenia or osteoporosis had elevated chitotriosidase levels (4741±4876 nmol/ml/hr) compared to others (478±415 nmol/ml/hr; p=0.035). Patients with advanced MRI disease (grades III & IV) had elevated levels of acid phosphatase (13.1±3.7 U/L) compared to grades I & II (8.6±1.8 U/L; p=0.011). Six months post- re-initiation of replacement therapy TRACP-5b levels (7.1±4.1 IU/L; p=0.011) and CCL3 levels (42±29 pg/ml; p=0.01) were significantly reduced.
In conclusion, our findings suggest that patients with active non-neuronopathic GD have abnormal MRI bone findings in the femoral bones and increased incidence of bone loss (osteopenia or osteoporosis). The enhanced osteoclast activity (assessed by the high TRACP-5b serum levels) which is present in GD, is - at least partially - due to elevated CCL3 (a potent osteoclast activator) and it seems to be implicated in the biology of bone involvement in non-neuronopathic GD. Replacement therapy reduces abnormal osteoclast function; longer follow-up will reveal if this reduction is followed by the reversal of bone involvement in this disease.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.