Our study results show a decrease in BP and skeletal complications and an increase in BMD in patients with type 1 GD treated with imiglucerase. Despite the predominance of the N370S genotype in these patients and the relatively mild hematological and visceral disease in this cohort, the patients had evidence of serious skeletal disease at baseline. When this study was initiated, imiglucerase was the sole proven effective therapy available for the hematological and visceral manifestations of type 1 GD found in our patients. Therefore, there was neither any alternative treatment arm proposed nor was a placebo arm included. There is, in fact, no evidence suggesting that established untreated Gaucher bone disease is spontaneously reversible (1
). Untreated, BP and bone crisis are frequently associated with irreversible bone pathology that leads to morbidity, deformity, fractures, multiple orthopedic surgeries, decreased QOL, and early mortality.
Decreased BMD is commonly observed in both men and women with type 1 GD (17
). Several studies have assessed the effect of ERT on BMD in GD, with variable results. Rosenthal et al. observed significant increases in cortical thickness after 42 months of treatment (13
). Using DXA, Ciana et al. reported statistically significant improvements in BMD at a mean follow-up time of 4.5 years (18
). However, Schiffmann et al. found a decrease in BMD using QCT of the lumbar spine in patients receiving ERT (19
) and Lebel et al. reported a mixture of improvement, no change, or decline over a period ranging from 24 to 108 months using DXA (20
). These results are difficult to compare and interpret because the studies were performed in different patient populations (pediatric vs
adult patients and different doses of ERT) and different methodologies were used to assess BMD.
DXA measurements are quantitative, reproducible, widely available in developed countries, and relatively inexpensive. The progressive increase in lumbar spine and femoral neck BMD that we observed supports previous suggestions that serial DXA measurements of these sites be included when monitoring the response to treatment in patients with type 1 GD (4
) and that improving lumbar and femoral BMD is an appropriate therapeutic goal (21
). The increases in BMD noted in this paper, which appeared more quickly than noted in some other studies using various doses of imiglucerase in GD (18
), suggest that the dosage used in this study (60 U/kg/2 weeks) may be an appropriate starting dose in osteopenic patients. Additionally, the lack of change in forearm BMD measurements indicates that assessment of this site may not provide clinically meaningful information when used in the monitoring of patients with type 1 GD.
Our results are consistent with, and complementary to, the recently published retrospective analysis from the ICGG Gaucher Registry. This analysis, in 342 ERT-treated patients, showed that pre-treatment lumbar DXA Z scores were significantly below normal but progressively improved with treatment over an 8-year period with a significant dose–response relationship (10
). In our study, patients received imiglucerase 60 U/kg every 2 weeks. This dose was noted to be the most effective in the Gaucher Registry study. Unlike the Gaucher Registry analysis, however, our trial is not confounded by possible concurrent use of bisphosphonates or by variance in DXA machine type or protocol, although other potential confounders such as smoking and use of female hormone replacement started prior to ERT are not excluded. In our patient cohort, improved BMD occurred concurrently with decreases in BC and BP. Of note, the incidence of fractures was low throughout the 48 months of the study. Few events occurred after month 24, and it is possible that events occurring early in the study were because of diseases present at baseline. Our study, however, neither demonstrated a definitive correlation between BMD and skeletal complications nor do we have any evidence as yet that increasing BMD in patients with type 1 GD will result in long-term reduction in fracture risk as has been shown in women with post-menopausal osteoporosis (22
). Nevertheless, improving BMD appears to be of benefit in other chronic inflammatory diseases with associated osteopenia such as rheumatoid arthritis and Crohn's disease (23
), and it is likely that further cumulative experience with ERT in GD will show similar results. The treatment-associated decreases in BP, and in occurrence of BC observed in this prospective study, are consistent with the retrospective experience reporting improvement in BP and BC in larger number of patients from the International Gaucher Registry (15
Although some previous studies have found that classical biochemical markers for bone formation (osteocalcin and bone-specific alkaline phosphatase) are of limited clinical value for monitoring the response to ERT in patients with type 1 GD (18
), our results, which demonstrate a consistent increase in these markers, suggest that further investigation of the utility of these markers to monitor bone formation is warranted. Increases in bone formation markers from baseline values have been used as an index of response in patients treated for post-menopausal osteopenia (25
). Adjuvant treatment of osteopenia/osteoporosis in patients with type 1 GD has largely focused on inhibition of osteoclasts and retardation of bone resorption with bisphosphonates (14
). However, the lack of consistent changes in markers of bone resorption (N-telopeptide crosslinks and D-PYD) suggests that they may be of limited utility in monitoring bone response to ERT in GD. Our preliminary findings revealed that imiglucerase may enhance bone formation in osteopenic GD patients and confirm the results of Schiffmann et al. (19
). Prospective trials using anabolic bone agents may be worthwhile to undertake in imiglucerase-treated GD patients with persistent osteopenia to determine whether bone formation and BMD can be further enhanced.
In summary, this prospective study confirms that ERT with imiglucerase improves the major symptomatic manifestations of Gaucher skeletal disease, bone crisis and BP, decreases the risk of skeletal events (infarction, lytic lesions, and fracture), and increases lumbar spine and femoral neck BMD during the first 4 years of treatment. Our results suggest that early initiation of treatment in symptomatic patients can substantially alleviate discomfort and may prevent potentially disabling bone complications and overall morbidity.