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The Bone in Gaucher Disease
differences in cellular uptake of imiglucerase,
39
and because bone
Figure 4: Impact of Imiglucerase Therapy on Changes in Bone
turnover is slower than cell cycling in other affected tissues,
40,41
reversal
Marrow Burden Score
of extensive bone marrow infiltration and loss of bone mass generally
70
takes longer to correct, and may require higher imiglucerase doses.
(n=22)
60
Enzyme therapy cannot reverse established osseous injuries, including
50
fractures and joint collapse, that occur as a result of osteonecrosis or the
40
effects of local osteolysis. However, initiation of imiglucerase treatment
early in the course of disease can avert these eventual catastrophic
2 points increase
30
(n=13)
rcentage of patients
≥
20
complications. Enzyme replacement therapy with alglucerase and/or Pe
with in bone marrow burden
imiglucerase permits restoration of bone growth in children, decreases
10
the frequency of necrosis, bone crises and non-specific bone pain,
0
p=0.04
reduces bone marrow infiltration by Gaucher cells, improves BMD, and,
01 2345 6
Years on therapy
often in conjunction with expert orthopaedic and rehabilitative services,
Academic Medical Center group of Gaucher patients initiated at median dose of
enhances health-related quality of life for patients with documented
Cerezyme 7.5U/kg bodyweight/two weeks, after year two increasing to median dose
skeletal disease.
27,29,42–48 of 15U/kg bodyweight/two weeks
Heinrich-Heine University group of Gaucher patients initiated and maintained at
median dose of Cerezyme 40U/kg bodyweight/two weeks
Bone Pain and Bone Crises
The International Collaborative Gaucher Group (ICGG) Gaucher Time to reach a decrease of two points in bone marrow burden (BMB) score from baseline of patients with a
Registry was established in 1991 as a voluntary observational database
baseline BMB of six to eight. Adapted from De Fost et al.
45
to track the clinical, biochemical and therapeutic characteristics of
patients with GD1, irrespective of disease severity and treatment
Figure 5: Dose-dependent Improvement in Bone Mineral Density
status.
14
The registry is supported by Genzyme Corporation and
After Eight Years of Treatment with Imiglucerase
supervised by the ICGG scientific board, a group of international
1
physician experts in GD1. The registry is the largest data set on patients
with GD1 worldwide and represents a sizeable portion of the total
known patients. ICGG Registry data on 229 patients with pre-
0
60
treatment bone pain and on 93 patients with pre-treatment history of
30
15
bone crises suggested that alglucerase and/or imiglucerase prevent -1
both new-onset and recurrent Gaucher bone crises and ameliorate
chronic bone pain.
33
However, those results that were based on
Lumbar spine DEXA Z-score
-2
aggregate pre- and post-treatment populations may have been
02468
subject to potential bias. A more recent analysis of registry data was
Years on therapy
Normal healthy population
restricted to patients with bone crisis (n=219) and/or bone pain
Gaucher patients not treated with Cerezyme (n=160)
(n=244) data for one year prior to alglucerase and/or imiglucerase and
Cerezyme 60U/kg bodyweight/two weeks (n=111)
Cerezyme 30U/kg bodyweight/two weeks (n=116)
for each of three years after the start of therapy.
47
This study showed Cerezyme 15U/kg bodyweight/two weeks (n=113)
that crises were reported in 17% of patients during the year before
Linear mixed models for 342 treated patients and 160 treatment-naïve patients.
starting imiglucerase. The frequencies of bone crises decreased to 5, 1
Adapted from Wenstrup et al.
28
and 3% for one, two and three years after initiation of treatment,
respectively. Bone pain was reported in 49% of patients the year fraction measurements and high BMB scores correlated with other
before treatment and decreased to 30% in the first year, 29% in the indices of bone complications.
5
second year and 30% in the third year of imiglucerase therapy.
Bone Mineral Density
Bone Marrow Infiltraton All imiglucerase-treated adults (females 18–50 years of age, males
There is ample evidence that using QSCI to calculate fat fraction and 18–70 years of age) from the ICGG Registry with available lumbar spine
bone marrow infiltration, particularly in the lumbar spine, begins to DEXA data to January 2006 were analysed for changes in BMD using
decrease early after starting imiglucerase treatment.
20–22
A recent study linear mixed modelling.
28
The treated patients (n=342) were compared
based on femoral BMB score showed that imiglucerase improves bone with 160 untreated patients with the same age and gender criteria. In
marrow infiltration in a dose-dependent manner.
45
In a retrospective the untreated category, the average baseline DEXA Z-score was -0.8
study of patients matched for common parameters associated with (lower than averages reported for patients with rheumatoid arthritis
49
disease severity and with similar glucocerebrosidase mutation or Crohn’s disease not exposed to corticosteroids
50
), and decreased
genotypes at the Academic Medical Center, Amsterdam (n=49, median slightly over eight years. In the treated patients, the average baseline
dose 15–30U/kg/four weeks) and the Heinrich-Heine University, DEXA Z-score was -1.2. Patients treated with imiglucerase at 60U/kg/
Düsseldorf (n=57, median dose 80U/kg/four weeks), improvement in two weeks achieved, on average, a normal Z-score (0) after about eight
haemoglobin, platelet count and hepatosplenomegaly was not years. Average eight-year Z-scores for patients treated with 30U/kg and
significantly different between cohorts, whereas plasma chitotriosidase 15U/kg were -0.6 and -0.8, respectively (see Figure 5). However, it is
and bone marrow involvement by MRI improved more quickly and was important to note that some patients with initially decreased BMD
more pronounced in the higher-dose group (see Figure 4). In previous remained osteopaenic even after eight years of therapy and that elderly
studies, persistence of bone marrow infiltration evidenced by low fat women were not included in this study. Despite having had enzyme
EUROPEAN MUSCULOSKELETAL REVIEW 2007 35
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