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Risk factors for osteonecrosis were evaluated in patients receiving therapy.1-3
Observational, retrospective, 20‑year study: Evaluation of risk factors for osteonecrosis in patients receiving treatment for Gaucher disease type 1 (GD1)4
Understanding the risk of osteonecrosis (also known as avascular necrosis, or AVN) is crucial when managing GD1. Osteonecrosis is one of the most debilitating, severe, and irreversible manifestations of GD1, and any patient with GD1 is at risk, even when receiving treatment.4,5
This 20-year, observational, retrospective study evaluated certain risk factors contributing to osteonecrosis in patients receiving therapy.4
Patients with GD1 may be at increased risk for osteonecrosis if they have4:
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Heteroallelic p.N409S GBA1 genotype
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Increased residual glucosylsphingosine (lyso-GL-1) levels after starting treatment
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Treatment history with a specific ERT
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History of osteonecrosis prior to initiation of treatment
About osteonecrosis
GD1 causes cellular accumulation of glucosylceramide and lyso-GL-1, leading to complex bone diseases, including osteonecrosis4
Osteonecrosis refers to the death of bone tissue, which may be caused by a lack of blood supply4
Osteonecrosis from GD1 is devastating and irreversible, causing5:
- Pain
- Chronic disability
- Need for orthopedic surgeries
- Reduced quality of life
The underlying mechanism(s) of osteonecrosis in Gaucher disease is not fully understood4
82% of patients with GD1 have evidence of bone disease, including osteonecrosis, which can manifest at all ages.3
Patients with GD1 are at risk for osteonecrosis, even while on treatment4
Observational, retrospective, 20-year study: Study design
- Retrospective, observational, single‑center study of 155 patients with GD1 followed longitudinally for 20 years
- Patients were followed every 1 to 2 years with standard-of-care evaluations, including magnetic resonance imaging (MRI) to assess organomegaly and bone marrow infiltration, and laboratory testing
- Serum samples were collected at each clinic visit to determine biomarker trends for lyso-GL-1 and chitotriosidase (chito), as well as other indicators of disease
- During the observational period, patients received a total of 834 treatment years for imiglucerase (ERT), 310 treatment years for velaglucerase alfa (ERT), and 238 treatment years for Cerdelga (SRT)
- Confirmed diagnosis of GD1
- Known treatment status and date of initiation/switch
- Known splenectomy status
- Known previous history of osteonecrosis
- Longitudinal data of MRI volumetrics for liver and spleen, cell blood count (CBC), and biomarkers including lyso-GL-1 and chito
- This is a single-center study. It was also retrospective and observational. This study was not a randomized, controlled study
- Tertiary referral center: The incidences of osteonecrosis reported in this study may or may not be reflective of the incidence that would be observed in other clinics, particularly ones that are not tertiary referral centers for Gaucher disease
- The treatment and management decisions reported were directed by the clinical judgment of the treatment team at this single center. Treatment decisions for each patient are due to a number of different factors, including but not limited to the patient’s clinical status and availability of each therapy option
No patients taking Cerdelga experienced osteonecrosis in this observational, 20-year study4
Incidence of osteonecrosis while on therapy
- Osteonecrosis episodes were counted per total number of years on each type of treatment; over this 20-year period, some patients may have switched from one treatment to another
- During the 20-year span of this study, there were 16 episodes of osteonecrosis in 14 patients, with 2 episodes each occurring in 2 patients
For Cerdelga and velaglucerase alfa, data are only available starting from 2014 and 2010, respectively, when they were approved by the FDA.6,7
For more information about this data and the study, see the article in eLife.
- Generally, episodes of osteonecrosis were associated with new, exacerbated, or chronic bone pain that prompted new visits earlier than regularly scheduled 1- to 2-year follow‑ups4
- Occasionally, new osteonecrosis was found on MRI scans taken at regularly scheduled follow-up visits. On closer evaluation, patients reported bone pain they had managed independently4
How treatment impacted GD-1–associated biomarkers over 20 years4
Levels of lyso-GL-1 while on therapy
Normal healthy control levels of lyso-GL-1 were ≤1 ng/mL.4
Patients with high levels of residual lyso‑GL-1a had an increased risk for osteonecrosis in this observational study4,8
Levels of chitotriosidase while on therapy
CHIT1 genotyping was performed to normalize serum levels.4
There was no observed association between levels of residual chito and the risk of osteonecrosis in this group of patients4
This study was observational and not designed to compare the outcomes of treatment or draw conclusions on the effect of one treatment over another.4
During this 20-year period, some patients may have switched treatments.4
aResidual lyso-GL-1 refers to serum concentration measured in a sample taken at close proximity to the onset of osteonecrosis (but not levels prior to treatment initiation).4
Findings: The 4 risk factors for osteonecrosis in patients with GD14
Heteroallelic p.N409S GBA1 genotype
Heteroallelic N409S GD1 patients were 10 times more likely than N409S homozygous GD1 patients to develop osteonecrosis during treatment4
Increased residual lyso-GL-1 levels after starting treatment
A higher residual serum lyso‑GL-1a was correlated with an increased risk of developing osteonecrosis during treatment4
Treatment history with a specific ERT
Patients received cumulative 310 treatment years velaglucerase and there were 10 episodes of osteonecrosis, which is 3.2 episodes per 100 treatment years of velaglucerase4
History of osteonecrosis prior to initiation of treatment
Patients had a 4.8 times higher risk for osteonecrosis while receiving treatment if they had a history of osteonecrosis prior to treatment initiation4
aResidual lyso-GL-1 refers to serum concentration measured in a sample taken at close proximity to the onset of osteonecrosis (but not prior to treatment initiation).4
Curious how Cerdelga impacted other bone health parameters in patients with GD1?
Explore clinical trial results for bone marrow burden, bone mineral density, and bone pain for patients with GD1
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Indication
References: 1. Data on file. Sanofi. 2. Cox TM, Charrow J, Lukina E, et al. Long-term effects of eliglustat on skeletal manifestations in clinical trials of patients with Gaucher disease type 1. Genet Med. 2023;25(2):100329. 3. Goker-Alpan O. Mol Genet Metab. 2011;104(4):438-447. 4. Basiri M, Ghaffari ME, Ruan J, et al. Osteonecrosis in Gaucher disease in the era of multiple therapies: biomarker set for risk stratification from a tertiary referral center. Elife. 2023;12:e87537. 5. Hughes D, Mikosch P, Belmatoug N, et al. Gaucher disease in bone: from pathophysiology to practice. J Bone Miner Res. 2019;34(6):996-1013. 6. Cerdelga (eliglustat) [prescribing information]. Genzyme Corporation, Cambridge, MA. 7. VPRIV (velaglucerase alfa) [prescribing information]. Takeda Pharmaceuticals, Lexington, MA. 8. Murugesan V, Chuang WL, Liu J, et al. Glucosylsphingosine is a key biomarker of Gaucher disease. Am J Hematol. 2016;91(11):1082‑1089.
