Bone events and evolution of biologic markers in Gaucher disease before and during treatment

Abstract

IntroductionKnown biomarkers of Gaucher-disease activity are platelets, chitotriosidase, angiotensin-converting enzyme (ACE), tartrate-resistant acid phosphatase (TRAP) and ferritin. The aim of this study was to retrospectively evaluate the frequency of bone events (BE) and biomarker changes during two periods: diagnosis to first enzyme-replacement therapy (ERT) and the latter to the closing date.MethodsBE of 62 treated patients, among the 73-patient cohort followed at Beaujon Hospital, Clichy, France, were described with Kaplan-Meier curves, and linear-mixed models were used to analyze their biomarker changes and the influence of several covariates (splenectomy, diagnosis year, genotype, age at diagnosis and sex).ResultsBE occurred before (54 events in 21 patients), but also during, ERT (12 events in 10 patients), with respective frequencies (95% confidence interval) at 10 years of 22.4% (13.3 to 36.3) and 20.0% (10.2 to 36.9). Biomarker slope changes before and during ERT differed significantly for platelets (+190/mm3/year and 7,035/mm3/year, respectively; P < 0.0001) and ferritin (+4% and -14%; P < 0.0001). High ferritin levels and low platelet counts at ERT onset were significantly associated with BE during ERT (P = 0.019 and 0.039, respectively). Covariates significantly influenced biomarker changes (baseline and/or slope): splenectomy affected platelets (baseline and changes), TRAP changes and chitotriosidase changes; diagnosis date influenced ACE and TRAP baseline values; and genotype influenced chitotriosidase baseline and changes.ConclusionsPlatelet counts and ferritin levels and their slope changes at ERT onset seem to predict BE during treatment. Biomarker baseline values and changes are dependent on several covariables.

Management of Bone Disease in Gaucher Disease Type 1: Clinical Practice

“…Bone turnover can be measured with specific biochemical markers [60] for enzyme activities, the release of various structural components of bone, and proteins involved in the processes of bone formation (Table 5). Over the years, most of these parameters have been tested in patients with GD [33][34][35][36][37][38][39][40]. Urinary total hydroxyproline levels are used to identify osteoclastic hyperactivity.…”

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

“…(6) The most impactful and dramatic clinical complications arising from bone involvement are AVN, osteopenia, and fractures. (2,5,7,8) These complications permanently alter the health status of affected patients due to chronic pain, disability, and the need for surgical interventions. (6) The precise risk of AVN in untreated GD1 (not receiving imiglucerase therapy) was estimated to be 22.8 per 1000 person years (95% confidence interval [CI], 20.2-25.7) of follow-up.…”

“…Other than the most conspicuous form of AVN, akin to that seen in sickle cell crises, there is also a silent variety of AVN in GD1 that occurs in the form of medullary infarction due to asymptomatic vascular obstruction of medullary blood vessels; this form of AVN is detected by magnetic resonance imaging (MRI) of the bone marrow. (11) The majority of GD1 patients exhibit osteopenia, (2,5,7) measured by dual-energy X-ray absorptiometry (DXA). (12,13) Although osteopenia in GD is commonly attributed to increased osteoclastic bone resorption, (14) it is more likely related to impaired osteoblast function (15,16) associated with accumulating lipids.…”

Biomarkers for osteonecrosis in Gaucher disease

“…Serum CCL5/RANTES was significantly elevated in patients who had osteonecrosis and in the small group of Gaucher patients who had not met therapeutic goals, despite enzyme therapy [72]. In a retrospective survey from France, based on routine physical assessments and the results of more conventional analytes such as serum ferritin, in a cohort of 62 patients, initial ferritin concentrations and platelet counts were associated with bone events reported during enzyme therapy [75].…”

“…Detailed analyses of the same cohort indicated that CXCL8/IL-8 and CCL5/RANTES had the best discriminatory characteristics for osteonecrosis (Figure 4) [72]. Other putative markers have been reported to be associated with the episodes of osteonecrosis despite treatment [72,75]. CXCL8/IL-8 is implicated in leukocyte--vascular endothelial interactions and appears to mediate angiogenesis driven by cells of macrophage lineage [96,97].…”