title: Osseous manifestations of adult Gaucher disease in the era of enzyme replacement therapy.
abstract: Enzyme replacement therapy (ERT) for Gaucher disease with mannose-terminated glucocerebrosidase has proved its therapeutic position with salutary effects on hematologic abnormalities, visceral infiltration, and quality of life. The frequency of new bone complications is reduced but not eliminated. Established osteonecrosis is beyond salvage. A systematic description of the burden of bone manifestations, persisting despite ERT, should inform future remedial strategies. Thus, we conducted this study to quantify the burden of residual skeletal disease and to explore putative relationships between clinical, radiologic, and biochemical factors and bone sequelae associated with disability.Consecutive adult patients attending 3 referral centers in the United Kingdom were invited to participate. A representative group of 100 patients agreed to a structured interview, clinical examination, radiologic review, and completion of questionnaires. Osteonecrosis was evident in 43%, Erlenmeyer flask deformity in 59%, fragility fracture in 28%, osteomyelitis in 6%, and lytic lesions in 4%. Mobility was impaired in 32% of patients, while 15% experienced significant pain. The EuroQol 5D (EQ5D) quality of life summary measure was reduced and was associated with osteonecrosis and fragility fracture. Eight patients experienced new osteonecrosis after the start of ERT, though the presentation and evolution were often atypical. Nine patients had been treated from childhood and had an excellent outcome. Osteonecrosis was associated with age of presentation and with splenectomy-indeed, we observed a strong temporal association between splenectomy and incidence of osteonecrosis.The biomarkers PARC/CCL18 and chitotriosidase were associated with prevalent osteonecrosis, and, in particular, with osteonecrosis occurring despite treatment. This study documents significant residual skeletal pathology and disability in patients in the mature phase of their treatment in a developed region. The temporal association between splenectomy and osteonecrosis implies causation. The relationship between clinical and biochemical markers and existing bone complications sets the scene for future prospective studies that will focus on management strategies informed by credible assessment of risk.
authors.affiliation: From Department of Medicine (PBD, EP, JT, PES, TMC), and Department of Radiology (PB), Addenbrooke's Hospital, Cambridge; Department of Medicine (PBD, EP, PES, TMC), University of Cambridge, Cambridge; Department of Haematology (AM, DH), Royal Free Hospital, London; and Royal Manchester Children's Hospital (JEW), Pendlebury, Manchester, United Kingdom.
authors.forename: Patrick B
authors.initials: PB
authors.lastname: Deegan
authors.forename: Elena
authors.initials: E
authors.lastname: Pavlova
authors.forename: Jane
authors.initials: J
authors.lastname: Tindall
authors.forename: Penelope E
authors.initials: PE
authors.lastname: Stein
authors.forename: Philip
authors.initials: P
authors.lastname: Bearcroft
authors.forename: Atul
authors.initials: A
authors.lastname: Mehta
authors.forename: Derralynn
authors.initials: D
authors.lastname: Hughes
authors.forename: J Edmund
authors.initials: JE
authors.lastname: Wraith
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Cox
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000032:analysis; D015519:Bone Density; D004185:Disability Evaluation; D056947:Enzyme Replacement Therapy / Q000379:methods*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005776:Gaucher Disease / Q000150:complications* / Q000201:enzymology / Q000453:epidemiology / Q000628:therapy*; D006596:Hexosaminidases / Q000032:analysis; D006801:Humans; D007407:Interviews as Topic; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010020:Osteonecrosis / Q000201:enzymology / Q000453:epidemiology / Q000209:etiology*; D011788:Quality of Life; D012042:Registries; D012307:Risk Factors; D013156:Splenectomy; D018709:Statistics, Nonparametric; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D006113:United Kingdom / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D006596:Hexosaminidases; C086400:chitotriosidase