Abstract
ABSTRACTGaucher disease (GD) is a rare, genetic lysosomal disorder leading to lipid accumulation and dysfunction in multiple organs. Involvement of the skeleton is one of the most prevalent aspects of GD and a major cause of pain, disability, and reduced quality of life. Uniform recommendations for contemporary evaluation and management are needed. To develop practical clinical recommendations, an international group of experienced physicians conducted a comprehensive review of 20 years’ of the literature, defining terms according to pathophysiological understanding and pointing out best practice and unmet needs related to the skeletal features of this disorder. Abnormalities of bone modeling, reduced bone density, bone infarction, and plasma cell dyscrasias accompany the displacement of healthy adipocytes in adult marrow. Exposure to excess bioactive glycosphingolipids appears to affect hematopoiesis and the balance of osteoblast and osteoclast numbers and activity. Imbalance between bone formation and breakdown induces disordered trabecular and cortical bone modeling, cortical bone thinning, fragility fractures, and osteolytic lesions. Regular assessment of bone mineral density, marrow infiltration, the axial skeleton and searching for potential malignancy are recommended. MRI is valuable for monitoring skeletal involvement: It provides semiquantitative assessment of marrow infiltration and the degree of bone infarction. When MRI is not available, monitoring of painful acute bone crises and osteonecrosis by plain X‐ray has limited value. In adult patients, we recommend DXA of the lumbar spine and left and right hips, with careful protocols designed to exclude focal disease; serial follow‐up should be done using the same standardized instrument. Skeletal health may be improved by common measures, including adequate calcium and vitamin D and management of pain and orthopedic complications. Prompt initiation of specific therapy for GD is crucial to optimizing outcomes and preventing irreversible skeletal complications. Investing in safe, clinically useful, and better predictive methods for determining bone integrity and fracture risk remains a need. © 2019 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.
Highlights
Pathophysiology, diagnosis, and treatment of Gaucher diseaseGaucher disease (GD) is a lysosomal disorder leading to lipid accumulation
Bioactive sphingolipids induce a cascade of changes that affect bone vascularity, intramedullary pressure, the immune environment, hematopoiesis, and the function of cells that reside in bone, disturbing skeletal growth and bone modeling and remodeling.[14]. Several of these effects are modified by specific therapies, but the underlying pathophysiology of bone disease remains poorly understood
We found that the division into four topics was somewhat artificial and overlapping; we decided to organize best practices and unmet needs in GD‐related bone disease into three key skeletal compartments: [1] the bone marrow (Gaucher cell infiltration, macrophage function, osteoclast differentiation, interactions among bone and marrow or immune cells, soluble messengers and biomarkers, fibrosis, and extraosseous “Gaucheromas”); [2] trabecular and cortical bone modeling and remodeling defects, delayed bone growth, and bone mineral loss and their consequences; and [3] medullary and cortical bone infarction
Summary
Gaucher disease (GD) is a lysosomal disorder leading to lipid accumulation. The lysosome is an intracellular organelle that degrades and recycles biological macromolecules derived either endogenously, from digestion of cellular components (autophagy), or from the breakdown of material incorporated from outside the cell by phagocytosis. In response to the inconvenience of parenteral administration, there have been initiatives to develop alternative treatments, including the use of oral agents that inhibit the formation of the substrate delivered to macrophages The first such agent approved, miglustat (Zavesca; Actelion Pharmaceuticals, San Francisco, CA, USA), reduced the sphingolipid content of circulating white cells and had modest effects on laboratory and clinical parameters of GD activity. Bioactive sphingolipids induce a cascade of changes that affect bone vascularity, intramedullary pressure, the immune environment, hematopoiesis, and the function of cells that reside in bone, disturbing skeletal growth and bone modeling and remodeling.[14] Several of these effects (eg, marrow infiltration by pathological macrophages and osteopenia) are modified by specific therapies, but the underlying pathophysiology of bone disease remains poorly understood. Bone disease is often asymptomatic[15] and may sometimes progress despite apparently effective disease‐modifying treatment.[16,17]
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