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Review • J. inborn errors metab. screen. 13 • 2025 • https://doi.org/10.1590/2326-4594-JIEMS-2024-0002 linkcopy

Open-access Exploration of Bone Alterations in Gaucher Disease Type 1: A Global and Systematic Analysis of Scientific Knowledge

AuthorshipSCIMAGO INSTITUTIONS RANKINGS

    Abstract

    Gaucher disease type 1 (GD1) is the most common lysosomal storage disorder, characterized by hepatomegaly, splenomegaly, anemia, thrombocytopenia, and skeletal manifestations, which significantly affect quality of life. This systematic review aimed to assess the current state of the disease, focusing on skeletal manifestations. A systematic search was conducted between 2000 and February 2024 in multiple languages using PRISMA-ScR and JBI methods. A total of 96 studies were identified: 23 systematic reviews, 23 descriptive studies, 17 case reports, 13 experimental studies, 10 retrospective studies, 4 observational studies, 4 prospective studies, and 2 cross-sectional studies. The highest number of articles on the topic was published in 2015, and the countries with the most publications were the USA, Italy, Brazil, and Argentina over the 23 years covered in the search. These studies cover various aspects of GD1, including skeletal features, patient phenotypes, clinical annotations, diagnostics, therapies, and patient perspectives. Despite advances, challenges such as disease heterogeneity and inconsistent results persist. This review underscores the importance of further research to improve understanding and management of GD1, with an emphasis on skeletal manifestations.

    Keywords:
    Gaucher Disease; Lysosomal Storage Disorders; Skeletal Manifestations; Systematic Review; Quality of Life

    Introduction

    GD1 is an autosomal recessive genetic disorder with an estimated worldwide incidence of one in 50,000 to 100,000 live births [1]. Three clinical forms of GD are conventionally classified based on the neurological involvement: type 1 (GD1) is considered non-neuronopathic, whereas types 2 (GD2) and 3 (GD3) are considered the neuronopathic forms. The most common form of the disease is GD1 [1,2].

    GD is caused by deficiency activity of the enzyme β-glucocerebrosidase (GCase; glucosylceramidase; EC 3.2.1.45), Gcase catalyzes the conversion of glucosylceramide (GlcCer) into ceramide and glucose. As GlcCer accumulates in lysosomal macrophages in the reticuloendothelial system, it undergoes deacetylation via an enzyme called acid ceramidase to become glycosylsphingosine (lyso-Gb1)[2,3], leading to the accumulation of sphingolipids in various tissues and organs, including the liver, spleen, and bone marrow. Among the multiple clinical manifestations, skeletal signs and symptoms affect 25 to 32% of patients, but often do not raise suspicions of GD. However, conditions such as bone pain, necrosis, fracture events, or growth deficient in children progressively decrease quality of life and could suggest the diagnosis of GD [4].

    It presents significant genetic heterogeneity, with approximately 460 genetic variants identified in the glucocerebrosidase (GBA) gene associated with its onset. These variants can have diverse impacts on the enzymatic activity of β-glucocerebrosidase and, therefore, on the clinical phenotype observed in patients. Certain genetic variants have been observed to be related to more severe forms of the disease, while others may be associated with milder clinical manifestations or even be asymptomatic. This phenotypic variability in GD reflects the complexity of its pathogenesis and underscores the importance of an individualized approach in the diagnosis and management of patients[5].

    Specifically, bone involvement is responsible for much of the morbidity presented by patients with GD. Bone and joint pain, often associated with pain crises, can be debilitating and chronic. Radiographic findings indicate a certain degree of bone marrow infiltration and replacement by Gaucher cells, resulting in loss of bone trabeculation and decreased density, being more common in the epiphyses and metaphyses of long bones [6]. Overall, according to the literature, approximately 50% of patients present bone pain; patients may exhibit bone marrow infiltration, severe bone crises, intermittent chronic bone pain, osteopenia, osteoporosis, and pathological fractures of long bones and vertebrae[6,7].

    GD1 manifests in a wide range of skeletal signs and symptoms that have a significant impact on patient health. Understanding and effectively addressing these symptoms are crucial for improving quality of life and treatment outcomes. For this reason, this comprehensive literature review is conducted, deeply exploring the knowledge of GD1 and its effects on bone health; in addition to seeking new perspectives on this disease globally, aspiring to recognize the current state of research in this field and obtaining comprehensive information on this pathology[8].

    This review is a synthesis of decades of research, an effort to highlight the vital importance of early detection of bone signs and symptoms of GD1, starting from childhood, with the aim of mitigating subsequent morbidity and mortality, as well as preventing damage to other organs and systems, particularly the skeletal system. This approach allows for a population-based, participatory medicine that accurately predicts, personalizes, and prevents.

    Methods

    This review followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist and was based on the Joanna Briggs Institute (JBI) method initially conceived by Arksey and O'Malley [9], which, in turn, is based on the methodological guide established by Peters et al., 2015 [10]. The suggested steps included: formulating the research question, identifying relevant studies, selecting studies, extracting data, summarizing, and reporting results, and drawing conclusions.

    Research question

    To guide the scoping review, the PICO question was constructed: "What is the state of knowledge regarding bone involvement in GD1 worldwide?" The question was designed based on Population, Intervention, Comparison, and Outcome (PICO) elements:

    1. P (Population): Patients clinically, enzymatically, and/or molecularly diagnosed with GD1

    2. I (Intervention): Experimental, descriptive, observational studies, systematic reviews, case reports.

    3. C (Comparison): Countries where the topic is most frequently published, years with the highest number of publications.

    4. O (Outcome): Database of scientific articles focused on bone disease in GD1 and its global application. No comparison/control was considered as it was not relevant during the research development, since there was no control group to compare results.

    Study selection

    Studies were included if they met the following inclusion criteria:

    Primary scientific studies, reviews, expert recommendations, conferences, guidelines, or protocols published in Spanish, English, French, Portuguese, and German between 2000 and 2024.

    Studies conducted worldwide on patients with GD1 with bone manifestations.

    Studies were excluded if they met the following exclusion criteria:

    • Studies that did not provide sufficient information on the equation used to understand bone disease in GD1.

    • Studies that only mentioned aspects of bone disease but were not the focus of the research.

    Participant types

    Studies were selected if they described aspects related to bone disease in GD1 in both methodology and results and provided a discussion and conclusion relevant to the topic.

    Identification of relevant studies

    For this review, primary sources such as original articles resulting from research were used, along with secondary sources like existing reviews on the described topic, which included studies conducted on populations affected by GD1 worldwide.

    An initial search was conducted to identify published literature: 1) A review was performed on databases including PubMed, Lilac, and Scielo using DeCS/MeSH Keywords: Algorithm, Alterations, Bone Damage, Densitometry, Gaucher Disease, Bone Manifestations, Radiography, Magnetic Resonance, Prediction, in Spanish, English, French, German, Portuguese, without time or publication origin site limits. From the analysis of the results of this initial search, additional keywords were identified that were most used in relevant studies that met inclusion criteria for this review.

    A second, more in-depth search was conducted using all the keywords identified in the previous step. No time limit was set for the search, and articles published in English, Portuguese, and Spanish were included.

    Keyword combinations were defined according to the PICO question, allowing for the creation of a search equation with the main descriptors and structured qualifiers in the Thesaurus, ensuring a higher degree of precision in locating linked terms in articles included in the bibliographic database of interest for the review.

    The term “Gaucher disease” was first combined with “bone” and then independently with “avascular necrosis,” “bone crisis,” “osteomyelitis,” “osteoporosis,” and “Erlenmeyer deformity” using the Boolean connector “OR.”

    The search equation generated was as follows:

    (("Gaucher disease") AND (Bone OR “avascular bone necrosis” OR “bone crisis” OR osteomyelitis OR osteoporosis OR “Erlenmeyer deformity”) AND NOT (“neurological disease” OR hepatosplenomegaly OR “heart disease” OR “Ophthalmological”))

    The search in the chosen databases was supplemented manually by reviewing bibliographic references of the articles found to ensure a comprehensive search. This process was repeated multiple times to avoid overlooking potentially useful studies.

    Data extraction

    Once the articles were identified and selected, the researchers conducted readings and compiled a descriptive table with the most relevant data. A team member removed duplicate articles and then filtered the remaining studies based on information from the title, abstract, and full text, classifying them as relevant or not relevant according to the established inclusion criteria. Quality control for the selection process was conducted by a second investigator, who reviewed excluded articles to avoid the loss of relevant information. There were no discrepancies among the researchers. Table 1 describes the characteristics of the articles: author, year of publication, country of origin, study population, sample size, and intervention results.

    Thumbnail
    Table 1.
    Characteristics of the articles reported in the study.

    Presentation of results

    A pipeline was created to describe the search process and the final number of included studies, as well as the description of the countries involved, languages, number of studies, authors, and main results obtained.

    Results

    Using the specific search equations, 293 studies were identified. The exclusion criteria automatically removed reviews and articles that were not in English, Spanish, French, Portuguese, and German through the Boolean operator NOT, as well as those with keywords like "neurological disease" "hepatosplenomegaly," or "heart disease" in the title. Specifically, 27 articles from LILACS, 157 from PubMed, and 10 from SciELO were eliminated. Additionally, 55 duplicate articles were removed. During the initial selection phase, 108 articles were considered; however, 12 articles were excluded based on the inclusion criteria. After excluding duplicate records, a total of 96 studies were included in the final study analysis (Figure 1, Table 1).

    thumbnail of Figure 1
    Figure 1
    Pipeline for systematic review.

    In 100% of the studies, an emphasis on bone disease as a determinant in GD1 was identified. The countries where publications of these studies were conducted include Albania, Germany, Argentina, Austria, Brazil, Canada, Chile, USA, Egypt, Spain, France, Greece, India, Israel, Italy, Japan, Macedonia, Mexico, Netherlands, Poland, Romania, Russia, and the United Kingdom (Figure). The top five countries with the highest number of publications on this topic were the United States (17.71%), Italy (14.58%), Argentina (9.38%), Brazil (9.38%), and the United Kingdom (7.29%), each contributing (14.55%) (Figure 2).

    thumbnail of Figure 2
    Figure 2
    Worldwide distribution of scientific production associated with bone manifestations in GD. The dark blue color details the scientific information published in the US, Italy, and Argentina.

    Of the total 96 studies, 23.96% (23/96) were corresponding to topic reviews and/or systematic reviews, another 23.96% (23/96) were descriptive studies, 17.71% (17/96) were case reports, followed by 13.54% (13/96) experimental studies. The remaining studies focused on prospective, observational, retrospective, and cross-sectional studies (20.84%). Prospective, non-randomized, and open studies were the least frequently used for literature reporting (Figure 3, Table 1).

    thumbnail of Figure 3
    Figure 3
    Type of studies focused on bone manifestations of GD1.

    The studies found were published over a period of 23 years, between 2001 and 2024. In the year 2015, the highest number of studies related to bone damage in GD1 was reported, accounting for 9.38% (9/96) of the registered articles. This was followed by the years 2014 and 2011, where scientific production on the topic amounted to approximately 8.33% (8/96) of publications each. For the year 2024, one recent scientific advance focused on reviewing data related to bone disease in GD1 in Germany according to the databases used in this systematic review (Figure 4).

    thumbnail of Figure 4
    Figure 4
    Number of publications of bone manifestations in GD1 per year.

    Discussion

    This review explored the state of knowledge regarding bone manifestations in GD1 through the exhaustive examination of 96 research articles. The reviewed evidence identified that countries such as the United States, Argentina, Brazil, and Italy have contributed most of the scientific production on bone issues in GD. It was also observed that case reviews and systematic reviews are the most frequent scientific productions on the topic, allowing for a general understanding of the pathology.

    With the results obtained, information regarding diagnosis has been updated, confirmed by the determination of low enzyme activity in leukocytes, the use of reference biomarkers, imaging techniques (X-ray, MRI, DEXA), the exploration of the dual mechanism of bone damage in GD, and the influential aspects in bone involvement. The relationship between genetic variants and clinical manifestations found, treatment, and updates based on culture studies, gene therapy, and CRISPR/Cas9 in GD1 were also explored.

    The diagnosis of GD1 should be supported by medical history, family history, physical examination, and laboratory tests that confirm low residual enzyme activity, as well as by the analysis of GBA1 variants. The expanded use of next-generation sequencing as a diagnostic tool has also led to the earlier recognition of GD in some cases[11].

    Enzymatic activity of β-glucocerebrosidase

    As a confirmatory test, determination of deficient activity of β-glucocerebrosidase enzyme in leukocytes, mononuclear cells, or cultured fibroblasts is used; it is considered the gold standard as a diagnostic test since histopathological findings in the liver, spleen, or bone marrow are not always reliable, and they represent highly invasive procedures[12].

    The common mutations found in the lysosomal enzyme deficient GD, β-glucocerebrosidase, earmark these proteins for destruction by the endoplasmic reticulum-localized protein folding machinery, resulting in enzyme insufficiency, lysosomal glycolipid storage, and subsequent pathology[13,14,15].

    Biomarkers

    Decisions regarding when to initiate treatment in GD may benefit from the measurement of specific biomarkers in addition to assessing pathological phenotypes. Although some biomarkers, such as ferritin, tartrate-resistant acid phosphatase (TRAP), and angiotensin-converting enzyme (ACE), are used to monitor GD, they are not disease-specific (16,17). Biomarkers like chitotriosidase and CCL18, although secreted by activated macrophages, are not specific to GD nor central to its pathology. In patients with a genetic deficiency of chitotriosidase, CCL18/PARC can be useful for monitoring therapeutic response [18]. A promising biomarker is serum glucosylsphingosine (lyso-Gb1), which directly reflects the accumulation of glucosylceramide and whose measurement correlates with disease severity, including neurological symptoms and treatment response.

    In addition to lyso-Gb1, other relevant biomarkers in GD include cathepsin K, which is involved in bone resorption and whose expression is increased in GD patients, and TRAP5b, a marker of osteoclast activation that correlates with the progression from osteopenia to osteoporosis [19,20,21]. TRAP5b reflects bone resorption and, along with chitotriosidase, ferritin, and ACE, is used in clinical monitoring of disease activity[22]. On the other hand, the osteocytic marker sclerostin, when elevated, is associated with bone pain, body mass index (BMI), and EM flask deformity, suggesting the involvement of the Wnt signaling pathway in bone disease associated with GD[23,24,25].

    Imaging techniques

    Standard Bone Radiographs: These are universally available and more economical than other methods, but they have low sensitivity in detecting mild changes in patients with GD. They are used to detect Erlenmeyer flask deformity of the femur with widening of the lower third. This may be accompanied by thinning of the cortical bone and sequelae of bone infarction (34% of cases), lytic lesions (18% of cases) which are generally well-defined without increased peripheral bone density, and sequelae of traumatic or pathological fractures. The use of multiple X-rays is no longer a standard practice due to the limited knowledge obtained from them and the risk of radiation exposure[26].

    Magnetic Resonance Imaging (MRI)

    MRI is an extremely sensitive method for evaluating pathology in GD. It allows for the recognition of bone infarctions and reflects the replacement of normal bone marrow fat by glucocerebroside. Gaucher cell infiltration displaces bone marrow fat, resulting in a less intense signal. Bone marrow infiltration is predominant at the proximal and distal ends[26]. T1-weighted sequences are recommended for detecting and quantifying bone marrow infiltration, while T2-weighted sequences are used to detect complications such as bone infarction. Hypointense signals are generally observed on T1-weighted sequences, reflecting the replacement of normal bone marrow fat by glucocerebroside. MRI is recommended at the time of diagnosis and every 12-24 months for untreated patients or those who have not achieved therapeutic goals [27].

    Previous studies have demonstrated that the degree of Gaucher cell infiltration is best estimated by Dixon magnetic resonance imaging-based quantitative chemical shift imaging (QCSI), which measures the displacement of fatty marrow by Gaucher cells. Findings have shown that the fat fraction (FF) score can predict the risk of clinically important bone events and can be useful in evaluating the bone marrow response to treatment. Dixon QCSI uses the mean of the FF in vertebrae L3-L5 to measure bone marrow infiltration by Gaucher cells. A QCSI score < 0.30 indicates a bone at risk[26, 27].

    Bone Densitometry (DXA)

    DXA is the gold standard for quantifying bone loss and diagnosing osteoporosis. It has been considered the technique of choice for quantitative assessment of bone in adults with GD. It is useful for diagnosing osteopenia/osteoporosis and for calculating lumbar spine and femoral bone mass. Osteopenia is defined as a T-score between -1 and -2.5, while osteoporosis is defined as a T-score ≤ -2.5. The severity of osteopenia may be correlated with genotype, splenomegaly, and hepatomegaly. According to the Latin American Consensus for GD, DXA should be performed on all patients with GD and repeated every 12-24 months in untreated individuals[27].

    The bone involvement in GD occurs through a dual mechanism:

    Compression by Gaucher Cells

    Accumulation of glucocerebrosides GL1 and Lyso Gl1 in the lysosomes of osteoclasts leads to infiltration of Gaucher cells and subsequent vascular occlusion and compression, resulting in osteonecrosis and the characteristic Erlenmeyer flask-shaped bones (28). Lyso-Gl1 activates the monocyte macrophage system, stimulating T lymphocytes that cause an altered CD4+/CD8+ ratio (with a decrease in CD8 lymphocytes), leading to the activation of inflammatory cytokines (IL-1b, IL6, and M-CSF), inhibiting osteoblastic activity and activating osteoclastic activity. This, combined with the accumulation of glucocerebrosides, disrupts bone remodeling, resulting in deformities, often acquiring an Erlenmeyer flask-like shape, particularly in the distal femur and proximal tibia[29].

    Imbalance in the Osteoclast/Osteoblast Ratio

    This leads to increased bone resorption and decreased bone formation. The bone remodeling process involves osteoclastic resorption of bone matrix and deposition of new matrix by osteoblasts. Macrophages can differentiate into osteoclasts, making them therapeutic targets for GD. During bone remodeling, osteoclasts resorb bone while osteoblasts deposit new matrix. Osteoclasts also regulate other cells such as osteoblasts, the egress of hematopoietic cells from the marrow, and function as immune cells during inflammation[29].

    The progressive accumulation of glucocerebrosides within the bone marrow cavity seems to be the initial step in the pathological process, leading to expansion of the marrow and progressive centrifugal expansion of red bone marrow. Displacement of inactive yellow marrow by new growth at the periphery disrupts vascularization; vascular occlusion and compression lead to bone infarction and increased intraosseous pressure may cause bone necrosis[30].

    In most GD patients, bone disease shows a progressive course over the years and is one of the most debilitating aspects of the disease, impairing mobility, increasing orthopedic conditions, delaying growth, and worsening quality of life[31].

    Bone manifestations

    Bone involvement often develops silently, without obvious symptoms. Bone manifestations include growth delay in children, osteopenia, lytic lesions, pathological fractures, pain, cortical osteonecrosis, marrow infarctions, and bone crises. Several systemic factors affect osteoblasts and osteoclasts in the molecular etiology of bone damage (corticosteroids, parathyroid hormone, prostaglandins, cytokines, platelet-mediated growth factor), which, when affected by GD, promote bone remodeling associated with abnormal osteoclastic function and bone infarctions. Studies have recognized that regardless of the age of onset, presence, or severity of visceral and hematologic involvement, all GD patients are at risk of bone complications[18].

    Glucocerebrosides accumulate in the bone marrow, causing a local inflammatory response, which is the cause of bone lesions. The pathophysiology of how infiltration leads to changes in bone is not well understood. The severity of bone findings depends on the extent of marrow cavity substitution. Replacement of bone marrow with glucocerebrosides can lead to marrow cavity expansion with cortical thinning, endosteal scalloping, and consequent diffuse osteopenia. Common signs include:

    Erlenmeyer flask deformity

    Characteristic, though not universal, in this disease. It occurs due to pressure from conglomerate medullary Gaucher cells on the endosteum in tubular bones, primarily the distal femur and proximal tibia, and inadequate remodeling of the metaphyseal region[32]. The deformity, generally asymptomatic, can be seen in many of the tubular or long bones of the skeleton, occasionally even the phalanges, in GD patients, but it does not affect bones that arise in membranes (eg, the skull vault). Although it is reported in up to 80% of adults with GD1, principally at the lower femur, and may provide a diagnostic clue, the Erlenmeyer flask deformity is not unique to GD, and its significance is uncertain[33].

    Bone infarction

    Bone crises are frequent episodes of acute localized pain in long bones accompanied by fever and systemic symptoms, caused by acute bone infarctions, more common in the first two decades of life[34].

    Osteonecrosis

    Also known as avascular necrosis, due to lack of blood supply and subsequent necrosis. It is more commonly seen in the femoral heads, proximal humerus, and vertebral bodies. Vertebral bodies may shorten, and vertebrae may adopt an H-shape, known as the Reynolds phenomenon. Joint collapse necessitates prosthetic surgery and is likely the most disabling bone complication of GD[35].

    Osteopenia and osteoporosis

    Osteopenia occurs when a person's bone density is below normal, increasing the risk of bone fractures. In the earliest stages of the disease, Gaucher cell infiltration begins in the vertebrae and subsequently spreads to the pelvis, femurs, and tibias. Osteopenia can become significant, localized, or diffuse, affecting both trabecular and cortical bone[36,37].

    Kyphosis and gibbus deformity

    Thoracic kyphosis may develop due to vertebral fragility fractures resulting from low bone mass. This deformity usually develops in late childhood or early adolescence and can lead to severe height loss, chest wall deformity, and restricted breathing. Many patients undergo corrective surgery using metal Harrington rods and spinal fusion. The cause of the gibbus deformity is debated and unclear, but it does not correlate with other skeletal manifestations of GD and is apparently not preventable with enzyme replacement therapy (ERT) [18,35,38].

    Bone manifestations and GBA variants

    It is important to note that GD presents a wide range of phenotypes partly explained by different genotypes of the GBA gene; however, few studies have been conducted on the genotype associated with a specific bone manifestation in GD patients, and many studies worldwide fail to provide a complete explanation of the genotype-phenotype correlation[39].

    Khan et al. (2012) reported GBA gene variants in over 70% of GD1 patients with and without fractures from the International Collaborative Gaucher Group (ICGG) (5894 patients in total). Most patients had at least one p. Asn409Ser allele (with fractures: 31.6% homozygous, 55.7% compound heterozygous; without fractures: 34.7% homozygous, 53.2% compound heterozygous)[28].

    Among the patients included in the analysis, 327 fractures were reported. The most common site of fracture in GD patients was the spine, accounting for 36.4% of all fractures (119/327), followed by the lower extremities (distal to the knee, femur, hip, knee), where 34.9% of fractures occurred. Fractures occurred at a relatively young age: the median age at the time of fracture for these sites was 45.9 years, 38.2 years, 33.8 years, 56.9 years, and 34.1 years, respectively. However, disease burden, indicated by the extent of hepatomegaly and splenomegaly, or the total body burden of Gaucher cells indicated by serum biomarkers, may not fully predict the onset of avascular osteonecrosis (AVN) or fractures, and instead, osteopenia has been proposed as a strong risk factor for fractures in GD[28].

    Treatment

    Regarding the treatment of GD, the objectives have been based on the elimination or reduction of signs and symptoms, prevention of irreversible complications, and improvement in overall health and quality of life of the patient and their family. An additional goal in children is growth optimization.

    Until 1991, the disease was considered a clinical rarity, with treatment being exclusively symptomatic. In 1974, it was demonstrated that intravenous infusion of purified placental glucocerebrosidase reduced hepatic and blood levels of glucocerebroside, but the results were inconsistent. Subsequently, after chemical modification of the enzyme to target it towards macrophages, objective clinical responses were observed in a pilot study conducted by Barton et al.

    Enzyme Replacement Therapy (ERT)

    ERT for GD involves the intravenous correction of the underlying enzyme deficiency, using modified versions of the enzyme glucocerebrosidase. Since its approval by the FDA in 1991, this therapy has significantly altered the natural course of the disease, improving hematologic, visceral, and skeletal symptoms in patients with GD type 1. However, ERT does not cross the blood-brain barrier, so it has shown no effects on neurological progression [40,41]. Imiglucerase (Cerezyme®) has been a cornerstone treatment, with studies showing improvements in bone pain, bone crises, and bone mineral density (BMD). However, some studies suggest that imiglucerase dosage in certain countries is suboptimal and that closer monitoring is needed to properly address the bone manifestations of the disease[40].

    Other ERT options include velaglucerase alfa (Vpriv®) and taliglucerase alfa (Uplyso®), which have shown long-term efficacy in treating patients with GD type 1 [42,43,44]. Velaglucerase alfa was approved in 2010 and has proven effective in managing bone burden in GD patients, while taliglucerase alfa, a plant-derived recombinant enzyme, was used in emergency situations when imiglucerase was in short supply. Although adverse reactions to taliglucerase alfa may be more common due to its plant origin, it has shown improvements in bone density in some patients, although bone mineral density remains a slow and variable treatment target. Despite clinical improvements in most patients receiving ERT, more precise and accessible assessment of bone marrow infiltration is still needed to evaluate therapeutic response and the efficacy of ERT in suboptimal responders[45,46,47].

    Substrate Reduction Therapy (SRT)

    The goal SRT is to minimize the accumulation of glucosylceramide within cells by inhibiting the enzyme glucosylceramide synthase, which reduces the production of harmful lipids and helps the residual enzyme establish a new steady state. Miglustat (Zavesca®), approved by the FDA in 2003, has been shown to improve bone density and prevent bone crises in patients with GD type 1. A study by Ficicioglu et al. (2008) showed that 83% of patients treated with miglustat reported no bone pain, and bone mineral density (BMD) improved significantly in both the lumbar spine and femoral neck. This beneficial effect of miglustat on bone symptoms may be explained by its wide tissue distribution and direct effect on bone cells[48,49].

    Eliglustat (Cerdelga®), approved in 2014, is another SRT agent with a better safety profile and greater efficacy. It works by partially inhibiting glucosylceramide synthase, reducing the production of glucocerebrosides. In the ENCORE trial [50] eliglustat showed a positive impact on BMD and reduced bone pain, with lumbar spine T-scores changing from abnormal to normal in treated patients. A follow-up analysis in 2023 confirmed its long-term efficacy in both treatment-naïve patients and those switching from ERT, with improvements in BMD and bone marrow burden. Additionally, eliglustat was shown to be more effective than other treatments like imiglucerase and velaglucerase in reducing serum GlcSph [51,52].

    Updates, cultures studies, gene therapy, and CRISPR/Cas9 in GD1

    In the past year (2023-2024), a significant number of published studies have focused on understanding bone health in GD1. A thematic review by Merkel (2024) asserts that bone involvement ranges from painful focal bone crises (especially in the pelvis and legs) to permanent diffuse bone pains. In addition to bone marrow infiltration, osteopenia/osteoporosis, lytic lesions, focal bone necrosis, bone marrow displacement, and, in some cases, mutilating joint destruction are observed[53].

    Crivaro et al. (2023) evaluated potential alterations in Gaucher Adipocyte (GD Ad) that could contribute to bone complications. Local mesenchymal stem cells (MSCs) were cultured in adipogenic media to assess expression of differentiation markers. Their results showed an alteration in lipid droplet metabolism in GD Ad, regardless of adipocyte differentiation process, suggesting increased lipolysis in early differentiation stages and reduced lipid synthesis, which may contribute to skeletal imbalance in GD[54].

    Ormazabal et al. (2023) used editing technology to develop a reliable, isogenic, and easy-to-handle cellular model of GD monocytes (GBAKO-THP1) to facilitate studies on GD pathophysiology and high-throughput drug screening. They reported that production of proinflammatory cytokines and osteoclastogenesis were restored, at least in part, by treating cells with recombinant human glucosidase, a synthase inhibitor substrate, a pharmacological chaperone, and an anti-inflammatory compound. In addition to confirming this model's suitability for high-throughput screening of therapeutic molecules acting through different mechanisms and on different phenotypic characteristics, the data provided insight into the pathogenic cascade leading to exacerbation of osteoclastogenesis and its contribution to bone pathology in GD[55].

    For many decades, gene therapy has been heralded as a promising therapeutic strategy for the treatment of different inherited disorders, including lysosomal storage disorders (LSDs). The goal of gene therapy is to modulate or manipulate the expression of genes to achieve a therapeutic effect in genetic disorders. Currently, there are a few active gene therapy clinical trials for the treatment of GD. The first (GALILEO-1), “A Gene Therapy Study in Patients with Gaucher Disease Type 1” (NCT05324943), conducted by Freeline Therapeutics, involves the administration of a liver-directed ssAAV to participants as a one-time intravenous infusion. The group made 37 GBA1 AAV constructs, which, when infused in mice with RC-04-26, resulted in the robust uptake of GCase by cells in spleen, bone marrow, and lung[56]. At this time, no results have been reported from the patient trial. Prevail Therapeutics and Eli Lilly & Company initiated a phase 1/2 study in GD1, AVR-RD-02, compared to enzyme replacement therapy, for the treatment of GD1 (NCT04145037 PROCEED), with intravenous administration of their construct. Studies designed to evaluate the efficacy and safety of autologous hematopoietic stem cell (HSC) gene therapy using a lentiviral vector for GD1 and GD3 (NCT05815004) by Avrobio were recently withdrawn voluntarily and not due to safety or medical reasons. However, outcome measures from the few patients who completed the 52-week clinical trial indicated low vector copy numbers per cell, slight reduction in spleen and liver size, slight reduction in glucosylsphingosine levels, no changes in hemoglobin or platelet levels, and minimal increase in GCase enzyme activity that decreased over time[56,57].

    Limitations

    All studies cited in this review have the same source limitations. Case studies, or studies based on information provided by the patients themselves, have inherent limitations because they are voluntary and depend on the collaboration of the treating physicians of these patients with GD. Additionally, unregistered cohorts from the Latin American region have a limited number of patients, as is often the case with rare diseases, and may not be representative of all patients with GD1. However, by presenting this data, a general idea of the frequency of skeletal manifestations in GD1 patients worldwide has been provided.

    Conclusion

    Skeletal manifestations are a predominant feature of GD, causing pain, disability, and a decrease in quality of life. These manifestations affect both the bone marrow and the mineralized components of the bone, leading to a variety of pathological changes including bone marrow infiltration, abnormalities in bone modeling and remodeling, and phenomena related to osteonecrosis. These combined effects significantly contribute to the physical and functional impairment experienced by GD patients, thus emphasizing the importance of comprehensive management of the skeletal aspects of this disease.

    With over 460 variants identified in the GBA gene, researchers are immersed in a continuous effort to establish associations that provide information on the relationship between genotype and phenotype in GD. It is generally recognized that regardless of age of disease onset, presence or severity of visceral and hematologic involvement, all GD patients are at risk of bone complications.

    Despite the inherent complexity of this task, the research field has experienced significant advances, particularly concerning the bone manifestations of the disease. There has been a marked interest in further understanding bone health-related aspects, from painful focal bone crises, especially in areas like the pelvis and legs, to persistent diffuse bone pain. A range of additional complications has been identified, including bone marrow infiltration, osteopenia/osteoporosis, lytic lesions, and focal bone necrosis.

    The present study represents a significant milestone in our country as it constitutes the first systematic review of GD, specifically focusing on its skeletal manifestations and research generated worldwide over the past 23 years. This analysis highlights the accumulated progress in understanding the disease, emphasizing the importance of continuing periodic review and publication to advance the identification of new perspectives and therapeutic approaches. This systematic and comprehensive search based on research generated in the past 23 years allowed for the current state-of-the-art review of the clinical manifestations of GD, highlighting the accumulated progress in understanding the disease, underlining the importance of ongoing review and continuous dissemination of findings to further advance knowledge in this field and improve clinical care for affected patients. The increased interest in research on the skeletal manifestations of GD at the national level indicates the need for constant review and continuous dissemination of findings to further drive knowledge in this field and enhance clinical care for affected patients.

    References

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    • Funding
      The author(s) received no financial support for the research, authorship, and/or publication of this article.

    Publication Dates

    • Publication in this collection
      02 May 2025
    • Date of issue
      2025

    History

    • Received
      07 Apr 2024
    • Accepted
      19 Mar 2025
    Creative Common - by 4.0
    This is an open-access article distributed under the terms of the Creative Commons Attribution License
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