graph LR
Intellectual_Disability["Intellectual Disability"]
Anemia["Anemia"]
Hepatic_Steatosis["Hepatic Steatosis"]
Cuproptosis["Cuproptosis"]
Joint_Swelling["Joint Swelling"]
Psychosis["Psychosis"]
Arthralgia["Arthralgia"]
Seizure["Seizure"]
Tetrathiomolybdate["Tetrathiomolybdate"]
Acute_Hepatitis["Acute Hepatitis"]
Acute_Hepatic_Failure["Acute Hepatic Failure"]
Hepatic_Copper["Hepatic Copper"]
Hepatitis["Hepatitis"]
Abdominal_Pain["Abdominal Pain"]
Focal_T2_Hyperintense_Brainstem_Lesion["Focal T2 Hyperintense Brainstem Lesion"]
Drooling["Drooling"]
Ataxia["Ataxia"]
Sunflower_Cataract["Sunflower Cataract"]
c.1707+2dupT_NM_000053.2["c.1707+2dupT (NM_000053.2)"]
Non_Ceruloplasmin_Bound_Serum_Copper["Non-Ceruloplasmin-Bound Serum Copper"]
Failure_To_Thrive["Failure To Thrive"]
Ascites["Ascites"]
Thrombocytopenia["Thrombocytopenia"]
Dietary_Copper["Dietary Copper"]
ATP7B["ATP7B"]
Anxiety["Anxiety"]
Renal_Tubular_Dysfunction["Renal Tubular Dysfunction"]
Splenomegaly["Splenomegaly"]
Erythrocyte_Oxidative_Membrane_Injury["Erythrocyte Oxidative Membrane Injury"]
Zinc_Acetate["Zinc Acetate"]
Heart_Failure["Heart Failure"]
AAV_Mediated_ATP7B_Gene_Therapy["AAV-Mediated ATP7B Gene Therapy"]
p.R778L["p.R778L"]
Bone_Pain["Bone Pain"]
Wilson_disease_patient_liver_organoids_with_prime_edited_ATP7B["Wilson disease patient liver organoids with prime-edited ATP7B"]
Excessive_Hepatic_ECM_Deposition["Excessive Hepatic ECM Deposition"]
Liver_Transplantation["Liver Transplantation"]
Dysphagia["Dysphagia"]
Systemic_Copper_Distribution["Systemic Copper Distribution"]
Pruritus["Pruritus"]
Vomiting["Vomiting"]
Ceruloplasmin["Ceruloplasmin"]
p.H1069Q["p.H1069Q"]
Impaired_Ceruloplasmin_Loading["Impaired Ceruloplasmin Loading"]
Parkinsonism["Parkinsonism"]
Dysarthria["Dysarthria"]
Personality_Changes["Personality Changes"]
Kayser_Fleischer_Rings["Kayser-Fleischer Rings"]
Clumsiness["Clumsiness"]
Jaundice["Jaundice"]
Abnormality_Of_The_Menstrual_Cycle["Abnormality Of The Menstrual Cycle"]
Cardiac_Arrhythmia["Cardiac Arrhythmia"]
Hepatomegaly["Hepatomegaly"]
Impaired_Biliary_Copper_Excretion["Impaired Biliary Copper Excretion"]
ATP7B_Copper_Trafficking_Defect["ATP7B Copper-Trafficking Defect"]
Aggressive_Behavior["Aggressive Behavior"]
Gait_Disturbance["Gait Disturbance"]
Arthritis["Arthritis"]
ATP7B_R778L_patient_iPSC_derived_hepatocyte_like_cells["ATP7B R778L patient iPSC-derived hepatocyte-like cells"]
Depression["Depression"]
N_24_Hour_Urinary_Copper["24-Hour Urinary Copper"]
Elevated_Circulating_Hepatic_Transaminase_Concentration["Elevated Circulating Hepatic Transaminase Concentration"]
Bruising_Susceptibility["Bruising Susceptibility"]
Pathologic_Fracture["Pathologic Fracture"]
Cardiomyopathy["Cardiomyopathy"]
Hemolytic_Anemia["Hemolytic Anemia"]
Low_Copper_Diet["Low Copper Diet"]
Osteopenia["Osteopenia"]
Chorea["Chorea"]
D_Penicillamine["D-Penicillamine"]
Osteoporosis["Osteoporosis"]
Hepatic_Stellate_Cell_Activation["Hepatic Stellate Cell Activation"]
Neurodegeneration["Neurodegeneration"]
Hepatic_Copper_Accumulation["Hepatic Copper Accumulation"]
Cirrhosis["Cirrhosis"]
Premature_Erythrocyte_Destruction["Premature Erythrocyte Destruction"]
Face_Of_The_Giant_Panda_Sign["Face Of The Giant Panda Sign"]
Dystonia["Dystonia"]
Excessive_Salivation["Excessive Salivation"]
Ferroptosis["Ferroptosis"]
Trientine["Trientine"]
ATP7B_H1069Q_homozygous_patient_iPSC_derived_hepatocyte_like_cells["ATP7B H1069Q homozygous patient iPSC-derived hepatocyte-like cells"]
Rigidity["Rigidity"]
Proximal_Lower_Limb_Muscle_Weakness["Proximal Lower Limb Muscle Weakness"]
Bradykinesia["Bradykinesia"]
Weight_Loss["Weight Loss"]
Hepatocyte_Injury["Hepatocyte Injury"]
Renal_Fanconi_Syndrome["Renal Fanconi Syndrome"]
Tremor["Tremor"]
ATP7B_Copper_Trafficking_Defect --> Impaired_Biliary_Copper_Excretion
ATP7B_Copper_Trafficking_Defect --> Impaired_Ceruloplasmin_Loading
Impaired_Biliary_Copper_Excretion --> Hepatic_Copper_Accumulation
Impaired_Ceruloplasmin_Loading --> Ceruloplasmin
Hepatic_Copper_Accumulation --> Hepatocyte_Injury
Hepatic_Copper_Accumulation --> Systemic_Copper_Distribution
Hepatic_Copper_Accumulation --> Hepatic_Copper
Hepatic_Copper_Accumulation --> Cuproptosis
Hepatic_Copper_Accumulation --> Ferroptosis
Systemic_Copper_Distribution --> Neurodegeneration
Systemic_Copper_Distribution --> Non_Ceruloplasmin_Bound_Serum_Copper
Systemic_Copper_Distribution --> N_24_Hour_Urinary_Copper
Systemic_Copper_Distribution --> Kayser_Fleischer_Rings
Systemic_Copper_Distribution --> Renal_Tubular_Dysfunction
Systemic_Copper_Distribution --> Renal_Fanconi_Syndrome
Systemic_Copper_Distribution --> Cardiomyopathy
Systemic_Copper_Distribution --> Heart_Failure
Systemic_Copper_Distribution --> Cardiac_Arrhythmia
Systemic_Copper_Distribution --> Osteopenia
Systemic_Copper_Distribution --> Osteoporosis
Systemic_Copper_Distribution --> Arthralgia
Systemic_Copper_Distribution --> Sunflower_Cataract
Systemic_Copper_Distribution --> Abnormality_Of_The_Menstrual_Cycle
Systemic_Copper_Distribution --> Bone_Pain
Systemic_Copper_Distribution --> Arthritis
Systemic_Copper_Distribution --> Joint_Swelling
Systemic_Copper_Distribution --> Pathologic_Fracture
Hepatocyte_Injury --> Hepatic_Stellate_Cell_Activation
Hepatocyte_Injury --> Neurodegeneration
Hepatocyte_Injury --> Hepatitis
Hepatocyte_Injury --> Hepatomegaly
Hepatocyte_Injury --> Jaundice
Hepatocyte_Injury --> Acute_Hepatic_Failure
Hepatocyte_Injury --> Erythrocyte_Oxidative_Membrane_Injury
Hepatocyte_Injury --> Vomiting
Hepatocyte_Injury --> Hepatic_Steatosis
Hepatocyte_Injury --> Acute_Hepatitis
Hepatocyte_Injury --> Pruritus
Hepatocyte_Injury --> Abdominal_Pain
Hepatocyte_Injury --> Failure_To_Thrive
Hepatocyte_Injury --> Weight_Loss
Hepatocyte_Injury --> Anemia
Hepatic_Stellate_Cell_Activation --> Excessive_Hepatic_ECM_Deposition
Excessive_Hepatic_ECM_Deposition --> Cirrhosis
Excessive_Hepatic_ECM_Deposition --> Ascites
Excessive_Hepatic_ECM_Deposition --> Splenomegaly
Excessive_Hepatic_ECM_Deposition --> Thrombocytopenia
Excessive_Hepatic_ECM_Deposition --> Bruising_Susceptibility
Neurodegeneration --> Tremor
Neurodegeneration --> Dystonia
Neurodegeneration --> Parkinsonism
Neurodegeneration --> Bradykinesia
Neurodegeneration --> Rigidity
Neurodegeneration --> Chorea
Neurodegeneration --> Dysarthria
Neurodegeneration --> Ataxia
Neurodegeneration --> Dysphagia
Neurodegeneration --> Drooling
Neurodegeneration --> Anxiety
Neurodegeneration --> Depression
Neurodegeneration --> Psychosis
Neurodegeneration --> Personality_Changes
Neurodegeneration --> Intellectual_Disability
Neurodegeneration --> Seizure
Neurodegeneration --> Gait_Disturbance
Neurodegeneration --> Clumsiness
Neurodegeneration --> Excessive_Salivation
Neurodegeneration --> Proximal_Lower_Limb_Muscle_Weakness
Neurodegeneration --> Focal_T2_Hyperintense_Brainstem_Lesion
Neurodegeneration --> Face_Of_The_Giant_Panda_Sign
Neurodegeneration --> Aggressive_Behavior
Cuproptosis --> Hepatocyte_Injury
Ferroptosis --> Hepatocyte_Injury
Erythrocyte_Oxidative_Membrane_Injury --> Premature_Erythrocyte_Destruction
Premature_Erythrocyte_Destruction --> Hemolytic_Anemia
Dietary_Copper --> Hepatic_Copper_Accumulation
D_Penicillamine --> Systemic_Copper_Distribution
Trientine --> Systemic_Copper_Distribution
Zinc_Acetate --> Hepatic_Copper_Accumulation
Low_Copper_Diet --> Hepatic_Copper_Accumulation
Tetrathiomolybdate --> Systemic_Copper_Distribution
Liver_Transplantation --> Impaired_Biliary_Copper_Excretion
AAV_Mediated_ATP7B_Gene_Therapy --> Impaired_Biliary_Copper_Excretion
ATP7B_R778L_patient_iPSC_derived_hepatocyte_like_cells --> ATP7B_Copper_Trafficking_Defect
ATP7B_H1069Q_homozygous_patient_iPSC_derived_hepatocyte_like_cells --> ATP7B_Copper_Trafficking_Defect
Wilson_disease_patient_liver_organoids_with_prime_edited_ATP7B --> ATP7B_Copper_Trafficking_Defect
Impaired_Ceruloplasmin_Loading -.-> Ceruloplasmin
Systemic_Copper_Distribution -.-> Non_Ceruloplasmin_Bound_Serum_Copper
Systemic_Copper_Distribution -.-> N_24_Hour_Urinary_Copper
Hepatic_Copper_Accumulation -.-> Hepatic_Copper
Hepatocyte_Injury -.-> Elevated_Circulating_Hepatic_Transaminase_Concentration
ATP7B --> ATP7B_Copper_Trafficking_Defect
ATP7B --> Impaired_Biliary_Copper_Excretion
ATP7B --> Impaired_Ceruloplasmin_Loading
p.H1069Q --> ATP7B
p.R778L --> ATP7B
c.1707+2dupT_NM_000053.2 --> ATP7B
style Intellectual_Disability fill:#fef3c7
style Anemia fill:#fef3c7
style Hepatic_Steatosis fill:#fef3c7
style Cuproptosis fill:#dbeafe
style Joint_Swelling fill:#fef3c7
style Psychosis fill:#fef3c7
style Arthralgia fill:#fef3c7
style Seizure fill:#fef3c7
style Tetrathiomolybdate fill:#fce7f3
style Acute_Hepatitis fill:#fef3c7
style Acute_Hepatic_Failure fill:#fef3c7
style Hepatic_Copper fill:#e0e7ff
style Hepatitis fill:#fef3c7
style Abdominal_Pain fill:#fef3c7
style Focal_T2_Hyperintense_Brainstem_Lesion fill:#fef3c7
style Drooling fill:#fef3c7
style Ataxia fill:#fef3c7
style Sunflower_Cataract fill:#fef3c7
style c.1707+2dupT_NM_000053.2 fill:#f3e8ff
style Non_Ceruloplasmin_Bound_Serum_Copper fill:#e0e7ff
style Failure_To_Thrive fill:#fef3c7
style Ascites fill:#fef3c7
style Thrombocytopenia fill:#fef3c7
style Dietary_Copper fill:#dcfce7
style ATP7B fill:#f3e8ff
style Anxiety fill:#fef3c7
style Renal_Tubular_Dysfunction fill:#fef3c7
style Splenomegaly fill:#fef3c7
style Erythrocyte_Oxidative_Membrane_Injury fill:#dbeafe
style Zinc_Acetate fill:#fce7f3
style Heart_Failure fill:#fef3c7
style AAV_Mediated_ATP7B_Gene_Therapy fill:#fce7f3
style p.R778L fill:#f3e8ff
style Bone_Pain fill:#fef3c7
style Wilson_disease_patient_liver_organoids_with_prime_edited_ATP7B fill:#ccfbf1
style Excessive_Hepatic_ECM_Deposition fill:#dbeafe
style Liver_Transplantation fill:#fce7f3
style Dysphagia fill:#fef3c7
style Systemic_Copper_Distribution fill:#dbeafe
style Pruritus fill:#fef3c7
style Vomiting fill:#fef3c7
style Ceruloplasmin fill:#e0e7ff
style p.H1069Q fill:#f3e8ff
style Impaired_Ceruloplasmin_Loading fill:#dbeafe
style Parkinsonism fill:#fef3c7
style Dysarthria fill:#fef3c7
style Personality_Changes fill:#fef3c7
style Kayser_Fleischer_Rings fill:#fef3c7
style Clumsiness fill:#fef3c7
style Jaundice fill:#fef3c7
style Abnormality_Of_The_Menstrual_Cycle fill:#fef3c7
style Cardiac_Arrhythmia fill:#fef3c7
style Hepatomegaly fill:#fef3c7
style Impaired_Biliary_Copper_Excretion fill:#dbeafe
style ATP7B_Copper_Trafficking_Defect fill:#dbeafe
style Aggressive_Behavior fill:#fef3c7
style Gait_Disturbance fill:#fef3c7
style Arthritis fill:#fef3c7
style ATP7B_R778L_patient_iPSC_derived_hepatocyte_like_cells fill:#ccfbf1
style Depression fill:#fef3c7
style N_24_Hour_Urinary_Copper fill:#e0e7ff
style Elevated_Circulating_Hepatic_Transaminase_Concentration fill:#fef3c7
style Bruising_Susceptibility fill:#fef3c7
style Pathologic_Fracture fill:#fef3c7
style Cardiomyopathy fill:#fef3c7
style Hemolytic_Anemia fill:#fef3c7
style Low_Copper_Diet fill:#fce7f3
style Osteopenia fill:#fef3c7
style Chorea fill:#fef3c7
style D_Penicillamine fill:#fce7f3
style Osteoporosis fill:#fef3c7
style Hepatic_Stellate_Cell_Activation fill:#dbeafe
style Neurodegeneration fill:#dbeafe
style Hepatic_Copper_Accumulation fill:#dbeafe
style Cirrhosis fill:#fef3c7
style Premature_Erythrocyte_Destruction fill:#dbeafe
style Face_Of_The_Giant_Panda_Sign fill:#fef3c7
style Dystonia fill:#fef3c7
style Excessive_Salivation fill:#fef3c7
style Ferroptosis fill:#dbeafe
style Trientine fill:#fce7f3
style ATP7B_H1069Q_homozygous_patient_iPSC_derived_hepatocyte_like_cells fill:#ccfbf1
style Rigidity fill:#fef3c7
style Proximal_Lower_Limb_Muscle_Weakness fill:#fef3c7
style Bradykinesia fill:#fef3c7
style Weight_Loss fill:#fef3c7
style Hepatocyte_Injury fill:#dbeafe
style Renal_Fanconi_Syndrome fill:#fef3c7
style Tremor fill:#fef3c7
graph LR
Vitamin_D_Deficiency["Vitamin D Deficiency"]
MLO_Y4_osteocyte_like_cell_line["MLO-Y4 osteocyte-like cell line"]
Osteocyte_SASP_Acquisition["Osteocyte SASP Acquisition"]
Smoking["Smoking"]
Estrogen_Deficiency["Estrogen Deficiency"]
Microgravity_Accelerated_Bone_Resorption["Microgravity-Accelerated Bone Resorption"]
N_3D_bone_organoid_with_coupled_osteoblast_osteoclast_remodeling["3D bone organoid with coupled osteoblast-osteoclast remodeling"]
Bone_Remodeling_Imbalance["Bone Remodeling Imbalance"]
Ovariectomized_rat["Ovariectomized rat"]
Glucocorticoid_Use["Glucocorticoid Use"]
Aged_mouse_skeleton_as_a_model_of_human_age_related_bone_loss["Aged mouse skeleton as a model of human age-related bone loss"]
QCT_based_finite_element_model_of_the_proximal_femur["QCT-based finite element model of the proximal femur"]
Aged_INK_ATTAC_senescent_cell_clearance_mouse["Aged INK-ATTAC senescent-cell clearance mouse"]
Senescent_Cell_Accumulation_in_the_Bone_Microenvironment["Senescent Cell Accumulation in the Bone Microenvironment"]
Microgravity_Exposure["Microgravity Exposure"]
Bone_cell_population_dynamics_model_of_the_remodeling_unit["Bone cell population dynamics model of the remodeling unit"]
Microarchitectural_Deterioration["Microarchitectural Deterioration"]
IDG_SW3_osteoblast_to_osteocyte_differentiation_line["IDG-SW3 osteoblast-to-osteocyte differentiation line"]
Denosumab["Denosumab"]
Marrow_Stromal_Lineage_Shift_Toward_Adipogenesis["Marrow Stromal Lineage Shift Toward Adipogenesis"]
RANKL_OPG_Dysregulation["RANKL/OPG Dysregulation"]
Osteocyte_Mechanosensing_Disruption_in_Microgravity["Osteocyte Mechanosensing Disruption in Microgravity"]
ESR1["ESR1"]
Osteocyte_SASP_Acquisition --> Senescent_Cell_Accumulation_in_the_Bone_Microenvironment
Osteocyte_SASP_Acquisition --> RANKL_OPG_Dysregulation
Senescent_Cell_Accumulation_in_the_Bone_Microenvironment --> Bone_Remodeling_Imbalance
Marrow_Stromal_Lineage_Shift_Toward_Adipogenesis --> Bone_Remodeling_Imbalance
Estrogen_Deficiency --> RANKL_OPG_Dysregulation
Vitamin_D_Deficiency --> Bone_Remodeling_Imbalance
Smoking --> Bone_Remodeling_Imbalance
Glucocorticoid_Use --> Bone_Remodeling_Imbalance
Microgravity_Exposure --> Microgravity_Accelerated_Bone_Resorption
Denosumab --> RANKL_OPG_Dysregulation
MLO_Y4_osteocyte_like_cell_line --> Osteocyte_Mechanosensing_Disruption_in_Microgravity
IDG_SW3_osteoblast_to_osteocyte_differentiation_line --> Bone_Remodeling_Imbalance
N_3D_bone_organoid_with_coupled_osteoblast_osteoclast_remodeling --> Bone_Remodeling_Imbalance
Ovariectomized_rat --> RANKL_OPG_Dysregulation
Ovariectomized_rat --> Microarchitectural_Deterioration
Aged_INK_ATTAC_senescent_cell_clearance_mouse --> Senescent_Cell_Accumulation_in_the_Bone_Microenvironment
Aged_mouse_skeleton_as_a_model_of_human_age_related_bone_loss --> Microarchitectural_Deterioration
QCT_based_finite_element_model_of_the_proximal_femur --> Microarchitectural_Deterioration
Bone_cell_population_dynamics_model_of_the_remodeling_unit --> Bone_Remodeling_Imbalance
ESR1 --> RANKL_OPG_Dysregulation
style Vitamin_D_Deficiency fill:#dcfce7
style MLO_Y4_osteocyte_like_cell_line fill:#ccfbf1
style Osteocyte_SASP_Acquisition fill:#dbeafe
style Smoking fill:#dcfce7
style Estrogen_Deficiency fill:#dcfce7
style Microgravity_Accelerated_Bone_Resorption fill:#dbeafe
style N_3D_bone_organoid_with_coupled_osteoblast_osteoclast_remodeling fill:#ccfbf1
style Bone_Remodeling_Imbalance fill:#dbeafe
style Ovariectomized_rat fill:#ede9fe
style Glucocorticoid_Use fill:#dcfce7
style Aged_mouse_skeleton_as_a_model_of_human_age_related_bone_loss fill:#ede9fe
style QCT_based_finite_element_model_of_the_proximal_femur fill:#ecfccb
style Aged_INK_ATTAC_senescent_cell_clearance_mouse fill:#ede9fe
style Senescent_Cell_Accumulation_in_the_Bone_Microenvironment fill:#dbeafe
style Microgravity_Exposure fill:#dcfce7
style Bone_cell_population_dynamics_model_of_the_remodeling_unit fill:#ecfccb
style Microarchitectural_Deterioration fill:#dbeafe
style IDG_SW3_osteoblast_to_osteocyte_differentiation_line fill:#ccfbf1
style Denosumab fill:#fce7f3
style Marrow_Stromal_Lineage_Shift_Toward_Adipogenesis fill:#dbeafe
style RANKL_OPG_Dysregulation fill:#dbeafe
style Osteocyte_Mechanosensing_Disruption_in_Microgravity fill:#dbeafe
style ESR1 fill:#f3e8ff
name: com_Wilsons_Disease__Osteoporosis
creation_date: '2026-02-20T00:00:00Z'
updated_date: '2026-02-20T00:00:00Z'
curation_status: CANDIDATE
notes: >-
Candidate literature-backed comorbidity linking Wilson disease to reduced bone
health and osteoporosis. Most available evidence is prevalence-focused
(cross-sectional or pooled prevalence), so temporal directionality remains
incompletely established despite biologic plausibility of Wilson disease
preceding bone loss.
disease_a:
slug: Wilsons_Disease
preferred_term: Wilson disease
term:
id: MONDO:0010200
label: Wilson disease
disease_b:
slug: Osteoporosis
preferred_term: osteoporosis
term:
id: MONDO:0005298
label: osteoporosis
directionality: UNKNOWN
hypotheses:
- description: >-
Hypothesis: copper-related multisystem toxicity in Wilson disease affects
both bone and renal tissues, creating a bone fragility milieu.
evidence:
- reference: PMID:38731973
reference_title: "Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update."
supports: SUPPORT
evidence_source: OTHER
snippet: "This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones"
explanation: Review summary supports direct involvement of both kidney and bone tissues in Wilson disease.
- reference: PMID:38731973
reference_title: "Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update."
supports: SUPPORT
evidence_source: OTHER
snippet: "Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia."
explanation: Renal tubular dysfunction and osteoporosis are co-listed clinical features, supporting a linked mineral-handling hypothesis.
pathophysiology:
- name: Copper toxicity with renal-bone interaction
description: >-
Copper toxicity in Wilson disease may simultaneously injure renal tubular
and skeletal compartments, predisposing to mineral dysregulation and bone
fragility.
biological_processes:
- preferred_term: bone remodeling
term:
id: GO:0046849
label: bone remodeling
evidence:
- reference: PMID:38731973
reference_title: "Wilson Disease: Copper-Mediated Cuproptosis, Iron-Related Ferroptosis, and Clinical Highlights, with Comprehensive and Critical Analysis Update."
supports: SUPPORT
evidence_source: OTHER
snippet: "This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones"
explanation: Supports multi-organ copper injury including kidney and bone.
- description: >-
Hypothesis: hepatic synthetic and nutritional status contributes to bone
health variability in Wilson disease.
evidence:
- reference: PMID:40950651
reference_title: "Bone Densitometry is a Valuable Marker for Bone Health Monitoring in Pediatric Wilson's Disease Patients: A Tertiary Center Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, serum albumin positively correlated with bone density (P = .018)."
explanation: Albumin-bone density correlation supports a liver function and nutritional mechanism affecting bone status.
pathophysiology:
- name: Albumin-linked bone vulnerability
description: >-
Lower albumin in Wilson disease may reflect hepatic dysfunction and/or
nutritional compromise associated with poorer bone mineralization.
evidence:
- reference: PMID:40950651
reference_title: "Bone Densitometry is a Valuable Marker for Bone Health Monitoring in Pediatric Wilson's Disease Patients: A Tertiary Center Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Bone disease is frequent and often subclinical in pediatric Wilson's disease."
explanation: Supports frequent, clinically subtle bone involvement in Wilson disease.
- reference: PMID:40950651
reference_title: "Bone Densitometry is a Valuable Marker for Bone Health Monitoring in Pediatric Wilson's Disease Patients: A Tertiary Center Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "However, serum albumin positively correlated with bone density (P = .018)."
explanation: Correlative evidence links albumin and bone density in pediatric Wilson disease.
- description: >-
Hypothesis: host factors (age and sex) modify osteoporosis risk expression
in Wilson disease.
evidence:
- reference: PMID:29110062
reference_title: "Osteoporosis and bone mineral density in patients with Wilson's disease: a systematic review and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Meta-regressionshowed significant impacts of age (negative correlation; P=0.002) and male status (positive correlation;P < 0.001) on the prevalence of osteoporosis."
explanation: Meta-regression indicates age/sex interaction with osteoporosis prevalence, suggesting biologic risk modifiers.
pathophysiology:
- name: Age-sex risk modulation
description: >-
Osteoporosis risk in Wilson disease appears modified by demographic and
host factors, implying interaction between copper-related pathology and
baseline bone-risk biology.
evidence:
- reference: PMID:29110062
reference_title: "Osteoporosis and bone mineral density in patients with Wilson's disease: a systematic review and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Meta-regressionshowed significant impacts of age (negative correlation; P=0.002) and male status (positive correlation;P < 0.001) on the prevalence of osteoporosis."
explanation: Quantifies host-factor dependence of osteoporosis prevalence in Wilson disease cohorts.
- description: >-
Hypothesis: treatment-course instability (adherence barriers and
therapy-associated neurologic worsening) may mediate osteoporosis risk in
Wilson disease through reduced mobility and disease-control disruption.
evidence:
- reference: PMID:37116715
reference_title: "Neurological worsening in Wilson disease - clinical classification and outcome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In this study, we identified two peaks in NW: an early (≤3 months) treatment-associated peak and a late (>12 months of treatment) adherence-associated peak."
explanation: Large multicenter cohort links treatment phase and adherence status to neurological destabilization.
- reference: PMID:35887738
reference_title: "Efficacy and Safety of Two Salts of Trientine in the Treatment of Wilson's Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "As adherence to treatment is a key factor in the successful management of WD, physicians need to be even more vigilant in detecting adherence difficulties in patients receiving treatment with TETA 2HCL."
explanation: Identifies adherence as a key determinant of Wilson disease control.
- reference: PMID:40950651
reference_title: "Bone Densitometry is a Valuable Marker for Bone Health Monitoring in Pediatric Wilson's Disease Patients: A Tertiary Center Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Larger studies are needed to evaluate the effects of treatment and micronutrient status on bone health."
explanation: Pediatric bone-density study explicitly flags treatment and micronutrient status as potential bone-health determinants requiring deeper study.
pathophysiology:
- name: Treatment-course instability and disuse-bone pathway
description: >-
In some Wilson disease patients, inadequate decoppering control from
adherence barriers or treatment-phase neurologic worsening may increase
functional dependency, reduce skeletal loading, and contribute to bone
loss and fracture risk.
evidence:
- reference: PMID:32398357
reference_title: "Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All were highly dependent before LT (median mRS score 5)."
explanation: Refractory neurologic Wilson disease can produce profound dependency consistent with reduced mechanical loading.
- reference: PMID:32398357
reference_title: "Liver transplantation as a rescue therapy for severe neurologic forms of Wilson disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "LT is a rescue therapeutic option that should be carefully discussed in selected patients with neurologic WD resistant to anticopper therapies (chelators or zinc salts) as it might allow patients to gain physical independency with a reasonable risk."
explanation: Improvement in physical independence after rescue therapy supports a disability-mediated intermediate mechanism.
- reference: PMID:29110062
reference_title: "Osteoporosis and bone mineral density in patients with Wilson's disease: a systematic review and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "When meta-analysis was limited only to adults, the estimated prevalence rates of osteopenia, osteoporosis, and vertebral fracture were 50.0% (95%CI: 42.0%-58.0%), 17.6% (95%CI: 6.7%-38.6%) and 8.01% (95%CI: 4.05%-15.2%), respectively."
explanation: Adult Wilson disease cohorts show clinically meaningful osteoporosis and vertebral fracture burden.
association_signals:
- source: COHD
method: EHR_COHORT_ASSOCIATION
signal_disorder_a_id: OMOP:436672
signal_disorder_b_id: OMOP:80502
population: >-
COHD dataset_id=3 (5-year hierarchical), patient-level co-occurrence in
Columbia University Irving Medical Center OMOP data.
mapping_notes: >-
Wilson disease did not return a directly observed COHD concept in this
dataset search. As a proxy, disorder A uses OMOP concept 436672
(SNOMED:79886009, "Disorder of copper metabolism"), which can include Wilson
disease and related copper disorders in hierarchical counts. Disorder B uses
OMOP concept 80502 (SNOMED:64859006, "Osteoporosis").
disorder_a_count: 168
disorder_b_count: 33975
pair_count: 7
limited_precision: true
precision_count_threshold: 10
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 0.00020603384841795438
metric_ci_lower: 0.000029026733621665555
metric_ci_upper: 0.0004477478284230321
notes: Relative frequency of osteoporosis among disorder-of-copper-metabolism patients in COHD.
- metric_type: LOG_OBS_EXP_RATIO
metric_value: 0.7532713092329928
metric_ci_lower: -1.1926388398223207
metric_ci_upper: 1.6405745042338955
notes: Natural-log observed/expected co-occurrence ratio from COHD obsExpRatio endpoint.
- metric_type: CHI_SQUARE
metric_value: 4.247044751791994
p_value: 0.03931869490225846
fdr: 1.0
notes: Chi-square association statistic from COHD; adjusted p-value from endpoint. Note FDR=1.0 — does not survive multiple-testing correction.
notes: Supportive but weak COHD EHR association signal; chi-square nominally significant (p=0.039) but FDR=1.0 after correction. Small co-occurrence count (n=7) limits statistical power.
- source: LITERATURE
method: LITERATURE_ASSOCIATION
population: Systematic review/meta-analysis of 4 studies (n=283 Wilson disease patients).
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 0.365
metric_ci_lower: 0.148
metric_ci_upper: 0.657
notes: Pooled prevalence of osteopenia in Wilson disease.
- metric_type: PREVALENCE
metric_value: 0.277
metric_ci_lower: 0.086
metric_ci_upper: 0.609
notes: Pooled prevalence of osteoporosis in Wilson disease.
evidence:
- reference: PMID:29110062
reference_title: "Osteoporosis and bone mineral density in patients with Wilson's disease: a systematic review and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The pooled prevalencerates of osteopenia and osteoporosis in WD patients were 36.5%"
explanation: Meta-analysis reports substantial pooled prevalence of both osteopenia and osteoporosis in Wilson disease cohorts.
- source: LITERATURE
method: LITERATURE_ASSOCIATION
population: Adult-only subgroup from meta-analysis of Wilson disease studies.
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 0.176
metric_ci_lower: 0.067
metric_ci_upper: 0.386
notes: Estimated adult prevalence of osteoporosis in Wilson disease.
- metric_type: PREVALENCE
metric_value: 0.0801
metric_ci_lower: 0.0405
metric_ci_upper: 0.152
notes: Estimated adult prevalence of vertebral fracture in Wilson disease.
evidence:
- reference: PMID:29110062
reference_title: "Osteoporosis and bone mineral density in patients with Wilson's disease: a systematic review and meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "When meta-analysis was limited only to adults, the estimated prevalence rates of osteopenia, osteoporosis, and vertebral fracture were 50.0% (95%CI: 42.0%-58.0%), 17.6% (95%CI: 6.7%-38.6%) and 8.01% (95%CI: 4.05%-15.2%), respectively."
explanation: Adult-only pooled data support clinically relevant osteoporosis and fracture burden in Wilson disease.
- source: LITERATURE
method: LITERATURE_ASSOCIATION
population: Pediatric cross-sectional Wilson disease cohort (n=15) with DEXA assessment.
directionality: UNKNOWN
statistics:
metrics:
- metric_type: PREVALENCE
metric_value: 0.20
notes: Osteoporosis prevalence in pediatric Wilson disease cohort.
evidence:
- reference: PMID:40950651
reference_title: "Bone Densitometry is a Valuable Marker for Bone Health Monitoring in Pediatric Wilson's Disease Patients: A Tertiary Center Experience."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "DEXA revealed bone disease in 60%: mild osteopenia (13%), moderate (27%), and osteoporosis (20%)."
explanation: Pediatric cohort indicates early bone involvement including osteoporosis in Wilson disease.