A

Disease A

Slug:Wilsons_Disease
B

Disease B

Slug:Osteoporosis
G

Causal Mechanism Graphs

Wilsons Disease

graph LR
    Parkinsonism["Parkinsonism"]
    Neurodegeneration["Neurodegeneration"]
    Depression["Depression"]
    Bone_Pain["Bone Pain"]
    Hepatomegaly["Hepatomegaly"]
    Excessive_Salivation["Excessive Salivation"]
    Osteoporosis["Osteoporosis"]
    Ferroptosis["Ferroptosis"]
    Dystonia["Dystonia"]
    Dysphagia["Dysphagia"]
    Renal_Tubular_Dysfunction["Renal Tubular Dysfunction"]
    Failure_To_Thrive["Failure To Thrive"]
    Sunflower_Cataract["Sunflower Cataract"]
    Cuproptosis["Cuproptosis"]
    Acute_Hepatic_Failure["Acute Hepatic Failure"]
    Acute_Hepatitis["Acute Hepatitis"]
    Cirrhosis["Cirrhosis"]
    Hepatic_Steatosis["Hepatic Steatosis"]
    Drooling["Drooling"]
    D_Penicillamine["D-Penicillamine"]
    Aggressive_Behavior["Aggressive Behavior"]
    Ascites["Ascites"]
    Non_Ceruloplasmin_Bound_Serum_Copper["Non-Ceruloplasmin-Bound Serum Copper"]
    Proximal_Lower_Limb_Muscle_Weakness["Proximal Lower Limb Muscle Weakness"]
    Pathologic_Fracture["Pathologic Fracture"]
    Ceruloplasmin["Ceruloplasmin"]
    Excessive_Hepatic_ECM_Deposition["Excessive Hepatic ECM Deposition"]
    Elevated_Circulating_Hepatic_Transaminase_Concentration["Elevated Circulating Hepatic Transaminase Concentration"]
    Abdominal_Pain["Abdominal Pain"]
    Intellectual_Disability["Intellectual Disability"]
    AAV_Mediated_ATP7B_Gene_Therapy["AAV-Mediated ATP7B Gene Therapy"]
    Systemic_Copper_Distribution["Systemic Copper Distribution"]
    Chorea["Chorea"]
    Rigidity["Rigidity"]
    Anxiety["Anxiety"]
    Splenomegaly["Splenomegaly"]
    Bradykinesia["Bradykinesia"]
    Hepatic_Stellate_Cell_Activation["Hepatic Stellate Cell Activation"]
    Weight_Loss["Weight Loss"]
    Gait_Disturbance["Gait Disturbance"]
    ATP7B["ATP7B"]
    Hepatic_Copper["Hepatic Copper"]
    Jaundice["Jaundice"]
    Hepatic_Copper_Accumulation["Hepatic Copper Accumulation"]
    Arthralgia["Arthralgia"]
    Osteopenia["Osteopenia"]
    Hepatitis["Hepatitis"]
    Clumsiness["Clumsiness"]
    Joint_Swelling["Joint Swelling"]
    Cardiomyopathy["Cardiomyopathy"]
    Heart_Failure["Heart Failure"]
    Cardiac_Arrhythmia["Cardiac Arrhythmia"]
    Ataxia["Ataxia"]
    Low_Copper_Diet["Low Copper Diet"]
    Liver_Transplantation["Liver Transplantation"]
    Arthritis["Arthritis"]
    Bruising_Susceptibility["Bruising Susceptibility"]
    Abnormality_Of_The_Menstrual_Cycle["Abnormality Of The Menstrual Cycle"]
    N_24_Hour_Urinary_Copper["24-Hour Urinary Copper"]
    Tremor["Tremor"]
    Seizure["Seizure"]
    Dysarthria["Dysarthria"]
    Pruritus["Pruritus"]
    Kayser_Fleischer_Rings["Kayser-Fleischer Rings"]
    Thrombocytopenia["Thrombocytopenia"]
    Impaired_Ceruloplasmin_Loading["Impaired Ceruloplasmin Loading"]
    Hepatocyte_Injury["Hepatocyte Injury"]
    Hemolytic_Anemia["Hemolytic Anemia"]
    Focal_T2_Hyperintense_Brainstem_Lesion["Focal T2 Hyperintense Brainstem Lesion"]
    Vomiting["Vomiting"]
    Personality_Changes["Personality Changes"]
    Trientine["Trientine"]
    Zinc_Acetate["Zinc Acetate"]
    ATP7B_Copper_Trafficking_Defect["ATP7B Copper-Trafficking Defect"]
    Psychosis["Psychosis"]
    Tetrathiomolybdate["Tetrathiomolybdate"]
    Impaired_Biliary_Copper_Excretion["Impaired Biliary Copper Excretion"]
    Anemia["Anemia"]

    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
    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 --> 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 --> Hemolytic_Anemia
    Hepatocyte_Injury --> Vomiting
    Hepatocyte_Injury --> Cuproptosis
    Hepatocyte_Injury --> Ferroptosis
    Hepatocyte_Injury --> Hepatic_Steatosis
    Hepatocyte_Injury --> Acute_Hepatitis
    Hepatocyte_Injury --> Elevated_Circulating_Hepatic_Transaminase_Concentration
    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 --> Aggressive_Behavior
    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
    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
    ATP7B --> ATP7B_Copper_Trafficking_Defect
    ATP7B --> Impaired_Biliary_Copper_Excretion
    ATP7B --> Impaired_Ceruloplasmin_Loading

    style Parkinsonism fill:#fef3c7
    style Neurodegeneration fill:#dbeafe
    style Depression fill:#fef3c7
    style Bone_Pain fill:#fef3c7
    style Hepatomegaly fill:#fef3c7
    style Excessive_Salivation fill:#fef3c7
    style Osteoporosis fill:#fef3c7
    style Ferroptosis fill:#dbeafe
    style Dystonia fill:#fef3c7
    style Dysphagia fill:#fef3c7
    style Renal_Tubular_Dysfunction fill:#fef3c7
    style Failure_To_Thrive fill:#fef3c7
    style Sunflower_Cataract fill:#fef3c7
    style Cuproptosis fill:#dbeafe
    style Acute_Hepatic_Failure fill:#fef3c7
    style Acute_Hepatitis fill:#fef3c7
    style Cirrhosis fill:#fef3c7
    style Hepatic_Steatosis fill:#fef3c7
    style Drooling fill:#fef3c7
    style D_Penicillamine fill:#fce7f3
    style Aggressive_Behavior fill:#fef3c7
    style Ascites fill:#fef3c7
    style Non_Ceruloplasmin_Bound_Serum_Copper fill:#e0e7ff
    style Proximal_Lower_Limb_Muscle_Weakness fill:#fef3c7
    style Pathologic_Fracture fill:#fef3c7
    style Ceruloplasmin fill:#e0e7ff
    style Excessive_Hepatic_ECM_Deposition fill:#dbeafe
    style Elevated_Circulating_Hepatic_Transaminase_Concentration fill:#fef3c7
    style Abdominal_Pain fill:#fef3c7
    style Intellectual_Disability fill:#fef3c7
    style AAV_Mediated_ATP7B_Gene_Therapy fill:#fce7f3
    style Systemic_Copper_Distribution fill:#dbeafe
    style Chorea fill:#fef3c7
    style Rigidity fill:#fef3c7
    style Anxiety fill:#fef3c7
    style Splenomegaly fill:#fef3c7
    style Bradykinesia fill:#fef3c7
    style Hepatic_Stellate_Cell_Activation fill:#dbeafe
    style Weight_Loss fill:#fef3c7
    style Gait_Disturbance fill:#fef3c7
    style ATP7B fill:#f3e8ff
    style Hepatic_Copper fill:#e0e7ff
    style Jaundice fill:#fef3c7
    style Hepatic_Copper_Accumulation fill:#dbeafe
    style Arthralgia fill:#fef3c7
    style Osteopenia fill:#fef3c7
    style Hepatitis fill:#fef3c7
    style Clumsiness fill:#fef3c7
    style Joint_Swelling fill:#fef3c7
    style Cardiomyopathy fill:#fef3c7
    style Heart_Failure fill:#fef3c7
    style Cardiac_Arrhythmia fill:#fef3c7
    style Ataxia fill:#fef3c7
    style Low_Copper_Diet fill:#fce7f3
    style Liver_Transplantation fill:#fce7f3
    style Arthritis fill:#fef3c7
    style Bruising_Susceptibility fill:#fef3c7
    style Abnormality_Of_The_Menstrual_Cycle fill:#fef3c7
    style N_24_Hour_Urinary_Copper fill:#e0e7ff
    style Tremor fill:#fef3c7
    style Seizure fill:#fef3c7
    style Dysarthria fill:#fef3c7
    style Pruritus fill:#fef3c7
    style Kayser_Fleischer_Rings fill:#fef3c7
    style Thrombocytopenia fill:#fef3c7
    style Impaired_Ceruloplasmin_Loading fill:#dbeafe
    style Hepatocyte_Injury fill:#dbeafe
    style Hemolytic_Anemia fill:#fef3c7
    style Focal_T2_Hyperintense_Brainstem_Lesion fill:#fef3c7
    style Vomiting fill:#fef3c7
    style Personality_Changes fill:#fef3c7
    style Trientine fill:#fce7f3
    style Zinc_Acetate fill:#fce7f3
    style ATP7B_Copper_Trafficking_Defect fill:#dbeafe
    style Psychosis fill:#fef3c7
    style Tetrathiomolybdate fill:#fce7f3
    style Impaired_Biliary_Copper_Excretion fill:#dbeafe
    style Anemia fill:#fef3c7
S

Association Signals

Signal 1
COHD EHR_COHORT_ASSOCIATION UNKNOWN
Population:COHD dataset_id=3 (5-year hierarchical), patient-level co-occurrence in Columbia University Irving Medical Center OMOP data.
Signal IDs: OMOP:436672 -> OMOP:80502
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").
Temporal: A before B: , B before A: , Same time:
PREVALENCE: 0.00020603384841795438
CI: 2.9026733621665555e-05 - 0.0004477478284230321
p:
FDR:
Relative frequency of osteoporosis among disorder-of-copper-metabolism patients in COHD.
LOG_OBS_EXP_RATIO: 0.7532713092329928
CI: -1.1926388398223207 - 1.6405745042338955
p:
FDR:
Natural-log observed/expected co-occurrence ratio from COHD obsExpRatio endpoint.
CHI_SQUARE: 4.247044751791994
CI: -
p: 0.03931869490225846
FDR: 1.0
Chi-square association statistic from COHD; adjusted p-value from endpoint. Note FDR=1.0 — does not survive multiple-testing correction.
Signal 2
LITERATURE LITERATURE_ASSOCIATION UNKNOWN
Population:Systematic review/meta-analysis of 4 studies (n=283 Wilson disease patients).
Temporal: A before B: , B before A: , Same time:
PREVALENCE: 0.365
CI: 0.148 - 0.657
p:
FDR:
Pooled prevalence of osteopenia in Wilson disease.
PREVALENCE: 0.277
CI: 0.086 - 0.609
p:
FDR:
Pooled prevalence of osteoporosis in Wilson disease.
PMID:29110062 (SUPPORT)
Source: HUMAN_CLINICAL
"The pooled prevalencerates of osteopenia and osteoporosis in WD patients were 36.5%"
Meta-analysis reports substantial pooled prevalence of both osteopenia and osteoporosis in Wilson disease cohorts.
Signal 3
LITERATURE LITERATURE_ASSOCIATION UNKNOWN
Population:Adult-only subgroup from meta-analysis of Wilson disease studies.
Temporal: A before B: , B before A: , Same time:
PREVALENCE: 0.176
CI: 0.067 - 0.386
p:
FDR:
Estimated adult prevalence of osteoporosis in Wilson disease.
PREVALENCE: 0.0801
CI: 0.0405 - 0.152
p:
FDR:
Estimated adult prevalence of vertebral fracture in Wilson disease.
PMID:29110062 (SUPPORT)
Source: HUMAN_CLINICAL
"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."
Adult-only pooled data support clinically relevant osteoporosis and fracture burden in Wilson disease.
Signal 4
LITERATURE LITERATURE_ASSOCIATION UNKNOWN
Population:Pediatric cross-sectional Wilson disease cohort (n=15) with DEXA assessment.
Temporal: A before B: , B before A: , Same time:
PREVALENCE: 0.2
CI: -
p:
FDR:
Osteoporosis prevalence in pediatric Wilson disease cohort.
PMID:40950651 (SUPPORT)
Source: HUMAN_CLINICAL
"DEXA revealed bone disease in 60%: mild osteopenia (13%), moderate (27%), and osteoporosis (20%)."
Pediatric cohort indicates early bone involvement including osteoporosis in Wilson disease.
H

Hypotheses

Hypothesis: copper-related multisystem toxicity in Wilson disease affects both bone and renal tissues, creating a bone fragility milieu.
PMID:38731973 (SUPPORT)
Source: OTHER
"This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones"
Review summary supports direct involvement of both kidney and bone tissues in Wilson disease.
PMID:38731973 (SUPPORT)
Source: OTHER
"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."
Renal tubular dysfunction and osteoporosis are co-listed clinical features, supporting a linked mineral-handling hypothesis.
Pathophysiology:
Copper toxicity with renal-bone interaction: Copper toxicity in Wilson disease may simultaneously injure renal tubular and skeletal compartments, predisposing to mineral dysregulation and bone fragility.
Biological processes:
PMID:38731973 (SUPPORT)
Source: OTHER
"This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones"
Supports multi-organ copper injury including kidney and bone.
Hypothesis: hepatic synthetic and nutritional status contributes to bone health variability in Wilson disease.
PMID:40950651 (SUPPORT)
Source: HUMAN_CLINICAL
"However, serum albumin positively correlated with bone density (P = .018)."
Albumin-bone density correlation supports a liver function and nutritional mechanism affecting bone status.
Pathophysiology:
Albumin-linked bone vulnerability: Lower albumin in Wilson disease may reflect hepatic dysfunction and/or nutritional compromise associated with poorer bone mineralization.
PMID:40950651 (SUPPORT)
Source: HUMAN_CLINICAL
"Bone disease is frequent and often subclinical in pediatric Wilson's disease."
Supports frequent, clinically subtle bone involvement in Wilson disease.
PMID:40950651 (SUPPORT)
Source: HUMAN_CLINICAL
"However, serum albumin positively correlated with bone density (P = .018)."
Correlative evidence links albumin and bone density in pediatric Wilson disease.
Hypothesis: host factors (age and sex) modify osteoporosis risk expression in Wilson disease.
PMID:29110062 (SUPPORT)
Source: HUMAN_CLINICAL
"Meta-regressionshowed significant impacts of age (negative correlation; P=0.002) and male status (positive correlation;P < 0.001) on the prevalence of osteoporosis."
Meta-regression indicates age/sex interaction with osteoporosis prevalence, suggesting biologic risk modifiers.
Pathophysiology:
Age-sex risk modulation: Osteoporosis risk in Wilson disease appears modified by demographic and host factors, implying interaction between copper-related pathology and baseline bone-risk biology.
PMID:29110062 (SUPPORT)
Source: HUMAN_CLINICAL
"Meta-regressionshowed significant impacts of age (negative correlation; P=0.002) and male status (positive correlation;P < 0.001) on the prevalence of osteoporosis."
Quantifies host-factor dependence of osteoporosis prevalence in Wilson disease cohorts.
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.
PMID:37116715 (SUPPORT)
Source: HUMAN_CLINICAL
"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."
Large multicenter cohort links treatment phase and adherence status to neurological destabilization.
PMID:35887738 (SUPPORT)
Source: HUMAN_CLINICAL
"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."
Identifies adherence as a key determinant of Wilson disease control.
PMID:40950651 (PARTIAL)
Source: HUMAN_CLINICAL
"Larger studies are needed to evaluate the effects of treatment and micronutrient status on bone health."
Pediatric bone-density study explicitly flags treatment and micronutrient status as potential bone-health determinants requiring deeper study.
Pathophysiology:
Treatment-course instability and disuse-bone pathway: 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.
PMID:32398357 (SUPPORT)
Source: HUMAN_CLINICAL
"All were highly dependent before LT (median mRS score 5)."
Refractory neurologic Wilson disease can produce profound dependency consistent with reduced mechanical loading.
PMID:32398357 (SUPPORT)
Source: HUMAN_CLINICAL
"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."
Improvement in physical independence after rescue therapy supports a disability-mediated intermediate mechanism.
PMID:29110062 (SUPPORT)
Source: HUMAN_CLINICAL
"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."
Adult Wilson disease cohorts show clinically meaningful osteoporosis and vertebral fracture burden.
Y

Raw YAML

Show YAML
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
    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
    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
      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
    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
      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
      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
    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
      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
    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
    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
    supports: PARTIAL
    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
      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
      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
      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
      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
      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
      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.
Source:GitHub