Novartis Pharmaceuticals Corporation

59 Route 10

East Hanover, NJ 07936

Appendix: 1\
Risk Factors/Conditions for Osteonecrosis

Zometa^®^ (zoledronic acid) Injection

and

Aredia^®^ (pamidronate disodium) Injection

Submitted: February 1, 2005

Oncologic Drugs Advisory Committee Meeting

March 4, 2005

Property of Novartis Pharmaceuticals Corporation\
All rights reserved\
**Available for public disclosure without redaction**

## Table of contents {#table-of-contents .TOC-Entry}

Table of contents [2](#table-of-contents)

1 Conditions leading to or associated with osteonecrosis
[3](#conditions-leading-to-or-associated-with-osteonecrosis)

2 Localized and systemic diseases and pathophysiologic processes
associated with ischemic osteonecrosis
[4](#localized-and-systemic-diseases-and-pathophysiologic-processes-associated-with-ischemic-osteonecrosis)

# Conditions leading to or associated with osteonecrosis

(From: \[Assouline-Dayan, et al (2002)\] Pathogenesis and natural
history of osteonecrosis. Sem Arthr & Rheum 32: 94-124)

  ----------------------------------- -----------------------------------
  Trauma                              Disorders

  Burns                               Systemic Lupus Erythematosus

  Fractures                           Polymyositis

  Dislocations                        Polymyalgia Rheumatica

  Vascular Trauma                     Raynaud's Disease

  Kienböck Disease                    Rheumatoid Arthritis

  Non-Traumatic Conditions            Ankylosing Spondylitis

  Hematologic                         Sjögren's Syndrome

  Hemoglobinopathies                  Giant Cell Arteritis

  Sickle-Cell Anemia                  Thrombophlebitis

  Thalassemias                        Lipid Emboli

  Disseminated Intravascular          Ehler-Danlos Syndrome
  Coagulation                         

  Polycythemia                        Orthopedic Problems

  Hemophilia                          Slipped Capital Femoral Epiphysis

  Metabolic/Endocrinologic            Congenital Hip Dislocation

  Hypercholesterolemia                Hereditary Dysostosis

  Gout                                Legg-Calvé-Perthes' Disease

  Hyperparathyroidism                 Extrinsic Dietary or Environmental
                                      Factors

  Hyperlipidemia                      Dysbaric Conditions (Caisson
                                      Disease)

  Pregnancy                           Alcohol Consumption

  Cushing's Disease                   Cigarette Smoking

  Chronic Renal Failure               Iatrogenic

  Gaucher'sDisease                    Corticosteroids

  Diabetes (in association with       Radiation Exposure
  obesity)                            

  Fabry's Disease                     Hemodialysis

  Gastrointestinal                    Organ Transplantation

  Pancreatitis                        Laser Surgery

  Inflammatory Bowel Disease          Idiopathic

  Neoplastic                          

  Marrow Infiltrative Disorders       

  Infectious                          

  Osteomyelitis                       

  Human Immunodeficiency Virus        

  Meningococcemia                     

  Vascular/Rheumatologic/Connective   
  Tissue                              
  ----------------------------------- -----------------------------------

# Localized and systemic diseases and pathophysiologic processes associated with ischemic osteonecrosis

(from \[Bouquot and McMahon (2000)\] Neuropathic pain in maxillofacial
osteonecrosis. J Oral Maxillofoc Surg 58: 1003-1020)

  ------------------ ------------------------- ------------------ --------------------------------
  **DISEASE OR\      **SUBCATEGORIES**         **DISEASE OR       **SUBCATEGORIES**
  ETIOLOGIC\                                   ETIOLOGIC FACTOR** 
  FACTOR**                                                        

  Alcohol abuse\     Cirrhosis\                Hypercoagulable    Antiphospholipid antibody
  \                  Pancreatitis\             state, systemic\   syndrome Factor V^Leiden^ gene
  Arthritis\         Subchondral cyst\         \                  mutation Hyperhomocystinemia
  \                  Subchondral marrow edema\ \                  Homozygosity for MTHFR or CBS
  \                  \                         \                  Protein C deficiency\
  Atmospheric        Caisson's disease\        \                  Protein S deficiency\
  pressure           Deep sea diving\          \                  \
  variations\        \                         \                  \
  \                  Disseminated              Hyperdipidemia and Diabetes mellitus\
  \                  intravascular             embolic fat\       Dysbaric phenomena\
  Blood dyscrasias\  coagulation\              \                  Fracture of bone\
  \                  Leukemia\                 \                  Hemoglobinopathies\
  \                  Sickle cell anemia\       \                  Osteomyelitis, acute\
  \                  Chemotherapy for cancer\  \                  \
  \                  Cancer-induced            \                  \
  Cancer\            hyperocoagulation\        \                  \
  \                  Lymphoma\                 Hypersensitivity   Allograft organ rejection\
  \                  Metastatic intraosseous   reactions\         Anaphylactic shock\
  \                  carcinoma\                \                  Immune globulin therapy\
  \                  Radiation therapy for     \                  Shwartzman reaction to
  \                  cancer\                   \                  endotoxin\
  \                  Bedridden\                \                  Transfusion reactions\
  \                  Full body cast\           \                  \
  \                  Paraplegic\               \                  \
  \                  Hypercortisolism\         Hypertension       Infection, bacterial and viral\
  Chronic            Inflammatory bowel        Hypothyroidism     Trauma (mild or severe)\
  inactivity\        disease\                  Inflammation,      Autoimmunity/hypersensitivity\
  \                  Lupus erythematosus\      intraosseous\      With corticosteroid therapy\
  \                  Transplants\              \                  Without corticosteroid therapy\
  Corticosteroids\   Birth control pills\      \                  Brain injury/surgery\
  \                  Estrogen replacement      \                  Regional or generalized\
  \                  therapy\                  Lupus              Anorexia nervosa\
  \                  Fertility drugs\          erythematosus\     Gaucher's disease\
  \                  Pregnancy\                \                  Tobacco smoking\
  \                  Prostate chemotherapy\    \                  \
  Estrogen\          Transient ischemic        Neurodamage        \
  \                  osteoporosis\             Osteoporosis\      \
  \                  \                         Starvation\        \
  \                  \                         Storage diseases\  \
  \                  \                         Tobacco use\       \
  \                  \                         Vascular occlusive \
  Gaucher's disease  Acute                     disease\           Atherosclerosis\
  Hemodialysis\      infection/inflammation    Vasculitis\        \
  Hypercoaguable     Chronic                   Vasoconstriction   \
  state,\            infection/inflammation\                      Local anesthetic use\
  local              Chronic                                      Raynaud phenomenon
                     infection/inflammation                       
                     Increased intrame-dullary                    
                     pressures                                    
  ------------------ ------------------------- ------------------ --------------------------------