Bone pain

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: Ostealgia; Osteodynia.

Overview

Bone pain is a debilitating form of pain emanating from the bone tissue. It occurs as a result of a wide range of diseases and/or physical conditions and may severely impair the quality of life for patients who suffer from it. Bone pain has multiple causes, such as extensive physical stress and diseases such as cancer. For many years it has been known that bones are innervated with sensory neurons. Yet their exact anatomy remained obscure due to the contrasting physical properties of bone and neural tissue. However, until recently, it was not determined what types of nerves innervated which sections of bone. The periosteal layer of bone tissue is highly pain-sensitive and an important cause of pain in several disease conditions causing bone pain, like fractures, osteoarthritis, etc. However, in certain diseases the endosteal and haversian nerve supply seems to play an important role, e.g. osteomalacia, osteonecrosis, and so on. Thus there are several types of bone pain, each with many potential sources or origins of cause.

Pathophysiology

Stimulation of specialized pain-sensitive nerve fibers (nociceptors) that innervate bone tissue leads to the sensation of bone pain. Bone pain originates from both the periosteum and the bone marrow which relay nociceptive signals to the brain creating the sensation of pain. Bone tissue is innervated by both myelinated (A beta and A delta fiber) and unmyelinated (C fiber) sensory neurons. In combination, they can provide an initial burst of pain, initiated by the faster myelinated fibers, followed by a slower and longer lasting dull pain initiated by unmyelinated fibers.

Nociceptors responsible for bone pain can be activated via several mechanisms including deterioration of surrounding tissue, bone destruction, and physical stress which shears the bone, vascular, muscle, and nervous tissue.

Bone Cancer

Main article: Bone tumor

Bone cancer is one of the most serious forms of pain. Because of its severity and uniqueness with respect to other forms of pain, it is extensively researched. According to studies of bone cancer in mouse femur models, it has been determined that bone pain related to cancer occurs as a result of destruction of bone tissue. Chemical changes that occur within the spinal cord as a result of bone destruction give further insight into the mechanism of bone pain.

Metastatic cancer cells often aim to establish themselves within the skeleton. When the cancer cells have metastasized, the mechanical dynamics of the bone matrix become weaker as skeletal strength decreases. This leads to several other complications throughout the body including pain, thus decreasing the patient’s quality of life.

Bone tumors are composed of a conglomeration of cell types including cancer and immune system cells. Oftentimes tumor cells secrete growth factors which activate receptors close to primary afferent neurons. Activation of these neural receptors is a contributing factor to pain sensation. Additionally, inflammatory lipids called prostaglandins, which are produced at high rates by cancer cells within tumors, activate nociceptors when they bind together.

Diseases affecting bones

• Viral illness (such as a cold that has spread to the bones/joints)
• Leukemia (blasts that have surfaced to the top of the bone, often with tenderness)less common)
• Blood infection (anemia/other)
• Trauma to the bone (such as a fall)
• Arthritis pain
• Weather changes
• Fibromyalgia (widespread body pain with tenderness)
• Cancer - can be primary bone tumor or spread from another cancer known as a Bony metastasis.
• Paget's disease
• Osteoporosis

Causes

Causes by Organ System

Cardiovascular	No underlying causes
Chemical / poisoning	Aluminium toxicity, Hydrogen fluoride
Dermatologic	SAPHO syndrome , Weber-Christian disease
Drug Side Effect	Cytosine arabinose syndrome, Granulocyte colony stimulating factor, Leflunomide,
Ear Nose Throat	Deafness-lymphoedema-leukemia
Endocrine	Hyperparathyroidism, Multiple endocrine neoplasia type 1
Environmental	No underlying causes
Gastroenterologic	Celiac disease, Primary biliary cirrhosis
Genetic	Camurati-Engelmann disease, Deafness-lymphoedema-leukemia, Diaphyseal medullary stenosis with malignant fibrous histiocytoma, Familial expansile osteolysis, Gaucher disease, Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia, Jaffe-Lichtenstein syndrome, Juvenile Paget disease, Majeed syndrome, Multiple hereditary exostoses, Nasu-Hakola disease, Paget disease of bone, Panostotic fibrous dysplasia, Thalassemia, WT limb blood syndrome , X-linked hypophosphatemia, Sickle cell disease
Hematologic	Acute myelosclerosis, Aplastic anemia, Chronic myeloproliferative disorders, Di Guglielmo syndrome, Erdheim-Chester disease, Hand-Schuller-Christian Syndrome, Hodgkin's Disease, Langerhans cell histiocytosis, Mastocytosis, Myelofibrosis, Myeloid sarcoma, Myeloproliferative diseases, Polycythemia vera, Sickle cell disease, Systemic mastocytosis, Waldenstrom macroglobulinemia, Deafness-lymphoedema-leukemia, Thalassemia, Ewing sarcoma, Leukemia, Lymphoma, Multiple Myeloma, Non-Hodgkin's lymphoma
Iatrogenic	Osteoradionecrosis, Cytosine arabinose syndrome, Radiation osteitis, Alveolar osteitis
Infectious Disease	Cytomegalic inclusion body disease, Osteomyelitis, Sepsis, Tuberculous osteomyelitis, Viral illness
Musculoskeletal / Ortho	Aneurysmal bone cysts, Aseptic osteitis , Avascular necrosis, Fibrous Dysplasia, Haferkamp syndrome, Infantile recurrent chronic multifocal osteomyolitis, Juvenile osteoporosis, MSBD syndrome, Osteitis, Osteitis fibrosa cystica, Osteoarthritis, Osteochondroses, Osteoid osteoma, Osteomalacia, Osteoporosis, Pathological fracture, Radiation osteitis, Ribbing disease, Rickets, Scheuermann's disease, Skeletal fluorosis, Van Buchem disease, SAPHO syndrome , Camurati-Engelmann disease, Diaphyseal medullary stenosis with malignant fibrous histiocytoma, Familial expansile osteolysis, Jaffe-Lichtenstein syndrome, Juvenile Paget disease, Majeed syndrome, Multiple hereditary exostoses, Nasu-Hakola disease, Paget disease of bone, Panostotic fibrous dysplasia, Myelofibrosis, Osteomyelitis, Tuberculous osteomyelitis, Adamantinoma, Angiosarcoma, Bone cancer, Bone metastases, Cartilage tumors, Chondrosarcoma, Enchondromatosis, Oncogenic osteomalacia, Osteoclastoma, Osteosarcoma, Parathyroid cancer, Periosteal chondrosarcoma, Phosphate diabetes, Renal osteodystrophy, Chronic recurrent multifocal osteomyelitis, Stress fracture, Osteitis condensans, Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia
Neurologic	Nasu-Hakola disease, Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia
Nutritional / Metabolic	Lysosomal storage disorders, Sphingolipidosis, Vitamin C deficiency, Gaucher disease, Rickets
Obstetric/Gynecologic	No underlying causes
Oncologic	Adamantinoma, Angiosarcoma, Bone cancer, Bone metastases, Cartilage tumors, Chondrosarcoma, Enchondromatosis, Epithelioid hemangioendothelioma, Ewing sarcoma, Leukemia, Lymphoma, Multiple Myeloma, Neuroblastoma, Non-Hodgkin's lymphoma, Oncogenic osteomalacia, Osteoclastoma, Osteosarcoma, Parathyroid cancer, Periosteal chondrosarcoma, Deafness-lymphoedema-leukemia, Chronic myeloproliferative disorders, Di Guglielmo syndrome, Myeloid sarcoma, Systemic mastocytosis, Waldenstrom macroglobulinemia, Osteoid osteoma
Opthalmologic	No underlying causes
Overdose / Toxicity	Cytosine arabinose syndrome, Granulocyte colony stimulating factor, Hypervitaminosis A, Hypervitaminosis D
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal / Electrolyte	Chronic kidney disease, Fanconi syndrome, Hypophosphatemia, Phosphate diabetes, Renal osteodystrophy, Renal rickets, X-linked hypophosphatemia
Rheum / Immune / Allergy	Chronic recurrent multifocal osteomyelitis, Primary biliary cirrhosis, Schnitzler syndrome
Sexual	No underlying causes
Trauma	Fracture of bone, Stress fracture
Urologic	No underlying causes
Dental	Alveolar osteitis, Osteitis condensans
Miscellaneous	Opiate withdrawal, Overuse

Causes in Alphabetical Order

Acute myelosclerosis Adamantinoma Aluminium toxicity Alveolar osteitis Aneurysmal bone cysts Angiosarcoma Aplastic anemia Aseptic osteitis Avascular necrosis Bone cancer Bone metastases Camurati-Engelmann disease Cartilage tumors Celiac Disease Chondrosarcoma Chronic kidney disease Chronic myeloproliferative disorders Chronic recurrent multifocal osteomyelitis Cytomegalic inclusion body disease Cytosine arabinose syndrome Deafness-lymphoedema-leukemia Di Guglielmo syndrome Diaphyseal medullary stenosis with malignant fibrous histiocytoma Enchondromatosis Epithelioid hemangioendothelioma Erdheim-Chester disease Ewing sarcoma Familial expansile osteolysis Fanconi syndrome Fibrous Dysplasia Fracture of bone Gaucher disease Granulocyte colony stimulating factor Haferkamp syndrome Hand-Schuller-Christian Syndrome Hodgkin's Disease Hydrogen fluoride Hyperparathyroidism Hypervitaminosis A Hypervitaminosis D Hypophosphatemia Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia Infantile recurrent chronic multifocal osteomyolitis Jaffe-Lichtenstein syndrome Juvenile osteoporosis Juvenile Paget disease Langerhans cell histiocytosis Leukemia Lymphoma Lysosomal storage disorders Majeed syndrome Mastocytosis MSBD syndrome Multiple endocrine neoplasia type 1

Multiple hereditary exostoses Multiple Myeloma Myelofibrosis Myeloid sarcoma Myeloproliferative diseases Nasu-Hakola disease Neuroblastoma Non-Hodgkin's lymphoma Oncogenic osteomalacia Opiate withdrawal Osteitis Osteitis condensans Osteitis fibrosa cystica Osteoarthritis Osteochondroses Osteoclastoma Osteoid osteoma Osteomalacia Osteomyelitis Osteoporosis Osteoradionecrosis Osteosarcoma Overuse Paget disease of bone Panostotic fibrous dysplasia Parathyroid cancer Pathological fracture Periosteal chondrosarcoma Phosphate diabetes Polycythemia vera Primary biliary cirrhosis Radiation osteitis Renal osteodystrophy Renal rickets Ribbing disease Rickets SAPHO syndrome Scheuermann's disease Schnitzler syndrome Sepsis Sickle cell disease Skeletal fluorosis Sphingolipidosis Stress fracture Systemic mastocytosis Thalassemia Tuberculous osteomyelitis Van Buchem disease Viral illness Vitamin C deficiency Waldenstrom macroglobulinemia Weber-Christian disease WT limb blood syndrome X-linked hypophosphatemia

Treatment

The use of anesthetics within the actual bone has been a common treatment for several years. This method provides a direct approach using analgesics to relieve pain sensations.

Another commonly used method for treating bone pain is radiotherapy, which can be safely administered in low doses. Radiotherapy utilizes radioactive isotopes and other atomic particles to damage the DNA in cells, thus leading to cell death. By targeting cancer tumors, radiotherapy can lead to decrease in tumor size and even tumor destruction. A form of radiotherapy that is often used in cases of bone cancer is systemic radioisotope therapy, where the radioisotopes target sections of the bone specifically undergoing metastasis.

In the case of bone fractures, surgical treatment is generally the most effective. Analgesics can be used in conjunction with surgery to help ease pain of damaged bone.

Scientific Research and Future Treatments

Mouse and other animal models are being heavily used to determine the neuron tissue densities in bone and mechanisms for maintenance of bone pain. This information is pertinent to determining the biological and physiological components of pain in the bone. By creating a detailed map relating the types of nerves going through the different sections of bone, it is possible to pin-point locations in the bone that are at a higher risk of being susceptible to bone pain.

Treatments focusing on biological components such as cannabinoid receptors are being tested for effectiveness. Through testing in mouse models, it has been shown that activation of the CB-1 receptor helps reduce reactions associated with acute pain, indicating that it alleviates bone pain. Thus, a new target for potential treatments is activation of the CB-1 receptor.

Modern research and techniques are attempting to provide longer lasting and more effective methods of treating bone pain by developing and applying new physiological knowledge of nervous tissue within the bone. If thorough understanding of the intra-neuronal mechanisms relating to pain can be developed, then new and more effective treatment options can be created and tested. Thus, it is critical to fully understand the mechanism which dictates bone pain.

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