Pathological fracture is a fracture that occurs when a bone breaks in an area that is weakened by another disease process. Causes of weakened bone varies from genetic disorders , tumours , and even chronic infection , each having its own pathogenesis which leads to pathological fracture.
Pathological fractures occur usually during normal routine activities of the patient.He may rest his hand on table when it fractured,he may be playing with grandchildren when the fracture occurs.These are only few of the examples.The reason is that the underlying disease process weakens the bone to the point where the bone is unable to perform its normal function.
Here are some of the causes of pathological fracture,whereby the pathophysiology of few of the condition will be explained briefly.
Generalized cause which include osteogenesis imperfecta , postmenopausal osteoporosis , metabolic bone disease , myelomatosis , Polyostotic fibrous dysplasia, and Paget’s disease. Secondly , local benign condition including chronic infection , solitary bone cyst , Fibrous cortical defect , chondromyxoid fibroma , aneurismal bone cyst , Chondroma , monostotic fibrous dysplasia.There are also few primary malignant tumors leading to pathological fracture which are chondrosarcoma , Osteosarcoma , Ewing’s tumor.Lastly few of the metastatic tumors , including Carcinoma breast , lung , kidney , thyroid , Colon , and prostate.
In Osteogenesis Imperfecta,the pathology lies in the disturbance in the synthesis of type I collagen, which is the predominant protein of the extracellular matrix of most tissues. In bone, this defect of extracellular matrix causes osteoporosis, which leads to an increase in the tendency to fracture. Besides bone, type I collagen is also a major constituent of dentin, sclerae, ligaments, blood vessels, and skin; therefore, individuals with osteogenesis imperfecta may also have abnormalities of these structures.




The process of collagen molecule formation starts with the synthesis of procollagen, consisting of a long triple-helix protein flanked by 2 propeptides at its 2 terminals.It is then secreted into the extracellular compartment, where the amino- and carboxy-terminal propeptides are cleaved,thus forming the functional collagen molecule. Then,fibrils are formed.Any Mutations that interfere with expression of the collagen gene, formation of the triple helix , or procollagen secretion will affect the structure and function of collagen fibrils, leading to osteogenesis imperfecta.
A number of genetic defects cause the abnormal type I collagen synthesis that leads to osteogenesis imperfecta. It generally arises from mutations in 1 of 2 genes that encode for the synthesis and structure of type I collagen: the COL1A1 gene on chromosome 17, and the COL1A2 gene on chromosome 7. Mutations in these genes leads to decrease in normal collagen. Milder forms of osteogenesis imperfecta are caused primarily by a decrease in production of normal collagen, whereas more severe forms are caused primarily by the production of abnormal collagen. These abnormalities may be dominantly inherited, or they may be the result of sporadic mutation.
Next is Postmenopausal Osteoporosis.Underlying pathology : imbalance of bone resorption and bone formation.In normal bone, there is constant matrix remodeling of bone and up to 10% of all bone mass may be undergoing remodeling at any point in time. Bone is resorbed by osteoclast cells , after which new bone is deposited by osteoblast cells.The main mechanism by which osteoporosis develops are an inadequate peak bone mass (the skeleton develops insufficient mass and strength during growth), excessive bone resorption and inadequate formation of new bone during remodeling. An interplay of these three mechanisms underlies the development of fragile bone tissue.Moreover,hormonal factors , for example the lack of estrogen( as a result of menopause) increases bone resorption,and decreases the deposition of new bone that normally takes place in weight-bearing bones. The α-form of the estrogen receptor appears to be the most important in regulating bone turnover.
In bone structure,trabecular bone is the sponge-like bone in the ends of long bones and vertebrae. Cortical bone is the hard outer shell of bones and the middle of long bones. Because osteoblasts and osteoclasts inhabit the surface of bones, trabecular bone is more active, more subject to bone turnover, to remodeling. Not only is bone density decreased, but the microarchitecture of bone is disrupted. The weaker spicules of trabecular bone break ("microcracks"), and are replaced by weaker bone. Common osteoporotic fracture sites, the wrist, the hip and the spine, have a relatively high trabecular bone to cortical bone ratio. These areas rely on trabecular bone for strength, and therefore the intense remodeling causes these areas to degenerate most when the remodeling is imbalanced.
Next is the metabolic bone disease,in which rickets and hyperparathyroidism discussed here.As for rickets,it involves mainly dietary deficiency of Vitamin D and calcium.Vitamin D is required for proper calcium absorption from the gut. Sunlight, especially ultraviolet light, lets human skin cells convert Vitamin D from an inactive to active state. In the absence of vitamin D, dietary calcium is not properly absorbed, resulting in hypocalcemia, leading to skeletal and dental deformities and neuromuscular symptoms.(eg of food containing vitamin D are butter,egg,fish liver oil,margarine etc)
Next is Hyperparathyroidism.Osteoporosis associated with hyperparathyroidism is caused by the high parathyroid hormone secreted by overactive parathyroid gland. Excess parathyroid hormone acts indirectly on osteoclasts as they lack a PTH receptor. Instead, PTH stimulates osteoblasts, which in turn increases their expression of RANKL. RANKL is then able to bind osteoclasts which stimulates their activation which ultimately leads to the removal of calcium from the bones.
Moving on to the next cause of pathological fracture, which is Myelomatosis.Myeloma bone pain usually involves the spine and ribs, and worsens with activity. Persistent localized pain may indicate a pathological bone fracture. Myeloma bone disease is due to the release of RANKL by plasma cells and bone marrow stroma which binds to activatory RANK receptors on the osteoclast. These bone lesions are lytic in nature.(punced out lesion and pepper pot appearance on radiograph)
Next on the list is the Paget’s Disease/ Osteitis deformans.It is associated with genetic or viral etiology. Sir James Paget first suggested that the disease was due to an inflammatory process. New evidence suggests that he may have been correct and that a paramyxovirus infection is the underlying cause of Pagets Disease. No infectious virus has yet been isolated as a causative agent, however, and other evidence suggests that an intrinsic hyperresponsive reaction to Vitamin D and RANK ligand is the cause. The pathogenesis of Paget's disease involves 3 stages,which are : Osteoclastic activity , Mixed osteoclastic-osteoblastic activity and exhaustive (burnt out) stage. Initially, there is a highly increased rate of bone resorption at localized areas due to large and numerous osteoclasts (seen radiologically as an advancing lytic wedge in long bones or osteoporosis circumscripta in the skull ) .Then, the osteolysis is followed by a compensatory increase in bone formation which is induces by osteoblasts recruited to the area,leading to accelerated deposition of lamellar bone in a disorganized fashion ("mosaic" pattern), rather than the normal linear lamellar pattern. After that,the resorbed bone is replaced , marrow spaces are filled by fibrous connective tissue with a marked increase in blood vessels ( hypervascular bone ). The bone hypercellularity may then diminish leaving a dense pagetic bone ,also known as burned-out Paget disease.

As for chronic infection,osteomyelitis is one of the example.Osteomyelitis is the infection of bone or bone marrow. In general, microorganisms may infect bone through bloodstream, contiguously from local areas of infection (as in cellulitis), or penetrating trauma, including iatrogenic .Once the bone is infected, leukocytes enter the infected area, and, in their attempt to engulf the infectious organisms, release enzymes that lyse the bone. Pus spreads into the bone's blood vessels, impairing their flow, and areas of devitalized infected bone, known as sequestra form the basis of a chronic infection.Often, the body will try to create new bone around the area of necrosis. The resulting new bone is often called an involucrum.On histologic examination, these areas of necrotic bone are the basis for distinguishing between acute osteomyelitis and chronic osteomyelitis. Osteomyelitis is an infective process which encompasses all of the bone components, including the bone marrow. When it is chronic it can lead to bone sclerosis and deformity.Because of the particulars of their blood supply, the tibia, femur, humerus, vertebra, the maxilla, and the mandibular bodies are especially susceptible to osteomyelitis. Abscesses of any bone, however, may be precipitated by trauma to the affected area.
Chronic osteomyelitis can lead to pathological fracture.It is due to excessively large diapyseal separation and the formation of involucrum that is inadequate to stand the normal stress brought to bear upon the limb.Moreover,fracture is facilitated by imperfect immobilization and support of the diseased bone,and is therefore more found in single bone – humerus and femur , compared to those that have companion bone for support

The other cause of pathological fracture is Fibrous Cortical Defect ( FCD ) ,nonaggressive fibrous lesion of bone , considered to be developmental defects. It typically occurred within the metaphysis of growing long tubular bones in children, most commonly about the knee. FCDs are asymptomatic, small (<3 cm), eccentrically located, metaphyseal cortical defects; most of these spontaneously disappear. However, some evolve and enlarge into fibroxanthomas. Conversely, fibroxanthomas (>3 cm) are larger, eccentric, intramedullary lesions that abut the cortex; they have a typical, superficial, scalloping pattern in the adjacent cortex.While these lesions also can heal spontaneously (with reactive bone filling in the central lucent fibrous tissue component), they can also persist, with interval growth that continues into adulthood. Typically, fibroxanthomas are asymptomatic. However, the larger lesions may become symptomatic, with a risk of pathologic fracture. Steiner suggested that these 2 lesions are secondary to cellular proliferation due to aberrations in local development.

Next is the Solitary bone cyst ,a benign, fluid-filled, radiolucent lesion that may appear in virtually any bone, but typically, it is found in either the proximal humerus or proximal femur. This lesion is found almost exclusively in children.It often leads to thinning of adjacent areas of bone, such that fracture or pain from microfracture may occur. When such cysts are immediately adjacent to a growth plate, they are referred to as active cysts, and when they have achieved some distance from the growth plate, they are considered to be latent cysts. It usually presents as a unifocal (one bone) problem, affecting patients who are skeletally immature.
Then comes the aneurysmal bone cyst (ABC) , an expansile cystic lesion that most often affects individuals during their second decade of life and may occur in any bone in the body. Although benign, it may become locally aggressive causing extensive weakening of the bony structure and impinge on the surrounding tissues. The true etiology and pathophysiology remain a mystery. However,different theories about several vascular malformations were suggested, these include arteriovenous fistulas and venous blockage. The vascular lesions then cause increased pressure, expansion, erosion, and resorption of the surrounding bone. The malformation is also believed to cause local hemorrhage that initiates the formation of reactive osteolytic tissue , further leading to the pathological fracture.
Moving on with chondromyxoid fibroma (CMF) , a rare benign tumor of bone. The etiology is unknown however, one report has pointed to an error in chromosome 6.The tumor arises from the cartilage-forming connective tissue of the marrow space. Histologically, as its name implies, this benign cartilaginous neoplasm consists of chondroid, myxoid, and fibrous tissue in variable amounts.Osteoclast-like giant cells may also be present, as may small cysts and hemorrhagic zones. Focal calcification is found microscopically in approximately one fourth of patients, although any gross evidence of calcification is rare.
Next is the fibous dysplasia , which is the skeletal developmental anomaly of the bone-forming mesenchyme that manifests as a defect in osteoblastic differentiation and maturation. It can affect any bone in the body. It is a nonhereditary disorder of unknown cause.However , there are suggestion that it may be due to abnormal growth process is related to a mutation in the gene that encodes the subunit of a stimulatory G protein (Gsα) located on chromosome 20.As a consequence of this mutation, there is a substitution of the cysteine or the histidine—amino acids of the genomic DNA in the osteoblastic cells—by another amino acid, arginine. The osteoblastic cells will elaborate a fibrous tissue in the bone marrow instead of normal bone. In fibrous dysplasia, lesions are characterized by woven ossified tissue and extensive marrow fibrosis. Mechanical quality of bones is decreased. As a consequence of this bone fragility, patients have an increased risk of fracture. Incidence of fractures is around 50% of cases.The risk of fractures or bone deformity is higher in the long bones, such as the femur, tibia, and humerus, but all the bones can be affected. There are 4 disease patterns recognized which are monostotic,polyostotic,cherubism, and craniofacial form.The monostotic type most frequently occurs in the rib (28%), femur (23%), tibia or craniofacial bones (10-25%), humerus, and vertebrae, in decreasing order of frequency.This form may present with pain or a pathologic fracture in patients aged 10-70 years, but this form most frequently occurs in those aged 10-30 years.
Next is Chondrosarcoma , a malignant tumor of cartilaginous origin in which tumor matrix formation is entirely chondroid in nature. Chondrosarcomas are classified as central (originating within the intramedullary canal) or peripheral. Rarely, they arise as juxtacortical lesionsTumors are predominantly axial most commonly involving the pelvic bones, femur, humerus, ribs, scapula, sternum, or spine. In tubular bones, the metaphysis is the most common site of origin. The proximal metaphysis is more frequently involved than the distal end of the bone. Involvement of the distal humerus is most unusual. Chondrosarcoma rarely occurs in the hands and feet; such occurrences usually arise as a complication of a multiple enchondromatosis syndrome. Chondrosarcoma arising de novo in the hands and feet is extremely unusual.The tumor may occasionally occur as a pathologic fracture.
Then,there is also osteosarcoma, the most common primary malignancy of bone. It is a malignant connective tissue tumor whose neoplastic cells present osteoblastic differentiation.The tumour may be localised at the end of the long bone. Most often it affects the upper end of tibia or humerus, or lower end of femur. The tumor is solid, hard, irregular ("fir-tree," "moth-eaten" or "sun-burst" appearance on X-ray examination) due to the tumor spicules of calcified bone radiating in right angles (Codman’s triangle). Surrounding tissues are infiltrated.The characteristic feature of osteosarcoma is presence of osteoid (bone formation) within the tumour. Tumor cells are very pleomorphic. These cells produce osteoid describing irregular trabeculae (amorphous, eosinophilic/pink) with or without central calcification (hematoxylinophilic/blue, granular) - tumor bone. Tumor cells are included in the osteoid matrix. Depending on the features of the tumour cells present (whether they resemble bone cells, cartilage cells or fibroblast cells), the tumour can be subclassified. The affected bone is not as strong as normal bones and may fracture with minor trauma (a pathological fracture)





Next,the Ewing sarcoma , a malignant round-cell tumor. It is a rare disease in which cancer cells are found in the bone or in soft tissue. The most common areas in which it occurs are the pelvis, the femur, the humerus, and the ribs.Genetic exchange between chromosomes can cause cells to become cancerous, like these cells from metastasized Ewing sarcoma. Ewing sarcoma is the result of a translocation between chromosomes 11 and 22, which fuses the EWS gene of chromosome 22 to the FLI1 gene of chromosome 11.EWS/FLI functions as the master regulator.Other translocations are at t(21;2) and t(7;22)The radiographic appearance of Ewing sarcoma may vary highly from a lytic one to a dominantly sclerotic one,and patient may present with pathological fracture.
Lastly is the bone metastases.The behavior of bone metastases can be characterized as osteoblastic, osteolytic or mixed, based on the effect on surrounding bone. All are due to dysregulation of the normal bone remodeling mechanisms, caused by tumor-host cell interactions. Osteoblastic tumors cause an abnormal formation of bone by direct secretion of bone extracellular matrix (ECM) proteins and by indirect stimulation of osteoblasts.Osteolytic tumors cause abnormal resorption of bone by proteolytic enzymes and through actions on osteoclasts. Osteolysis can release sequestered growth factors from the ECM, resulting in a cyclical feedback loop that leads to further stimulation of osteoclasts and continued bone resorption. As bone mass is lost, tumors can then continue to proliferate in their place,grow in size,causing further weakening of bone and thus leading to pathological fracture.
It is important to look into the underlying causes of pathological fracture in order for the treatment to be effective and safe.Some pathologic fracture require the same treatment as the other fractures,while others may require a highly specialized care.In a nutshell,pathological fracture involves a spectrum of causes wherein lies the modality of the treatment and care we will be giving to our patients.





















Reference:


Apley’s System of Orthopaedics and Fractures 8th Edition – Louis Solomon ,
David J. Warwick , Selvadurai Nayagam

http://orthopedics.about.com/cs/brokenbones/g/pathologic.htm

http://www.wheelessonline.com/ortho/pathologic_fracture

http://emedicine.medscape.com/article/411919-overview

http://en.wikipedia.org/wiki/Osteoporosis

http://en.wikipedia.org/wiki/Hyperparathyroidism

http://en.wikipedia.org/wiki/Myelomatosis

http://en.wikipedia.org/wiki/Paget%27s_disease_of_bone

http://emedicine.medscape.com/article/1254784-overview

http://emedicine.medscape.com/article/388738-overview

http://emedicine.medscape.com/article/389714-overview

http://emedicine.medscape.com/article/1255262-overview

http://emedicine.medscape.com/article/388869-overview

http://en.wikipedia.org/wiki/Osteosarcoma

http://emedicine.medscape.com/article/389464-overview

http://emedicine.medscape.com/article/1257331-overview

http://emedicine.medscape.com/article/389590-overview

NB: This article was an e-learning excercise by Siti Raidah bt Mohd Yassin a student of Melaka Manipal Medical College Malaysia