paget's disease of bone paget's disease of bone paget's disease of bone (commonly known as paget's disease or, historically, osteitis deformans) is a condition involving cellular remodeling and deformity of one or more bones. the affected bones show signs of dysregulated bone remodeling at the microscopic level, specifically excessive bone breakdown and subsequent disorganized new bone formation. these structural changes cause the bone to weaken, which may result in deformity, pain, fracture or arthritis of associated joints. for other diseases named after paget, see paget's disease (disambiguation). paget's disease of boneother namesosteitis deformans, paget's disease"this 92 year-old male patient presented for assessment of sudden inability to move half his body. an incidental finding was marked thickening of the calvarium. the diploic space is widened and there are ill-defined sclerotic and lucent areas throughout. the cortex is thickened and irregular. the findings probably correspond to the 'cotton wool spots' seen on plain films in the later stages of paget’s disease."pronunciation"paget" /ˈpædʒət/, rhymes with "gadget" specialtyrheumatology the exact cause is unknown, although leading theories indicate both genetic and acquired factors (see causes). paget's disease may affect any one or several bones of the body (most commonly pelvis, tibia, femur, lumbar vertebrae, and skull), but never the entire skeleton, and does not spread from bone to bone. rarely, a bone affected by paget's disease can transform into a malignant bone cancer. as the disease often affects people differently, treatments of paget's disease can vary. although there is no cure for paget's disease, medications (bisphosphonates and calcitonin) can help control the disorder and lessen pain and other symptoms. medications are often successful in controlling the disorder, especially when started before complications begin. paget's disease affects from 1.5 to 8.0 percent of the population, and is most common in those of british descent. it is primarily diagnosed in older people and is rare in people less than 55 years of age. men are more commonly affected than women (3:2). the disease is named after english surgeon sir james paget, who described it in 1877. signs and symptoms progressive effects of paget's disease of bone in the head ("hyperostosis cranii") mild or early cases of paget's are asymptomatic, and so most people are diagnosed with paget's disease incidentally during medical evaluation for another problem. approximately 35% of patients with paget's have symptoms related to the disease when they are first diagnosed. overall, the most common symptom is bone pain. when symptoms do occur, they may be confused with those of arthritis or other disorders, and so diagnosis may be delayed. paget's may first be noticed as an increasing deformity of a person's bones. paget's disease affecting the skull may cause frontal bossing, increased hat size, and headaches. often patients may develop loss of hearing in one or both ears due to auditory foramen narrowing and resultant compression of the nerves in the inner ear. rarely, skull involvement may lead to compression of the nerves that supply the eye, leading to vision loss. associated conditions paget's disease is a frequent component of multisystem proteinopathy. advanced paget's disease may lead to other medical conditions, including: osteoarthritis may result from changes in bone shape that alter normal skeletal mechanics. for example, bowing of a femur affected by paget's may distort overall leg alignment, subjecting the knee to abnormal mechanical forces and accelerating degenerative wear. heart failure is a rare, reported consequence of severe paget's disease (i.e. more than 40% skeletal involvement). the abnormal bone formation is associated with recruitment of abnormal blood vessels, forcing the cardiovascular system to work harder (pump more blood) to ensure adequate circulation. kidney stones are somewhat more common in patients with paget's disease. nervous system problems may occur in paget's disease, resulting from increased pressure on the brain, spinal cord, or nerves, and reduced blood flow to the brain and spinal cord. when paget's disease affects the facial bones, the teeth may become loose. disturbance in chewing may occur. chronic dental problems may lead to infection of the jaw bone. angioid streaks may develop, possibly as a result of calcification of collagen or other pathological deposition. paget's disease is not associated with osteoporosis. although paget's disease and osteoporosis can occur in the same patient, they are different disorders. despite their marked differences, several treatments for paget's disease are also used to treat osteoporosis. causes viral paget's disease may be caused by a slow virus infection (i.e., paramyxoviridae) present for many years before symptoms appear. associated viral infections include respiratory syncytial virus, canine distemper virus, and the measles virus. however, recent evidence has cast some doubt upon the measles association. laboratory contamination may have played a role in past studies linking paramyxovirus (e.g. measles) to paget's disease. genetic there is a hereditary factor in the development of paget's disease of bone. two genes, sqstm1 and rank, and specific regions of chromosome 5 and 6 are associated with paget's disease of bone. genetic causes may or may not involve a family history of paget's disease. about 40–50% of people with the inherited version of paget's disease have a mutation in the gene sqstm1, which encodes a protein, called p62, that is involved in regulating the function of osteoclasts (bone cells). however, about 10-15 percent of people that develop the disease without any family history also have a mutation in the sqstm1 gene. paget's disease of bone is associated with mutations in rank. receptor activator of nuclear factor κ b (rank), which is a type i membrane protein that is expressed on the surface of osteoclasts and is involved in their activation upon ligand binding. additional genetic associations include: name omim locus gene pdb1 167250 6p ? pdb2 18q22.1 rank pdb3 5q35 sqstm1 pdb4 606263 5q31 ? pathogenesis micrograph showing paget's disease of the bone with the characteristic jigsaw puzzle-like/mosaic pattern, h&e stain the pathogenesis of paget's disease is described in four stages: osteoclastic activity mixed osteoclastic – osteoblastic activity osteoblastic activity malignant degeneration initially, there is a marked increase in the rate of bone resorption in localized areas, caused by large and numerous osteoclasts. these localized areas of pathological destruction of bone tissue (osteolysis) are seen radiologically as an advancing lytic wedge in long bones or the skull. when this occurs in the skull, it is called osteoporosis circumscripta. the osteolysis is followed by a compensatory increase in bone formation induced by the bone-forming cells, called osteoblasts, that are recruited to the area. this is associated with accelerated deposition of lamellar bone in a disorganized fashion. this intense cellular activity produces a chaotic picture of trabecular bone ("mosaic" pattern), rather than the normal linear lamellar pattern. the resorbed bone is replaced and the marrow spaces are filled by an excess of fibrous connective tissue with a marked increase in blood vessels, causing the bone to become hypervascular. the bone hypercellularity may then diminish, leaving a dense "pagetic bone," also known as burned-out paget's disease. a later phase of the disease is characterized by the replacement of normal bone marrow with highly vascular fibrous tissue. sir james paget first suggested the disease was due to an inflammatory process. some evidence suggests that a paramyxovirus infection is the underlying cause of paget's disease, which may support the possible role of inflammation in the pathogenesis. however, no infectious virus has yet been isolated as a causative agent, and other evidence suggests an intrinsic hyperresponsive reaction to vitamin d and rank ligand is the cause. further research is therefore necessary. diagnosis an ivory vertebra due to probable paget diseasethe first clinical manifestation of paget's disease is usually an elevated alkaline phosphatase in the blood. paget's disease of right innominate bone. man of 80 years age. paget's disease may be diagnosed using one or more of the following tests: pagetic bone has a characteristic appearance on x-rays. a skeletal survey is therefore indicated. an elevated level of alkaline phosphatase in the blood in combination with normal calcium, phosphate, and aminotransferase levels in an elderly patient are suggestive of paget's disease. markers of bone turnover in urine eg. pyridinoline elevated levels of serum and urinary hydroxyproline are also found. bone scans are useful in determining the extent and activity of the condition. if a bone scan suggests paget's disease, the affected bone(s) should be x-rayed to confirm the diagnosis. differential diagnosis comparison of bone pathology condition calcium phosphate alkaline phosphatase parathyroid hormone comments osteopenia unaffected unaffected normal unaffected decreased bone mass osteopetrosis unaffected unaffected elevated unaffected thick dense bones also known as marble bone osteomalacia and rickets decreased decreased elevated elevated soft bones osteitis fibrosa cystica elevated decreased elevated elevated brown tumors paget's disease of bone unaffected unaffected variable (depending on stage of disease) unaffected abnormal bone architecture treatment although initially diagnosed by a primary care physician, endocrinologists (internal medicine physicians who specialize in hormonal and metabolic disorders), rheumatologists (internal medicine physicians who specialize in joint and muscle disorders), orthopedic surgeons, neurosurgeons, neurologists, oral and maxillofacial surgeons, and otolaryngologists are generally knowledgeable about treating paget's disease and may be called upon to evaluate specialized symptoms. it can sometimes be difficult to predict whether a person with paget's disease, who otherwise has no signs or symptoms of the disorder, will develop symptoms or complications (such as a bone fracture) in the future. medication the goal of treatment is to relieve bone pain and prevent the progression of the disease. these medications are usually recommended for people with paget's disease who: have bone pain, headache, back pain, or a nerve-related symptom (such as "shooting" pains in the leg) that is directly associated with the disease; have elevated levels of serum alkaline phosphatase (alp) in their blood; display evidence that a bone fracture will occur; require pretreatment therapy for affected bones that require surgery; have active symptoms in the skull, long bones, or vertebrae (spine); have the disease in bones located next to major joints, placing them at risk of developing osteoarthritis; develop hypercalcemia that occurs when a person, with several bones affected by paget's disease and a high serum alkaline phosphatase level, is immobilized. bisphosphonates five bisphosphonates are currently available. in general, the most commonly prescribed are risedronic acid, alendronic acid, and pamidronic acid. etidronic acid and other bisphosphonates may be appropriate therapies for selected patients but are less commonly used. in one study it was reported that people experienced side effects when taking bisphosphonates for six months, however the quality of evidence was low. none of these drugs should be used by people with severe kidney disease. neridronate etidronate disodium the approved regimen is once daily for six months; a higher dose is more commonly used. no food, beverage, or medications should be consumed for two hours before and after taking. the course should not exceed six months, but repeat courses can be given after rest periods, preferably of three to six months duration. pamidronate disodium in intravenous form: the approved regimen uses an infusion over four hours on each of three consecutive days, but a more commonly used regimen is over two to four hours for two or more consecutive or nonconsecutive days. alendronate sodium is given as tablets once daily for six months; patients should wait at least 30 minutes after taking before eating any food, drinking anything other than tap water, taking any medication, or lying down (patient may sit). tiludronate disodium is taken once daily for three months; they may be taken any time of day, as long as there is a period of two hours before and after resuming food, beverages, and medications. risedronate sodium tablet taken once daily for 2 months is the prescribed regimen; patients should wait at least 30 minutes after taking before eating any food, drinking anything other than tap water, taking any medication, or lying down (patient may sit). zoledronic acid is given as an intravenous infusion; a single dose is effective for two years. this is recommended for most people at high risk with active disease. calcitonin salcatonin, also called calcitonin-salmon is a synthetic copy of a polypeptide hormone secreted by the ultimobranchial gland of salmon. miacalcin is administered by injection, three times per week or daily, for 6–18 months. repeat courses can be given after brief rest periods. miacalcin may be appropriate for certain patients but is seldom used. calcitonin was putatively linked to increased chance of cancer. the