Paget's disease of bone

Paget's disease of bone
Classification and external resources
"This 92 year-old male patient presented for assessment of acute hemiparesis. 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." (dr Dawes)
ICD-10	M88.
ICD-9	731.0
OMIM	602080
DiseasesDB	9479
MedlinePlus	000414
eMedicine	med/2998 radio/514 pmr/98
MeSH	D010001

Paget's disease of the bone (often just Paget's disease) or osteitis deformans, is the most common Paget's disease. It is a chronic disorder that typically results in enlarged and deformed bones.^[1] The disease is named after Sir James Paget, the British surgeon who first described it in 1877.^[2] The excessive breakdown and formation of bone tissue that occurs with Paget's disease can cause bone to weaken, resulting in bone pain, arthritis, deformities, and fractures.

Paget's disease is rarely diagnosed in people less than 40 years of age. Men are more commonly affected than women. Prevalence of Paget's disease ranges from 1.5 to 8 percent depending on age and country of residence. Prevalence of familial Paget's disease (where more than one family member has the disease) ranges from 10 to 40 percent in different parts of the world.^{[citation needed]}Because early diagnosis and treatment is important, after age 40, siblings and children of someone with Paget's disease may wish to have an alkaline phosphatase blood test every two or three years. If the alkaline phosphatase level is above normal, other tests such as a bone-specific alkaline phosphatase test, bone scan, or x-ray can be performed.

Contents 1 Causes 1.1 Viral 1.2 Genetic 2 Pathogenesis 3 Symptoms 4 Diagnosis 5 Prognosis 6 Associated medical conditions 7 Treatment 7.1 Types of physicians 7.2 Drug therapy 7.2.1 Bisphosphonates 7.2.2 Calcitonin 7.3 Surgery 7.4 Diet and Exercise 8 References In Pop Culture 9 References

Causes

Viral

Paget disease may be caused by a slow virus infection (i.e., paramyxoviruses) present for many years before symptoms appear. Candidates include:

• Measles.^[3][4] Recent evidence has cast some doubt upon the measles association.^[5]

• Canine distemper virus^[6][7]

• Respiratory syncytial virus.^[8]

It has been suggested that contamination may have played a role in producing past positive results.^[9]

Genetic

There is also a hereditary factor.^[10][11] Associations include:

Name	OMIM	Locus	Gene
PDB1	167250	6p	?
PDB2		18q22.1	RANK
PDB3		5q35	SQSTM1
PDB4	606263	5q31[12]	?

Pathogenesis

The pathogenesis of Paget's disease is described in 3 stages which are:
i. Osteoclastic activity
ii. Mixed osteoclastic-osteoblastic activity
iii. Exhaustive (burnt out) stage

Initially, there is a marked increase in the rate of bone resorption at localized areas caused by large and numerous osteoclasts and elevated sereum akaline phosphatase. These localized areas of osteolysis are seen radiologically as an advancing lytic wedge in long bones or osteoporosis circumscripta in the skull. The osteolysis is followed by a compensatory increase in bone formation induced by osteoblasts 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 disease.

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 infectuous 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. Further research is therefore necessary. ^[13]

Symptoms

Many patients do not know they have Paget's disease because they have a mild case with no symptoms. Sometimes, symptoms may be confused with those of arthritis or other disorders. In other cases, the diagnosis is made only after complications have developed. Symptoms can include:

• Bone pain is the most common symptom. Bone pain can occur in any bone affected by Paget's disease. It often localizes to areas adjacent to the joints.
• Headaches and hearing loss may occur when Paget's disease affects the skull.
• Pressure on nerves may occur when Paget's disease affects the skull or spine.
• Somnolence (drowsiness) due to vascular steal syndrome of the skull.
• Paralysis due to vascular steal syndrome of the vertebrae.
• Increased head size, bowing of limb, or curvature of spine may occur in advanced cases.
• Hip pain may occur when Paget's disease affects the pelvis or thighbone.
• Damage to joint cartilage may lead to arthritis.
• Teeth may spread intraorally - due to the intra-oral force placed on the anterior teeth (especially maxillary central and lateral incisors) by the labial tissues, especially the muscles.
• Chalkstick fractures.
• Mosaic bone pattern
• Hypercementosis in teeth may occur

Diagnosis

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.
• 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.

Prognosis

The outlook is generally good, particularly if treatment is given before major changes in the affected bones have occurred. Any bone or bones can be affected, but Paget's disease occurs most frequently in the spine, skull, pelvis, thighs, and lower legs. In general, symptoms progress slowly, and the disease does not spread to normal bones. Treatment can control Paget's disease and lessen symptoms but is not a cure. Osteogenic sarcoma, a form of bone cancer, is an extremely rare complication that occurs in less than one percent of all patients.

Associated medical conditions

Paget's disease may lead to other medical conditions, including:

• Arthritis: Long bones in the leg may bow, distorting alignment and increasing pressure on nearby joints. In addition, Pagetic bone may enlarge, causing joint surfaces to undergo excessive wear and tear. In these cases, pain may be due to a combination of Paget's disease and osteoarthritis.
• Loss of hearing in one or both ears may occur when Paget's disease affects the skull and the bone that surrounds the inner ear. Treating the Paget's disease may slow or stop hearing loss. Hearing aids may also help. It is believed by some that the disease was responsible for Beethoven's deafness.^{[citation needed]}
• Cardiovascular disease: In severe Paget's disease (i.e. with more than 15% skeletal involvement), AV connections often form in the bone, and so the heart has to work harder (pump more blood) to ensure adequate oxygen supply to the tissues. This increase in cardiac output can lead to calcification of the aortic valve and the resulting aortic stenosis causes left ventricular hypertrophy and eventually high-output congestive failure.
• Kidney stones are somewhat more common in patients with Paget's disease.
• Nervous system: Pagetic bone can cause pressure on the brain, spinal cord, or nerves, and reduced blood flow to the brain and spinal cord.
• Sarcoma: Rarely, Paget's disease is associated with the development of a malignant tumor of bone. When there is a sudden onset or worsening of pain, sarcoma should be considered.
• When Paget's disease affects the facial bones, the teeth may become loose. Disturbance in chewing may occur.
• Rarely, when the skull is involved, the nerves to the eye may be affected, causing some loss of vision.
• 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.

Treatment

Types of physicians

The following types of physicians are generally knowledgeable about treating Paget's disease.

• Internists
• Endocrinologists -- Internists who specialize in hormonal and metabolic disorders.
• Rheumatologists -- Internists who specialize in joint and muscle disorders.
• Specialists -- Orthopedic surgeons, neurologists, and otolaryngologists may be called upon to evaluate specialized symptoms.

Drug therapy

The goal of treatment is to relieve bone pain and prevent the progression of the disease. The U.S. Food and Drug Administration has approved the following treatments for Paget's disease:

Bisphosphonates

Five bisphosphonates are currently available. In general, the most commonly prescribed are: Risedronic acid (Actonel), Alendronic acid (Fosamax) and Pamidronic acid (Aredia). Etidronic acid (Didronel) and other bisphosphonates may be appropriate therapies for selected patients but are less commonly used. As a rule, bisphosphonate tablets should be taken with 6–8 oz of tap water (not from a source with high mineral content) on an empty stomach. None of these drugs should be used by people with severe kidney disease.

• Didronel (etidronate disodium) -- Tablet; approved regimen is 200–400 mg once daily for 6 months; the higher dose (400 mg) is more commonly used; no food, beverages, or medications for 2 hours before and after taking; course should not exceed 6 months, but repeat courses can be given after rest periods, preferably of 3–6 months duration.
• Aredia (pamidronate disodium) -- Intravenous; approved regimen 30 mg infusion over 4 hours on 3 consecutive days; more commonly used regimen 60 mg over 2–4 hours for 2 or more consecutive or non-consecutive days.
• Fosamax (alendronate sodium) -- Tablet; 40 mg once daily for 6 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).
• Skelid (tiludronate disodium) -- Tablet; 400 mg (two 200 mg tablets) once daily for 3 months; may be taken any time of day, as long as there is a period of 2 hours before and after resuming food, beverages, and medications.
• Actonel (risedronate sodium) -- Tablet; 30 mg once daily for 2 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).
• Reclast (Aclasta) (zoledronic acid) -- intravenous infusion; one single dose (5 mg over 15 min), effective for 2 years.

Calcitonin

• Miacalcin is administered by injection; 50 to 100 units daily or 3 times per week for 6–18 months. Repeat courses can be given after brief rest periods. Miacalcin may be appropriate for certain patients but is seldom used. The nasal spray form of this drug is not approved for the treatment of Paget's disease.

Surgery

Medical therapy prior to surgery helps to decrease bleeding and other complications. Patients who are having surgery should discuss pre-treatment with their physician. There are generally three major complications of Paget's disease for which surgery may be recommended.

• Fractures—Surgery may allow fractures to heal in better position.
• Severe degenerative arthritis—If disability is severe and medication and physical therapy are no longer helpful, joint replacement of the hips and knees may be considered.
• Bone deformity—Cutting and realignment of Pagetic bone (osteotomy) may help painful weight bearing joints, especially the knees.

Complications resulting from enlargement of the skull or spine may injure the nervous system. However, most neurologic symptoms, even those that are moderately severe, can be treated with medication and do not require neurosurgery.

Diet and Exercise

In general, patients with Paget's disease should receive 1000-1500 mg of calcium, adequate sunshine, and at least 400 units of vitamin D daily. This is especially important in patients being treated with bisphosphonates. Patients with a history of kidney stones should discuss calcium and vitamin D intake with their physician.

Exercise is very important in maintaining skeletal health, avoiding weight gain, and maintaining joint mobility. Since undue stress on affected bones should be avoided, patients should discuss any exercise program with their physician before beginning.

References In Pop Culture

• C.S.I. New York: Murder victim in Season 2 episode "Youngblood" was afflicted with Paget's disease.
• Retired Boston Red Sox centerfielder Dom DiMaggio suffers from Paget's Disease and has served as a member of the board of directors of the Paget Foundation^[14].

References

v • d • e Osteochondropathy (M80-M94, 730-733) Osteopathies Osteitis endocrine bone disease: Osteitis fibrosa cystica (Brown tumor) infectious bone disease: Osteomyelitis (Sequestrum, Involucrum) · Sesamoiditis · Brodie abscess · Periostitis Bone density and structure Density / metabolic bone disease Osteoporosis · Osteopenia · Osteomalacia Continuity of bone Pseudarthrosis · Stress fracture Other Fibrous dysplasia (Monostotic, Polyostotic) · Skeletal fluorosis · bone cyst (Aneurysmal bone cyst) · Hyperostosis (Infantile cortical hyperostosis) · Osteosclerosis (Melorheostosis) Bone resorption Osteolysis · Hajdu-Cheney syndrome · Ainhum Ischemia Avascular necrosis Other Paget's disease of bone · Algoneurodystrophy · Hypertrophic pulmonary osteoarthropathy · Nonossifying fibroma Chondropathies Chondritis Relapsing polychondritis Other Tietze's syndrome Both Osteochondritis Osteochondritis dissecans Juvenile osteochondrosis lower limb: hip (Legg–Calvé–Perthes syndrome) · tibia (Osgood-Schlatter disease, Blount's disease) · foot (Köhler disease, Sever's disease) upper limb: wrist (Kienbock's disease) bone and cartilage navs: anat/physio/dev, noncongen/congen/neoplasia, symptoms+signs/eponymous signs, proc