Paget's disease of bone

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Overview
Paget's disease, otherwise known as osteitis deformans, is a chronic disorder that typically results in enlarged and deformed bones. It is named after Sir James Paget, the British surgeon who first described this disease. 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 may be caused by a slow virus infection (i.e., paramyxoviruses such as measles and respiratory syncytial virus), present for many years before symptoms appear. There is also a hereditary factor since the disease may appear in more than one family member.

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. 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 2 or 3 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.

Risk Factors

 * Not known

Epidemiology and Demographics
The incidence of
 * Likelihood of occurrence increases with age
 * Radiologic surveys show the frequency in adults is less than 1% in the US, Great Britain, and Australia
 * The disease is rare in India, Japan, Scandanavia, and the Middle East

Pathophysiology & Etiology
In the next phase, called the scelrotic phase, the resorptive rate declines relative to the rate of bone formation leading to the development of less vascular bone and a positive calcium balance.
 * The cause of Paget's Disease is unknown
 * The early phase of the disease is termed the destructive phase of disease
 * The next phase, commonly termed the mixed phase, involves the formation of new pagetic bone.

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.
 * Chalkstick fractures.

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.
 * Urinary Hydroxyproline has been elevated in many patients and it is a marker used traditionally.
 * 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.

Electrolyte and Biomarker Studies
There is an elevation of the alkaline phosphatase

Differential Diagnosis
Since many patients are asymptomatic, the disorder is commonly discovered by radiologic examination for an unrelated disease or because of an elevated plasma alkaline phosphatase.

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.

Other 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.
 * Cardiovascular disease: In severe Paget's disease (i.e. with more than 15% skeletal involvement), the heart works harder to pump blood to affected bones. Left ventricular hypertrophy is an associated finding. High-output congestive failure may rarely occur. Similarly, calcification of the aortic valve and associated vessels may occur due to turbulent flow caused by increased cardiac output.
 * 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.

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.

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


 * Endocrinologists -- Internists who specialize in hormonal and metabolic disorders.
 * Rheumatologists -- Internists who specialize in joint and muscle disorders.
 * Specialists -- Orthopedic surgeons, neurologists, and otolaryngologists (physicians who specialize in ear, nose, and throat disorders) 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:

Chronic Pharmacotherapies
Cytotoxic drugs like plicamycin and dactinomycin are no longer used for therapy Common bisphosphonates and their use:
 * Bisphosphonates are used to inhibit bone resorption
 * Etidronate has been used at 20 mg/kg body weight per day and is effective in producing clinical improvement
 * osteomalacia is a potential complication of therapy
 * Alendronate, pamidronate, risendronate, and tiludronate are the bisphosphonates most commonly used now as they are more potent than etidronate and do not result in the same mineralization defects
 * Alendronate is approx. 700-fold more potent than etidronate
 * Alendronate (oral administration) and pamidronate (intravenous administration) are approved for use in the US
 * Alendronate is administered orally with water 30-60 minutes before breakfast after an overnight fast
 * Dose is 40 mg/d for 6 months
 * Pamidronate is given intravenously
 * Dose is 30 mg/d in 5% glucose in water or normal saline over 4h ion 3 successive days


 * Calcitonin will be replaced by bisphosphonates for primary treatment of severe disease, but calcitonin can still be used for patients who cannot tolerate alendronate due to gastrointestinal side effects
 * The administration of calcitonins suppresses the pagetic lesion which leads to a decrease in bone pain.
 * Calcitonin also improves neurologic symptoms and decreases elevated cardiac output
 * Some individuals do not respond to porcine or salmon calcitonins
 * Calcitonin can be administered by nasal spray at doses of 200 IU/d.

Bisphosphonates
Five bisphosphonates are currently available. In general, the most commonly prescribed are the three most potent bisphosphonates: Actonel®, Fosamax® and Aredia®. Didronel® and Skelid® 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 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).

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 sunlight, 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.

Microscopical Findings of Paget disease
