What is Pagetâ€™s Disease ?
First diagnosed by Sir James Paget in 1877, Pagetâ€™s disease of bone, or osteitis deformans, is a disease of the osteoclast and is the most exaggerated example of disordered bone remodeling. It is a focal disorder of accelerated skeletal remodeling that can involve a single bone or multiple bones. Pagetâ€™s disease is characterized by excessive osteoclastic bone resorption followed by excessive bone formation from osteoblasts, resulting in bone that is architecturally unsound. This can lead to bone pain, bone deformity and skeletal fragility.
Pathology of Pagetâ€™s Disease
The initial abnormality in Pagetâ€™s disease is a dramatic increase in the rate of bone resorption in one or more areas of the skeleton. Pagetic osteoclasts are abnormal — approximately five times larger than normal containing an average number of 20 nuclei per cell compared with three to four nuclei in normal adult osteoclasts. However, the osteoblasts, though numerous, are not abnormal. Because bone resorption triggers bone formation, the rate of bone resorption is matched by a rapid rate of bone formation over time. The new bone is structurally disorganized, however, resulting in an overall decrease in bone strength and an increase in susceptibility to bowing and fractures. In addition, a high level of vascularity and an excess of fibrous connective tissue in the marrow mark the abnormal bone.
Clinical Presentation of Pagetâ€™s Disease
While Pagetâ€™s disease may affect any bone, the most commonly involved bones are the pelvis, vertebrae, skull, femur and tibia. Prevalent signs and symptoms of Pagetâ€™s disease are skeletal deformity and bone pain. Pain usually results from the rheumatologic and neurologic complications of the disease rather than from the abnormal bone. When bone pain does occur among patients, its onset is frequently late in the disease process and is usually unrelated to physical activity. Pain from a pagetic lesion in the femur or tibia, however, may increase with weight bearing. A sudden onset of pain usually indicates that a fracture has occurred.
Skeletal deformities that occur as a result of Pagetâ€™s disease are most often noted in the lower extremities and the skull. Long bones tend to exhibit bowing, while the skull can become enlarged.
An enlarged skull can lead to headaches or hearing loss when the disease affects the temporal bone.
When present in the spine, the increased bone volume may cause compression of the spinal cord or nerve roots and may result in severe pain and impaired neurological function. In addition, the skin over the pagetic lesions is frequently warm due to the increased blood flow to the bone and overlying soft tissue.
A number of complications may result from Pagetâ€™s disease. Of these, the most devastating is a transformation of the bone that becomes cancerous. Osteosarcoma or other types of sarcoma occurs in less than 1 percent of patients with Pagetâ€™s disease, but at a significantly higher rate than in non-affected individuals. Osteosarcoma is often fatal in patients with Pagetâ€™s disease, possibly because of delayed diagnosis.
Diagnostic Evaluation and Recommendations
Pagetâ€™s disease can be diagnosed in patients through radiology, radionuclide bone scanning, biochemical testing of bone resorption parameters, or biochemical testing of bone formation
parameters. When tested through roentgenographic or radiographic means, Pagetâ€™s disease displays three distinctive stages. In the earliest stage of the disease, an osteolytic lesion may be observed in the skull or a long bone. In the second stage of the disease, x-rays reveal both osteolytic and sclerotic changes in the same bone. In the last stage of the disease, the sclerotic lesion dominates the bone and there may be an increase in the dimensions of the bone itself.
A radionuclide bone scan using a radiolabeled bisphosphonate is the most efficient means of detecting Pagetâ€™s disease in the skeleton, although it is not a specific test. The bisphosphonate is injected intravenously and is concentrated in areas of increased blood flow and high levels of bone formation, both common characteristics of Pagetâ€™s disease. This test is used primarily to establish the full extent of skeletal involvement for a patient.
Biochemical tests reflecting osteoclast activity and resultant bone collagen resorption include measurements of urinary hydroxyproline/creatinine as well as measurements of urinary and serum deoxypyridinoline, N-telopeptide and C-telopeptide. As a marker of osteoblast activity, the measurement of serum total alkaline phosphatase activity provides a general indication of bone turnover and disease activity in Pagetâ€™s disease. Serum bone specific alkaline phosphatase activity is helpful in patients who also have liver disease.
At least one measurement of bone metabolic activity and x-rays of affected bones are the minimum recommended level of evaluation to track and monitor the progression of treatment in a patient with Pagetâ€™s disease. For most patients, a decrease in the total serum alkaline phosphatase activity is sufficient to indicate and determine changes in overall disease activity. Since the total serum alkaline phosphatase level is a reflection of both the total bone surface affected by Pagetâ€™s disease as well as the total activity of the disease at those sites, serum alkaline phosphatase can be normal in patients with a small focus of symptomatic Pagetâ€™s disease. Serial radiographs should be performed on those patients with lytic lesions in weight-bearing long bones in order to document healing. A bone scan is valuable in defining the full extent of the disease and identifying asymptomatic lesions
located in “at risk” areas.
Indications for Treatment
Treatment for Pagetâ€™s disease is based upon antiresorptive therapy. There are four general indications for treatment of Pagetâ€™s disease:
1. Symptoms due to metabolically active Pagetâ€™s disease warrant treatment. This includes bone
pain related to a pagetic site or fatigue fracture, headache resulting from an affected skull, back pain from affected pagetic vertebrae or other neurological syndromes associated with pagetic changes.
2. Treatment is warranted in a patient planning to undergo elective surgery on a pagetic site, such as hip replacement, in an attempt to minimize the operative blood loss due to hypervascularity present in active pagetic bone. Postoperative treatment may be helpful in preventing acceleration of disease activity which has been reported after surgery or fractures.
3. Treatment is indicated in the management of hypercalcemia, a rare occurrence when a patient with multiple bones affected by Pagetâ€™s disease and a highly elevated serum alkaline phosphatase level undergoes prolonged immobilization.
4. Many investigators believe that treatment is indicated as an attempt to decrease local progression and reduce the risk of future complications — even in asymptomatic patients whose sites of disease and degree of metabolic hyperactivity place them at risk of progression and complications. This group includes individuals who may be at risk for bowing deformities in their long bones; for hearing loss because of skull enlargement; for neurological complications due to pagetic changes in their vertebrae; or for secondary arthritis as a complication of Pagetâ€™s disease located next to major joints.
There is no direct evidence that aggressive treatment of Pagetâ€™s disease is associated with prevention of progression or reduction in risk of future complications. Investigators have looked to indirect evidence, however, to suggest this possibility. This evidence includes:
· The failure to treat Pagetâ€™s disease has been associated with the further destruction of the bone and the progression of bone deformities;
· Successful treatment of Pagetâ€™s disease has been associated with restoration of normal patterns of new bone deposition; and
· One study has shown that facial and skull deformities improved after successful treatment.
Some investigators conclude, therefore, that it is good clinical practice to treat both symptomatic patients whose symptoms may respond to a reduction in abnormal bone turnover as well as asymptomatic patients with active Pagetâ€™s disease.
Four main methods of treatment exist for a patient with Pagetâ€™s disease: non-pharmacological therapy (focusing mainly on physical therapy as a means of improving muscle strength to help control some types of pain); pharmacological therapy using either bisphosphonates or calcitonins; pain management using analgesics; or surgery.
Bisphosphonates suppress or reduce bone resorption by osteoclasts. They do this both directly, by hindering the recruitment and function of osteoclasts and perhaps indirectly, by stimulating osteoblasts to produce an inhibitor of osteoclast formation. There is now a reasonable understanding of how these drugs work and the differences between the various types of bisphosphonates are better understood.
Currently, five bisphosphonates are approved by the US Food and Drug Administration for the treatment of Pagetâ€™s disease. These include pamidronate, which is given intravenously, and etidronate, tiludronate, alendronate and risedronate, all of which are taken orally.
A mild form of Pagetâ€™s disease can be suppressed with one or two 60-90 mg infusions of pamidronate, while a more severe manifestation of the disease may require several infusions of 60-90 mg of pamidronate on a weekly or twice-weekly basis. Serum alkaline phosphatase testing should occur approximately two to three months after the appropriate number of infusions is administered. Oral calcium and vitamin D supplementation is recommended for patients using this therapy to lessen hypocalcemia, a common but rarely symptomatic side effect.
Both alendronate and risedronate have been shown to reduce the biochemical indices for bone turnover into the normal range in many patients with a moderate-to-severe form of Pagetâ€™s disease.
Alendronate is taken as a daily 40 mg tablet for six months; risedronate is taken as a daily 30 mg tablet for two or three months. Calcium and vitamin D supplementation is also recommended for patients using either of these drugs.
Etidronate and tiludronate are less potent than alendronate and risedronate. They are
both taken as daily 400 mg tablets. Etidronate — the original bisphosphonate used in treating Pagetâ€™s disease — is taken for six months, while tiludronate is taken for three months. With both of these bisphosphonates, calcium supplements should not be taken for several hours following the bisphosphonate dose.
Investigators have recognized that secondary resistance to individual bisphosphonates can occur. Therefore, it may be necessary for a patient to use more than one bisphosphonate in long-term management of the disease. Due to certain properties of each of these medications, it is vital that patients take oral bisphosphonates in their prescribed manner to avoid poor absorption of the drugs or severe gastrointestinal problems. Zoledronic acid, the most potent bisphosphonate, is undergoing clinical trials. It is given as a 15-minute intravenous infusion.
Subcutaneous injection of salmon calcitonin was the first widely utilized therapy for Pagetâ€™s disease. Salmon calcitonin has been shown to reduce elevated indices of bone turnover by 50 percent, decrease symptoms of bone pain, reduce warmth over affected bones, improve some neurological complications and promote healing of lytic lesions. Its use today is limited mostly to patients who do not tolerate bisphosphonates. In the case of secondary resistance to salmon calcitonin, a switch to bisphosphonate therapy is necessary.
Pain Management: Analgesics
Pain directly attributable to Pagetâ€™s disease is generally relieved through anti-osteoclast treatment as described above. Some pain may be the result of bone deformity or arthritic or neurological complications. In this case, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), or cox-2 inhibitors may be helpful for the management of pagetic pain in addition to the main pagetic therapy chosen.
Different orthopedic interventions may be necessary in pagetic patients:
· Fixing a complete fracture through pagetic bone;
· Realigning the knee through tibial osteotomy to decrease mechanical pain, particularly if medical therapy is unsuccessful in managing severe pain symptoms; and/or
· Replacing the hip and/or knee through total joint arthroplasty for patients unresponsive to anti-osteoclast treatment and therapy for the osteoarthritis.
When repairing a pagetic fracture, total immobilization of that site should be avoided if possible. Pre-treatment with a bisphosphonate will reduce the hypervascularity and reduce the risk of greater-than-normal operative blood loss. Post-operative treatment may prevent acceleration of disease activity that has been reported after surgery or fractures.
Bisphosphonates Approved for Pagetâ€™s disease of bone
(Listed in Chronological Order of FDA Approval)
Administration and Dosage
(Procter & Gamble)
FDA approval: 1977
· 200 to 400 mg once daily for 6 months
· 200-400 mg dose is approved; 400 mg dose is preferred
· Must be taken with 6-8 ounces of water on an empty stomach (no food, beverages, or medications for 2 hours before and after dose).
· Course of Didronel® should not exceed 6 months.
· Repeat courses can be given after rest periods of 3-6 months duration.
FDA approval: 1994
Generic pamidronate, Pamidronate Disodium for Injection
is also available.
· The FDA approved regimen is a 30 mg intravenous infusion over 4 hours on 3 consecutive days
· A single infusion of 60-90 mg given over 2-4 hours is effective in mild disease.
· For more severe disease, 60 mg infusions given over 2-4 hours for 2 or more consecutive or non-consecutive days may be administered.
A course of pamidronate may be readministered at intervals as needed.
· Serum creatinine should be tested before each pamidronate treatment.
· 40 mg once daily for 6 months
· Must be taken on an empty stomach, with 6-8 ounces of water, in the morning.
· Wait at least 30 minutes after taking Fosamax® before eating any food, drinking anything other than tap water, or taking any medication.
· Do not lie down for at least 30 minutes after taking Fosamax®. (Patient may sit.)
Administration and Dosage
FDA approval: 1997
· 400 mg (two 200 mg tablets) once daily for 3 months
· Must be taken on an empty stomach with 6-8 ounces of water.
· Skelid® 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.
(Procter & Gamble/Aventis)
FDA approval: 1998
· 30 mg once daily for 2 months
· Must be taken on an empty stomach, with 6-8 ounces of water in the morning.
· Wait at least 30 minutes after taking Actonel® before eating any food, drinking anything other than water, or taking any medication.
· Do not lie down for at least 30 minutes after taking Actonel®. (Patient may sit.)
Administration and Dosage
Trade Name: Miacalcin®
Approved by FDA 1990
· 50 to 100 units daily or 3 times per week for 6-18 months
The Paget Foundation for Pagetâ€™s Disease of Bone and Related Disorders provides information and programs for consumers and health professionals on several bone disorders including Pagetâ€™s disease of bone, primary hyperparathyroidism, fibrous dysplasia, osteopetrosis, and the complications of certain cancers on the skeleton.
Foundation programs and services include:
Patient Education and Assistance, Professional Education, Public Education,
Research & Advocacy
A copy of the Foundationâ€™s annual report is available by writing to the Foundation office or the Office of the Attorney General, Charities Bureau, 120 Broadway, New York, NY 10271.
120 Wall Street, Suite 1602, New York, NY 10005-4001
Toll-free: 800-23-PAGET Phone: 212-509-5335 Fax: 212-509-8492
Website: http://www.paget.org E-mail: PagetFdn@aol.com
ãCopyright, The Paget Foundation, 2004