NORD gratefully acknowledges Roy D. Altman, MD, Professor of Medicine, Division of Rheumatology and Immunology, University of California, Los Angeles, for assistance in the preparation of this report.
Paget’s disease of bone is a chronic, slowly progressive skeletal condition of abnormally rapid bone destruction (osteolytic) and reformation (osteoblastic). The new bone may occur in one or more regions of the body and is structurally abnormal, dense and fragile. This abnormal development may cause bone pain, arthritis, deformities and fractures. The bones most frequently affected are in the spine, skull, pelvis and lower legs. The exact cause of Paget’s disease is not known.
Early symptoms of Paget’s disease include bone pain, joint pain (especially in the back, hips and knees), and headache. Physical signs include enlargement and bowing of the thighs (femurs) and lower legs (tibias), and enlargement of the skull in the area of the forehead. Most individuals with Paget’s disease do not have any symptoms (asymptomatic) or only develop mild symptoms.
As the disease progresses, other signs and symptoms often appear. These may include further bowing of the affected limbs, a waddling manner of walking (gait), pain and inflammation of the joints (arthritis), fractures of affected bones, and muscle and sensory disturbances.
Up to 50 percent of individuals with skull involvement may develop hearing loss. Additional symptoms that may occur include loss of vision and hydrocephalus, a condition in which accumulation of excessive cerebrospinal fluid (CSF) in the skull causes pressure on the tissues of the brain.
Spinal stenosis, a rare complication characterized by abnormal narrowing (stenosis) of the spaces within the spinal canal, spinal nerve root canals, or the bones of the spinal column (vertebrae), may develop in some cases. Congestive heart failure (high-output) may also occur. Tumors of the bone (sarcoma) are a rare complication.
The exact cause of Paget’s disease is unknown. Researchers speculate that the cause of the disorder may be multifactorial (e.g. caused by the interaction of certain genetic and environmental factors). In most cases, no specific cause for Paget’s disease can be identified (sporadic).
Research findings suggest that Paget’s disease may be related to a “slow virus” infection of bone, a condition that is present for many years before symptoms appear.
In approximately 15-30 percent of cases there is a family history of the disorder. Researchers have discovered several genes that may predispose individuals to developing Paget’s disease (genetic predisposition). Genes associated with this condition are the sequestosome 1 gene, the TNFRSFIIA gene that codes for the RANK protein, and the VCP gene. The exact role that these genes play in the development of the disorder is unknown. This hereditary factor may be the reason that family members are susceptible to the suspected virus.
Paget’s disease is rarely diagnosed in people under the age of 40 years but may occur in up to three percent of the population over the age of 60 years. Paget’s disease affects individuals of all ethnic and racial groups. However, it affects individuals of Asian descent less frequently. Both men and women ca be affected with a slight male predominance. The prevalence of Paget’s disease in the United States is estimated to be 1-2 percent of the general population.
The diagnosis of Paget’s disease may be confirmed by a thorough clinical evaluation, detailed patient history, and a variety of specialized tests, such as blood tests, x-rays, and urine tests. A blood test may reveal elevated levels of the enzyme alkaline phosphatase suggesting the diagnosis of Paget’s disease, usually confirmed by x-ray. A bone scan may also be used to determine the extent of the abnormalities in the bones. Urine tests, such as pyrilinks and osteomark, may also be used to assist in the diagnosis and response to therapy of Paget’s disease.
Four main methods of treatment exist for the patient with Paget’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; and surgical intervention.
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 various types of bisphosphonates are better understood.
Currently, six bisphosphonates are approved by the U.S. Food and Drug Administration (FDA) for the treatment of Paget’s disease. These include zoledronic acid (Reclast) and pamidronate disodium (Aredia) which are given intravenously.
Zoledronic acid (Reclast) is the preferred treatment. Intravenous adminstration is in 5 mg infusion given over 15 minutes. Prior to therapy, patients should receive 1500 mg units of calcium and 1000 units of vitamin D daily for two weeks to reduce their risk of low blood calcium after infusions. Zoledronic acid (Reclast) is not indicated for individuals with low blood calcium or vitamin D deficiency and those with a compromised renal function.
Zoledronic acid (Reclast) is also marketed for treating Paget’s disease with the name Aclasta in several countries outside of the United States.
A mild form of Paget’s disease can be suppressed with one or two 60 mg infusions of pamidronate disodium, 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 amount of infusion is administered. Several generic forms of pamidronate disodium are also available.
Oral calcium and vitamin D supplementation is recommended for patients using this therapy to lessen hypocalcemia, a common side effect and patients with low blood calcium levels and or vitamin D deficiency should not be treated with paidronate disodium
Patients with either low blood calcium or vitamin D deficiency should not be treated with zoledronic acid and the drug is not indicated for patients with compromised renal functions.
Etidronate (Didronel), tiludronate (Skelid), alendronate (Fosamax), and risedronate (Actonel) are taken orally. Both alendronate sodium and risedronate sodium have been shown to reduce the biochemical indices for bone turnover into the normal range in patients with a moderate-to-severe form of Paget’s disease. Alendronate is taken as a daily 40 mg tablet for six months; risedronate is taken as a 30 mg tablet for two or three months. Calcium and vitamin D supplementation is also recommended for patients using either of these drugs. Alendronate (Fosamax) 40mg tables are available in generic form at retail pharmacies with the name Alendronate sodium tablets. A prescription is required.
Etidronate disodium and tiludronate disodium are less potent than alendronate and risedronate. They are both taken as daily 400 mg tablets. Etidronate, the original bisphosphonate used in treating Paget’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 bisphosphonates in their prescribed manner to avoid poor absorption of the drugs or severe gastrointestinal problems.
Subcutaneous injection of salmon calcitonin was the first widely used therapy for Paget’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 essential. Miacalcin, an injection taken daily or three times a week, is the only calcitonin approved for Paget’s disease. A nasal spray form of Miacalcin is approved for treating osteoporosis. This spray is not approved or recommended for individuals with Paget’s disease.
Pain Management: Analgesics
Pain directly attributable to Paget’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, non-steroidal anti-inflammatory drugs (NSAIDS), or the 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 individuals with Paget’s disease. These include:
1. Fixing a complete fracture through pagetic bone
2. Realigning the knee through tibial osteotomy to decrease mechanical pain, particularly if medical therapy is unsuccessful in managing severe pain syndromes
3. Replacing the hip and/or knee through total joint arthroplasty for patients unresponsive to anti-osteoclast treatment and therapy for osteoarthritis
When repairing a pagetic fracture, total immobilization of that site should be avoided if possible. In all cases of surgical intervention, pre-treatment with a potent bisphosphonate is very important. Since hypervascularity is a symptom of Paget’s disease, this may lead to serious bleeding during an operation. Pre-treatment with a bisphosphonate will reduce the hypervascularity and reduce the risk of greater-than-normal operative blood loss.
The development of specific inhibitors of osteoclast-mediated resorption, particularly the potent bisphosphonates, has brought about major changes in the treatment of Paget’s disease. Although the long-term effects of disease suppression are unknown, the capacity to restore the bone remodeling process to normal gives reason to believe that reduction in long-term complications and their related morbidity is now possible.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about Paget’s disease:
Roy D. Altman, MD
Professor of Medicine
Division of Rheumatology and Immunology
University of California, Los Angeles
email: [email protected]
Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7th ed. An official publication of The American Society for Bone and Mineral Research. Sheridan WY: The Sheridian Press; 2008.
Tiegs RD. Paget Disease of Bone. In: NORD Guide to Rare Disorders, Philadelphia, PA: Lippincott, Williams and Wilkins; 2003:24-5.
Singer FR, Krane SM. Paget’s Disease of Bone. In: Avioli LV, Krane SM, eds. Metabolic Bone Disease, 4th ed. San Diego, CA: Academic Press;, 1998.
Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med. 2005;353:898-908.
Lyles, KW, Siris ES, Singer FR, et al. Perspective: A clinical approach to diagnosis and management of Paget’s disease of bone. J Bone Min Res. 2001;16:1379-87.
The information in NORD’s Rare Disease Database is for educational purposes only and is not intended to replace the advice of a physician or other qualified medical professional.
The content of the website and databases of the National Organization for Rare Disorders (NORD) is copyrighted and may not be reproduced, copied, downloaded or disseminated, in any way, for any commercial or public purpose, without prior written authorization and approval from NORD. Individuals may print one hard copy of an individual disease for personal use, provided that content is unmodified and includes NORD’s copyright.
National Organization for Rare Disorders (NORD)
55 Kenosia Ave., Danbury CT 06810 • (203)744-0100