Paget's disease of bone

Paget's disease of bone (also known as osteitis deformans) is a nonmalignant disease involving accelerated bone resorption followed by deposition of dense, chaotic, and ineffectively mineralized bone matrix. The origin of the disease is unknown, and it is frequently asymptomatic; however, the patient may present with symptoms depending on the bones involved. The most common symptom is pain in the affected bone; neurologic, hearing, vision, cardiac, and oncologic complications are possible. Diagnosis is primarily made by radiographs. Bisphosphonates are the most common treatment. (Am Fam Physician 2002;65:2069-72. Copyright[C] 2002 American Academy of Family Physicians.)

Aside from osteoporosis, Paget's disease is the most common bone disorder.(1) Paget's disease is equally prevalent in men and women, with increased incidence in persons older than 50 years. It affects approximately 3 percent of persons in the United States, and as many as 10 percent of persons older than 80 years.(2,3)

Paget's disease occurs in three phases.(1,4) The initial phase consists of intense osteoclastic activity and bone resorption, with bone turnover as high as 20 times the normal rate.(5) This phase is followed by an osteolytic-osteoblastic phase during which osteoblasts begin to produce an abundance of woven bone, but mineralization is ineffective. In the final phase, dense cortical and trabecular bone deposition dominates, but it is sclerotic, disorganized, and weaker than normal bone.(4)

Paget's disease most commonly involves the axial skeleton, but it can affect any area (Table 1).(4) In the majority of patients, Paget's disease affects at least two bones, but in one third of patients only one bone is affected.(1)

Etiology

Although the etiology of Paget's disease is unknown, studies have provided some support for both viral and hereditary causes. Viral antigens have been detected in affected osteoclasts by numerous methods and research teams.5 In the United States, the measles virus antigen is most commonly detected in patients with Paget's disease.6-8

A positive family history is reported in as many as 40 percent of patients with Paget's disease. Much attention has been focused on a pagetic susceptibility locus at human chromosome 18q.(1,4,5,9-11)

Diagnosis

An estimated 70 percent of patients who have Paget's disease have no symptoms.(4) The diagnosis is typically found incidentally on radiographs and laboratory investigations. Clinical manifestations, when present, may be wide in spectrum (Table 2).(12)

Table 2

Symptoms of Paget's Disease

Bone pain from microfractures or osteoarthritis; if the jaw is involved, teeth may become loose

Headaches and loss of hearing or vision from pressure on nerves, brain, or spinal cord and reduced blood flow

Pain or neuropathy from pressure on nerves

Increased head size, bowing of a limb, or curvature of the spine

Hip pain

Damage to cartilage of joints, which may lead to osteoarthritis

Heart failure (only in severe cases, especially in patients with heart disease)

Kidney stones (more common in patients with Paget's disease)

Sarcoma, in less than 1 percent of patients with Paget's disease

Information from National Institutes of Health, Osteoporosis and Related Bone Disease, National Resource Center. Information for patients about Paget's disease of bone. Retrieved October 2001, from: www.osteo.org/pdisbone.html.

Patients with bone pain caused by Paget's disease usually describe the pain as continuous. Unlike osteoarthritis, pagetic bone pain usually increases with rest, on weight bearing, when the limbs are warmed, and at night.(1,4) Paget's disease can cause osteoarthritis if the affected section of bone is near a joint.(1)

A variety of deformities may occur, including kyphosis; shortened or bowed limbs(9) (Figure 1); leonine facies(3); frontal bossing of the forehead(3); dental abnormalities; and, in severe cases, an enlarged cranium that may be difficult to hold erect.

Neurologic symptoms arise from the compression of nerves, which is caused by osseous growth. Resulting sequelae include cranial nerve, brain stem and cerebellar deficits, and deficits caused by spinal stenosis. Although cardiovascular involvement is uncommon, patients with widespread Paget's disease and extensive hypervascularization of the bone marrow can present with an arteriovenous shunt leading to high output cardiac failure.

The incidence of malignant degeneration of pagetic bone ranges from less than 1 percent to 10 percent, depending on disease severity.(1) Usually, these tumors are highly malignant osteosarcomas, fibrosarcomas, or undifferentiated spindle cell sarcomas.(13,14) Radiologic characteristics suggestive of malignant transformation include cortical breakthrough and soft tissue masses.(15)

Patients with Paget's disease may also develop several types of pseudomalignancy, including pseudosarcoma and pseudo giant cell tumors that are responsive to corticosteroids. Paget's pseudosarcoma typically presents as a slow-growing, localized, periosteal mass on pagetic bone. It has a predilection for long bones, especially the femur, and differs from a true sarcoma in that it does not destroy cortical bone or invade surrounding soft tissue.(16) Patients may present with metabolic abnormalities, including hypercalcemia, hypercalcuria, and hyperuricemia.(1)

Diagnosis of Paget's disease may be suspected based on the symptoms, but radiographs are the most specific diagnostic test. Asymptomatic patients with a first-degree relative with Paget's disease should be screened with a serum alkaline phosphatase test every two to three years. If the serum alkaline phosphatase level is elevated, a bone scan can be performed to determine the extent and activity of Paget's disease. Radiographs should be taken to confirm the diagnosis in a patient with bone scans suggestive of Paget's disease.

BIOCHEMICAL MARKERS

There are many biochemical markers for Paget's disease, but the two most important are total serum alkaline phosphatase and urinary pyridinoline.(17) These markers may be normal in patients with the monostotic form of Paget's disease (15 percent of patients) therefore, serum bone-specific alkaline phosphatase measurements may be useful. Urinary hydroxyproline is no longer considered an accurate marker of activity or extent of the disease.(18-20)

RADIOGRAPHY

Radiographs include both lytic (early) and sclerotic findings (Table 3). Many patients are diagnosed incidentally in the asymptomatic phase by plain radiographs that show localized enlargement of bone. These radiographs often have a high specificity because of their classic nature, but a low sensitivity. Bone scans can be used to increase the sensitivity in patients suspected of having Paget's disease; however, the bone scan is less specific and should be interpreted cautiously.(21) Once a diagnosis of Paget's disease is confirmed, repeat radiographs are required only to monitor degeneration around weight-bearing joints. Computed tomography and magnetic resonance imaging are not necessary.

Table 3

Radiologic Findings in Patients with Paget's Disease

Radiographic

Osteoporosis circumscripta in skull

Flame-shaped lesions in long bones

Osteolytic lesions near thickened lesions

Sclerotic bone

Bowed limbs

Fractures, including "banana" or "chalk" transverse fractures

Bone scintigraphy

Areas of increased uptake of technetium-99m

"Mouse face" pattern on scan of affected vertebra

If the results of the biochemical markers and radiography are inconclusive, a biopsy of the affected bone may be indicated in rare cases.

Treatment

Treatment of Paget's disease does not cure the disease but can provide prolonged periods of remission. Bisphosphonates, which decrease bone resorption by inhibiting osteoclast resorption, are the treatment of choice. Disease activity stays low for months or years after cessation of these medications. Alendronate (Fosamax) and pamidronate (Aredia) are used most frequently and will cause about a 70 percent decrease in biochemical markers in one half of patients.(2) Newer-generation bisphosphonates that are still in development are thousands of times more potent than first-generation agents. Calcitonin (Calcimar) also inhibits osteoclastic bone resorption. Calcitonin-salmon is available in injectable and nasal-spray forms, but only the injectable form is approved for treatment of Paget's disease by the U.S. Food and Drug Administration(22,23) (Table 4(12)). Compared with the bisphosphonates, calcitonin is not as powerful and does not suppress the disease activity for as long after cessation. Patients with Paget's disease should receive adequate doses of calcium (1,000 to 1,500 mg per day) and vitamin D (400 IU per day). Exercise is recommended to maintain skeletal health in patients with Paget's disease; however, exercise programs should be individualized to prevent stress on affected bones.

SURGICAL

Rarely, surgical treatment with elective joint replacements or osteotomy may be required in patients with the following conditions: progressive bowing of the tibia or femur; delayed union of fractures; unstable fractures; arthritis refractory to medical treatment; or focal nerve compression of the spine or cranium.1,23

INITIATION OF TREATMENT

Although no established standard for initiating therapy exists, the literature generally supports treating the following patients: all symptomatic patients; asymptomatic patients whose biochemical markers suggest an increase in bone remodeling; and patients with pagetic lesions located at weight-bearing regions or adjacent to joints.(1,3,4) Many sources(2,21) recommend initiating treatment when the serum alkaline phosphatase level rises to 125 to 150 percent of normal values. Recommendations for follow-up serum alkaline phosphatase monitoring range from every three months to annually. Patients should be followed indefinitely because of the increased risk of malignant transformation in patients with longstanding Paget's disease. Treatment goals should also include aggressive pain control.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

REFERENCES

(1.) Ankrom MA. Shapiro JR. Paget's disease of bone (osteitis deformans). J Am Geriatr Soc 1998;46:1025-33.

(2.) Delmas PD, Meunier PJ. The management of Paget's disease of the bone. N Engl J Med 1997;336:558-66.

(3.) Meunier PJ, Salson C, Mathieu L, Chapuy MC, Delmas P, Alexandre C, et al. Skeletal distribution and biochemical parameters of Paget's disease. Clin Orthop 1987;217:37-44.

(4.) Ooi CG, Fraser WD. Paget's disease of bone. Postgrad Med J 1997; 73:69-74.

(5.) Roodman GD. Paget's disease and osteoclast biology. Bone 1996;19:209-12.

(6.) Bone HG, Kleerekoper M. Clinical review 39: Paget's disease of bone. J Clin Endocrinol Metab 1992;75:1179-82.

(7.) Mills BG, Frausto A, Singer FR, Ohsaki Y, Demulder A, Roodman GD. Multinucleated cells formed in vitro from Paget's bone marrow express viral antigens. Bone 1994;15:443-8.

(8.) Nuovo MA, Nuovo GJ, MacConnell P, Forde A, Steiner GC. In situ analysis of Paget's disease of bone for measles-specific PCR-amplified cDNA. Diagn Mol Pathol 1992;1:256-65.

(9.) Siris ES. Paget's disease of bone. J Bone Miner Res 1998;13:1061-5.

(10.) Mills BG, Oizumi J, Kudo E, Rude R. Robertsonian translocations in Paget's disease of bone. J Orthop Res 1997;15:477-81.

(11.) Haslam SI, Van Hul W, Morales-Piga A, Balemans W, San-Millan JL, Nakatsuks K, et al. Paget's disease of bone: evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity. J Bone Miner Res 1998;13:911-7.

(12.) National Institutes of Health, Osteoporosis and Related Bone Disease, National Resource Center. Information for patients about Paget's disease of bone. Retrieved October 2001, from: www. osteo.org/pdisbone.html.

(13.) Gebhart M, Vandeweyer E, Nemec E. Paget's disease of bone complicated by giant cell tumor. Clin Orthop 1998;352:187-93.

(14.) Boulanger V, Chauveaux D, Kantor G, Loyer-Lecestre MJ, Rivel J, Coindre JM, et al. Primary angiosarcoma of bone in Paget's disease. Eur J Surg Oncol 1998;24:611-3.

(15.) Brandolini F, Bacchini P, Moscato M, Bertoni F. Chondrosarcoma as a complicating factor in Paget's disease of bone. Skeletal Radiol 1997;26:497-500.

(16.) Khraishi M, Howard B, Fam AG. Paget's pseudosarcoma. Arthritis Rheum 1991;34:241-3.

(17.) Uebelhart D, Gineyts E, Chapuy MC, Delmas PD. Urinary excretion of pyridinium crosslinks: a new marker of bone resorption in metabolic bone disease. Bone Miner 1990;8:87-96.

(18.) Rosen HN, Dresner-Pollak R, Moses AC, Rosenblatt M, Zeind AJ, Clemens JD, et al. Specificity of urinary excretion of cross-linked N-telopeptides of type I collagen as a marker of bone turnover. Calcif Tissue Int 1994;54:26-9.

(19.) Garnero P, Delmas PD. Assessment of serum levels of bone alkaline phosphatase with a new immunoradiometric assay in patients with metabolic bone disease. J Clin Endocrinol Metab 1993;77:1046-53.

(20.) Alvarez L, Guanabens N, Peris P, Monegal A, Bedini JL, Deulofeu R, et al. Discriminative value of biochemical markers of bone turnover in assessing the activity of Paget's disease. J Bone Miner Res 1995;10:458-65.

(21.) Tiegs RD. Paget's disease of bone: indications for treatment and goals of therapy. Clin Ther 1997;19:1309-29.

(22.) Ryan WG, Schwartz TB. Mithramycin treatment of Paget's disease of bone. Exploration of combined mithramycin-EHDP therapy. Arthritis Rheum 1980;23:1155-61.

(23.) Gonzalez D, Vega E, Ghiringhelli G, Mautalen C. Comparison of the acute effect of the intranasal and intramuscular administration of salmon calcitonin in Paget's disease. Calcif Tissue Int 1987; 41:313-5.

DORON SCHNEIDER, M.D., is associate director of the internal medicine residency program at Abington (Pa.) Memorial Hospital. Dr. Schneider received his medical degree from New Jersey Medical School, Newark. He completed a residency in internal medicine at New England Deaconess Hospital, Boston.

MARY T. HOFMANN, M.D., is chief and fellowship director, section of geriatric medicine and director for Muller Center for Senior Health at Abington (Pa.) Memorial Hospital, and associate professor of medicine at MCP-Hahnemann University School of Medicine, Philadelphia. Dr. Hofmann received her medical degree from Temple University School of Medicine, Philadelphia. She completed a residency in internal medicine and a fellowship in geriatric medicine at the Medical College of Pennsylvania, Philadelphia.

JEANNETTE A. PETERSON, M.D., J.D., is currently a second-year resident in internal medicine at the University of California-Davis School of Medicine, Sacramento. Dr. Peterson received her medical degree from the Medical College of Pennsylvania, and her law degree from the University of California, Berkeley.

Address correspondence to Doron Schneider, M.D., Department of Internal Medicine and the Muller Center for Senior Health, Abington Memorial Hospital, 1200 Old York Rd., Abington, PA 19001-3788. Reprints are not available from the authors.

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