Paget’s disease of bone
1. What is Paget’s disease of bone?
Paget’s disease affects approximately 1.5 million people in the United States. It is characterized by abnormal bone architecture resulting from an imbalance between osteoblastic bone formation and osteoclastic bone resorption. Skeletal remains indicate that Paget’s disease first appeared in Western European populations during the Roman period. Sir James Paget first described this disease in 1876, and he called the condition osteitis deformans. We now know that Paget’s disease of bone is not an inflammation of bone (osteitis) and only rarely results in deformity.
2. Discuss how Paget’s disease is diagnosed.
The diagnosis of Paget’s disease is generally based on a combination of clinical manifestations, radiographic signs, and characteristic biochemical changes. Although histologic examination of pagetic bone is diagnostic, a bone biopsy is often unnecessary. Bone biopsy should be performed when the diagnosis of Paget’s disease is unclear or when osteogenic sarcoma or metastatic carcinoma must be excluded.
3. What are the clinical manifestations of Paget’s disease?
Most patients (70%-80%) with Paget’s disease are asymptomatic. This disorder is often suspected from radiographs performed for other reasons or from an unexpected elevation of the serum alkaline phosphatase concentration. The most common symptom of Paget’s disease is bone or joint pain. The pain is often described as dull and aching. Other manifestations of Paget’s disease, such as headache, bone deformity, skull enlargement, fracture, change in skin temperature over an involved bone, high-output congestive heart failure, and entrapment neuropathies that may cause hearing loss or other neurologic deficits, are much less common (Box 12-1). Neurologic deficits may arise from bony impingement on the brain or cranial nerves exiting from the skull, spinal nerve entrapment, or direct pressure of pagetic vertebrae on the spinal cord. Bone deformity is usually seen in patients with long-standing Paget’s disease. Most commonly, the skull, clavicles, and long bones are deformed and exhibit both an increase in size and an abnormal contour. There is speculation that Ludwig van Beethoven’s hearing loss, headaches, and progressive hyperostosis frontalis were the results of advanced Paget’s disease of bone.
4. What disorders are associated with Paget’s disease of bone?
Several disorders are more prevalent in patients with Paget’s disease than in unaffected individuals. They include arthritis, fractures, primary hyperparathyroidism, osteoporosis, thyroid disease, and kidney stones.
5. What are the three phases of Paget’s disease of bone?
Paget’s disease progresses through three distinct phases. The initial phase is an osteolytic phase characterized by predominantly osteoclastic bone resorption. Approximately 1% to 2% of patients exhibit this purely lytic phase. The osteolytic phase evolves into one marked by both osteoclastic and osteoblastic overactivity. This mixed phase is followed by a phase characterized by less active bone remodeling and marked sclerosis. In this final phase, excessive osteoblastic bone deposition predominates. Most patients who come to medical attention exhibit findings compatible with this phase.
6. Describe the radiographic findings associated with the osteolytic phase of Paget’s disease.
The characteristic radiographic finding in patients in the initial osteolytic phase of Paget’s disease of bone is an advancing wedge-shaped resorption front at either end of long tubular bones. In the skull, this phase is manifested by large circumscribed osteolytic lesions (termed osteoporosis circumscripta).
7. What are the radiographic findings most commonly found in the osteoblastic phase of the disease?
Evolution of osteolytic lesions into the osteoblastic phase may require years or even decades, during which the affected bone may become sclerotic and enlarged and may demonstrate bowing deformities, incomplete transverse fractures (pseudofractures), and even complete fractures. When the skull is involved in the osteoblastic phase, thickening of the calvarium and a patchy increase in bone density may give the skull a “cotton-wool” appearance. In this phase, the sclerotic bone changes may be so extensive that they may be confused with metastatic disease. Both metastatic cancer and Paget’s disease are common in the elderly and may coexist in the same patient. Thus, clinicians caring for patients with Paget’s disease must be alert for evidence of metastatic disease to bone.
8. What is the best radiographic evaluation to determine the extent of Paget’s disease?
The metabolic activity of osteoblastic pagetic bone lesions is most easily assessed by radionuclide scanning because these lesions avidly take up the technetium-labeled bisphosphonate. Although bone scans are diagnostically less specific than radiographic studies, they identify approximately 15% to 30% of pagetic lesions not visualized on radiographs. Conversely, when radiographs demonstrate pagetic involvement but the serum alkaline phosphatase concentration is normal and the bone scan reveals little isotope uptake at those sites, the diagnosis of relatively inactive or “burned out” Paget’s disease is most likely. Predominantly lytic bone lesions (such as osteoporosis circumscripta) may not be detected on bone scan. Computed tomography (CT) and magnetic resonance imaging (MRI) add little to the workup of patients with uncomplicated Paget’s disease.
9. Which bones are involved in Paget’s disease?
Paget’s disease is monostotic (i.e., involves only one bone) in about 20% of patients. Polyostotic Paget’s disease involves more than one area of the skeleton. Common sites of pagetic involvement are the pelvis, hip, spine, skull, tibia, and humerus. Less common sites of involvement (< 20% of cases) include the forearm, clavicles, scapulae, and ribs.
10. Discuss the laboratory abnormalities associated with Paget’s disease.
The abnormal laboratory values associated with Paget’s disease reflect either increased bone formation or increased bone resorption. Unless a patient with widespread Paget’s disease is immobilized, serum calcium and phosphate concentrations should be normal. An elevated serum alkaline phosphatase concentration reflects increased osteoblastic function. Measurement of serum osteocalcin, another marker of bone formation, provides little additional information to that given by measurement of alkaline phosphatase. The serum bone-specific alkaline phosphatase is a more sensitive marker of bone formation than the total alkaline phosphatase concentration and thus may be a useful parameter to follow in the management of monostotic disease. Measurement of urinary pyridinium collagen crosslinks (pyridinoline) is a better indicator of increased bone resorption than measurement of urinary hydroxyproline.
11. Which laboratory test should be used to monitor patients with Paget’s disease?
When the Paget’s disease is primarily lytic, the alkaline phosphatase concentration may be normal. Otherwise, the serum alkaline phosphatase activity generally parallels other chemical indices of bone resorption. Thus, the total serum alkaline phosphatase concentration is the simplest and least expensive laboratory value for following the course and the response to treatment in most cases of Paget’s disease. Of interest, a markedly elevated alkaline phosphatase concentration (e.g., 10 times the upper limit of normal) is usually associated with pagetic involvement of the skull, whereas widespread disease in the rest of the skeleton without involvement of the skull may be associated with more modest elevations of serum alkaline phosphatase. In patients with increased total alkaline phosphatase concentrations, liver disease should be excluded, because this enzyme is abundant in both liver and bone. If liver-specific measurements, such as of 5′-nucleotidase, gamma-glutamyl transpeptidase, or the liver alkaline phosphatase isoenzyme, are normal, it is likely that the elevated alkaline phosphatase value originates from bone.
12. What are the histologic findings in bone affected by Paget’s disease?
The early lesions of Paget’s disease are characterized by increased numbers of large multinucleated osteoclasts, some containing up to 100 nuclei. In the mixed osteolytic-osteoblastic phase, large numbers of active osteoblasts are seen forming bone at sites of prior osteoclastic bone resorption. In areas of intense osteoblastic activity, bone is deposited in a chaotic fashion (in a mosaic or woven pattern) rather than in the orderly lamellar pattern of normal bone. The woven bone of Paget’s disease is structurally weaker than normal lamellar bone and explains the propensity for pagetic bone to fracture or deform.
13. Which patients are most likely to have Paget’s disease?
The incidence of Paget’s disease varies with age, gender, and geographic location. Although Paget’s disease may manifest in younger individuals, this disease is most common in patients older than 50 years. Men are more commonly affected than women (the male-to-female ratio is approximately 3:2). Although there is no definite hereditary pattern, between 15% and 40% of affected patients have a first-degree relative with Paget’s disease. The disease is more common in the populations of eastern and northern Europe and in areas where Europeans have immigrated (such as the United States, Australia, New Zealand, and South Africa). Paget’s disease is uncommon in Scandinavia, Asia, and Africa, as well as in African American populations.
14. What is the cause of Paget’s disease?
Although the cause of Paget’s disease is unknown, both genetic and nongenetic factors have been implicated in its pathogenesis. Several Paget’s disease–associated polymorphisms have been identified. The SQSTM1 mutation is present in up to 50% of patients with familial disease and 10% to 20% of sporadic cases. Patients carrying this mutation have more extensive disease than noncarriers. However, the finding of monostotic disease, the variable penetrance of Paget’s disease in families with a genetic disposition, and the observation that the incidence of Paget’s disease has been decreasing over the past 25 years support a role for environmental factors in the etiology of this disease. Reports of structures resembling paramyxovirus nucleocapsids in the osteoclasts of active pagetic bone suggest a viral etiology. The measles virus, respiratory syncytial virus, and canine distemper virus have been suggested as etiologic agents, although to date no virus has ever been cultured from pagetic osteoclasts or osteoclast precursors.
15. What medications are available to treat Paget’s disease?
Although there is no cure for Paget’s disease, several medications are available to control the accelerated osteoclastic bone resorption seen in this disease. The medications used for the treatment of Paget’s bone disease include bisphosphonates and calcitonin (Calcimar, Miacalcin injection). At present, five bisphosphonates are approved and available for the treatment of Paget’s disease of bone in the United States: etidronate (Didronel), alendronate (Fosamax), risedronate (Actonel), pamidronate (Aredia), and zoledronic acid (Reclast, Aclasta). Another bisphosphonate, ibandronate (Boniva), has been used for the treatment of Paget’s disease in research studies. However, this drug has not been approved for the treatment of Paget’s disease. Salmon calcitonin is a parenteral preparation requiring daily or three-times-a-week intramuscular or subcutaneous injections for 6 months. Calcitonin nasal spray (Miacalcin, Fortical) is not effective for treating Paget’s disease because of low drug bioavailability.
16. Which agents are the drugs of choice for Paget’s disease of bone?
Bisphosphonates are the agents of choice for the treatment of Paget’s disease. Treatment with bisphosphonates often results in suppression of disease activity for prolonged periods, sometimes several years, whereas the response to calcitonin is generally short-lived after treatment is discontinued. Etidronate and calcitonin are rarely used because of the availability of more potent medications. One study has compared a 15-minute infusion of zoledronic acid with 60 days of oral risedronate in patients with Paget’s disease. The single infusion of zoledronic acid produced a more rapid, complete, and sustained response than daily treatments with risedronate. Thus, intravenous bisphosphonate therapy may be more appropriate for extensive active disease or for disease that is unresponsive to oral bisphosphonate therapy. Treatment of symptomatic patients should also include other therapeutic modalities, such as analgesics, nonsteroidal antiinflammatory drugs, canes, orthotics, hearing aids, and surgery.
17. Does resistance to therapy for Paget’s disease of bone occur?
Resistance to both bisphosphonates and calcitonin does occur. Resistance to treatment of Paget’s disease with salmon calcitonin is usually associated with the production of neutralizing antibodies. Development of resistance after therapy with some of the bisphosphonates has also been reported. However, studies suggest that resistance to one bisphosphonate does not preclude a good response to a second bisphosphonate.
18. What is osteonecrosis of the jaw, and do patients with Paget’s disease treated with bisphosphonates get this disorder?
Osteonecrosis of the jaw (ONJ) is a rare finding in which an area of exposed bone in the maxillofacial area persists for more than 6 weeks. This condition usually occurs following dental surgery. The symptoms vary from painless exposed bone to severe jaw pain. ONJ has also been described in patients receiving prolonged intravenous bisphosphonates for cancer, although there have been a few reports of this condition occurring in patients with Paget’s disease. Thus the risk of ONJ should not preclude the use of bisphosphonates for the treatment of Paget’s disease. However, it is recommended that treatment with bisphosphonates be delayed until after planned extensive dental work or oral surgery is completed. All patients treated with bisphosphonates should receive routine dental examinations and oral care.
19. What are the indications for treatment of Paget’s disease?
The primary indication for treatment is the presence of symptoms. However, not all symptoms respond to treatment. Bone pain usually responds, as do certain neurologic compression syndromes. In contrast, hearing loss, bony deformities, and mechanically dysfunctional joints are not likely to improve with therapy. Additional indications for treatment of Paget’s disease are the prevention of local progression, planned surgery at a pagetic site, widespread pagetic involvement in patients in whom prolonged immobilization is anticipated (to decrease the risk of hypercalcemia), and possible prevention of future complications. Treatment of asymptomatic patients with Paget’s disease is controversial. However, untreated Paget’s disease appears to be progressive with time, and not all asymptomatic patients remain so. Thus, many physicians treat patients with osteolytic Paget’s disease or asymptomatic patients with active disease involving weight-bearing bones, vertebral bodies, the skull, or areas adjacent to major joints (Box 12-2).
20. What is the most serious complication of Paget’s disease of bone?
The most serious complication of Paget’s disease is the development of malignant sarcoma in pagetic bone. Such tumors are usually isolated, but 20% may be multicentric. Fortunately, this is a rare complication of Paget’s disease, occurring in less than 1% of patients with clinically apparent disease. This tumor is extremely aggressive, and patients with Paget’s sarcoma generally survive less than a year. The pelvis and long bones (humerus, femur, and tibia) are the most common sites for sarcomatous transformation. The tumor is usually an osteogenic sarcoma, but fibrosarcomas and chondrosarcomas have also been reported in bone affected by Paget’s disease. A biopsy of the involved bone is usually diagnostic. Other bone neoplasms, such as benign giant cell tumors, are also associated with Paget’s disease, but these tumors do not carry such a grave prognosis.
21. When should malignant sarcoma in a pagetic bone lesion be suspected?
Malignant transformation within pagetic bone is usually heralded by the onset of new or worsening bone pain and/or soft tissue swelling. Usually, progressive destruction of pagetic bone is found on radiographs. Less commonly, increasing sclerosis or masses of dense amorphous deposits in bone are suggestive of malignant change. The serum concentration of alkaline phosphatase may rise rapidly in an otherwise previously stable patient. Bone scans usually demonstrate decreased uptake of radionuclide in the area of the tumor. Gallium scans also show increased uptake in the involved area(s).
KEY POINTS 1: PAGET’S DISEASE OF BONE
1. Paget’s disease is the second most common metabolic bone disease, affecting up to 5% of the Caucasian population over age 50 years.
2. Paget’s disease is characterized by abnormal bone architecture resulting from an imbalance between osteoblastic bone formation and osteoclastic bone resorption.
3. Bisphosphonates are the most effective treatment for Paget’s disease of bone.
WEBSITECundy, T, Reid, IR. Paget’s disease of bone. Clin Biochem. 2012;45:43.
Drake, WM, Kendler, DL, Brown, JP. Consensus statement on the modern therapy of Paget’s disease of bone from a Western Osteoporosis Alliance Symposium. Clin Ther. 2001;23:620.
Falchetti, A, Masi, L, Brandi, ML, Paget’s disease of bone. there’s more than the affected skeletal—a clinical review and suggestions for the clinical practice. Curr Opin Rheumatol 2010;22:410.
Hadjipavlou, A, Lander, P, Srolovitz, H, Enker, IP. Malignant transformation in Paget’s disease of bone. Cancer. 1992;70:2802.
Hain, SF, Fogelman, I. Nuclear medicine studies in metabolic bone disease. Semin Musculoskelet Radiol. 2002;6:323.
Joshua, F, Epstein, M, Major, G. Bisphosphonate resistance in Paget’s disease of bone. Arthritis Rheum. 2003;48:2321.
Michou, L, Brown, JP. Emerging strategies and therapies for treatment of Paget’s disease of bone. Drug Des Devel Ther. 2011;5:225.
Mills, BG. Etiology and pathophysiology of Paget’s disease–update. Endocrinologist. 1997;7:222.
Naot, D, Paget’s disease of bone. an update. Curr Opin Endocrinol Diabetes Obes 2011;18:352.
Proceedings of the Third International Symposium on Paget’s Disease. J Bone Mineral Res. 14(Suppl 2), 1999.
Ralston, SH, Albagha, OME. Genetic determinants of Paget’s disease of bone. Ann NY Acad Sci. 2011;1240:53.
Reid, IR, Hosking, DJ. Bisphosphonates in Paget’s disease. Bone. 2011;49:89.
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;353:9.
Roodman, GD, Windle, JJ. Paget disease of bone. J Clin Invest. 2005;115:200.
Roodman, GD. Insights into the pathogenesis of Paget’s disease. Ann NY Acad Sci. 2010;1192:176.
Sawin, CT, Historical note. Sir James Paget and osteitis deformans. Endocrinologist 1997;7:205. (Also see page 255 in the same issue for a reproduction of one of James Paget’s original articles on osteitis deformans)
Sellars, SL. Beethoven’s deafness. S Afr Med J. 1974;48:1585.
Siris, ES, Lyles, KW, Singer, FR, Meunier, PJ, Medical management of Paget’s disease of bone. indications for treatment and review of current therapies. J Bone Miner Res. 2006;21(Suppl 2):94.
Siris, ES, Roodman, GD. Paget’s disease of bone. In: Favus MJ, ed. Primer on the metabolic bone diseases and disorders of mineral metabolism. ed 6. New York: Raven Press; 2006:320.
Whyte, MP. Paget’s disease of bone. N Engl J Med. 2006;355:593.
Wimalawansa, SJ, Gunasekera, RD. Pamidronate is effective for Paget’s disease of bone refractory to conventional therapy. Calcif Tissue Int. 1993;53:237.
