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Monograph Series on Aging-related Diseases: VII. Paget's Disease (Osteitis Deformans)
Paget's disease of the bone (PDB) is a chronic disorder of the adult skeleton in which localized areas of hyperactive bone are replaced by a softened and enlarged osseous structure. Nature and Classification In 1876 1 Sir James Paget described the advanced clinical form of the bone disease that now bears his name. Paget called it "osteitis deformans" due to the gross thickening, elongation and deformity of the bones of the five patients he described, coupled with his belief that the cause was a form of chronic inflammation. Today it is clear that the disease can be very localized, frequently without apparent gross deformity, and hence the preferred name is "Paget's disease." However, Paget's original description of the disease is said to be remarkably eloquent and accurate.2 Paget's disease of the bone has been defined as having two phases: an active phase and an inactive phase.3,4 During the active phase, there is increased bone resorption (osteoclastic activity) followed by intense bone formation (osteoblastic activity). During the inactive phase, there is a reduced rate of bone turnover (i.e. the number of osteoclasts and osteoblasts returns to normal).2-4 This process of increased rates of bone resorption and new bone formation results in altered bone architecture.4-7 The disease may involve single (monostotic form) or multiple (polyostotic form) bones.2,4,6,8,9 PDB is diagnosed by evaluation of medical history, physical examination, laboratory tests and radiographic studies (bone scans, x-rays). Occasionally, bone biopsies are performed.2,4,5 X-rays of the involved site are straightforward in the diagnosis of PDB since changes in bone appearance are quite apparent.2,5 Other methods of diagnosing PDB involve measuring urinary hydroxyproline and serum alkaline phosphatase. Urinary hydroxyproline levels are a measure of bone resorption, or osteoclastic activity,6,9,10 whereas serum alkaline phosphatase levels are an indicator of osteoblastic activity, or bone formation.6,8-13 According to Thomas and Shepherd,10 "alkaline phosphatase is the more sensitive and hydroxyproline the more accurate of the indices." The majority of Paget's disease patients are asymptomatic;2,4,8,14-16 however, when symptoms are apparent, they can include pain, fracture, neurological deficits, deafness and arthritis.4,6-9,11,17-21 Affected sites feel warm to the touch due to increased blood flow through these affected areas.9 The most common sites of PDB include the pelvis, spine, skull, femur and tibia;2,5,6,8,9 the hands and feet are rarely affected.5 Neurological complications associated with PDB of the skull include deafness, vertigo, tinnitus and headaches.6 While Paget's disease is a localized chronic bone disease, often undiagnosed and symptom-free, about 20-30% of people who have bone sarcomas also have Paget's disease.
Age of Onset PDB is usually found in older age groups.22-28 It is believed that 1-3% of the population aged 40 and over is affected by Paget's disease 5,6,29,30 and that diagnosis of the disease increases with age to about 8-15% in the older population (age 75 and over).6,18,30 The current hypothesis that Paget's disease is a slow virus disorder would mean that the actual age of onset of the disease is much earlier in life. A West German study 14 revealed that men seem to be diagnosed about one decade earlier than women: men more commonly in their sixth decade and women in their seventh decade.
Mortality Paget's disease is rarely fatal; therefore, mortality statistics give a very low indication of incidence. Evidence from mortality statistics, in which Paget's disease is given as the underlying cause of death, shows a secular trend of a decline in deaths from the disease between 1950 and 1970, both in Britain and the US.31 This decline coincides with a similar decline in mortality from bone tumours. Mortality in Canada Age Sex Geographic distribution |
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Morbidity Incidence Dalinka et al.46 and Fallon and Schwamm 8 have reported that the incidence of PDB increases with aging. Prevalence The prevalence of Paget's disease in Western Europe was estimated through a postal questionnaire sent to 1416 radiologists.32 The range of prevalence in Europe is much lower than in Britain: from a high of 2.7% in Bordeaux, France, to a low of 0.4% in Malmo, Sweden. Similar studies were conducted in the US 48 and Western Australia,49 where regional variations were also found. Prevalence tends to be higher in Britain, the US and Australia compared with other Western European countries. Only rare and isolated cases of the disease occur in Africa, the Middle East, India, Japan and China.4,6,9,50 The reported age-standardized prevalences are summarized in Table 3. Barker 51,52 has reported that the prevalence of PDB increases with age. |
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Morbidity in Canada Age Sex Geographic distribution |
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Etiology Several etiologic factors have been considered; however, most have not been consistently positively associated with PDB. The theory that PDB is hereditary or a genetic abnormality could possibly explain the striking geographic variation in the frequency of occurrence of the disease. Environmental influences have also been suggested in the etiology of PDB since disease rates are somewhat similar in American blacks and whites as compared to the rarity of PDB among African blacks.31 Current thinking, however, focuses on the role of viral infections 4,11 and, in particular, on the role of interleukin-6. 53 Aging of Body Tissues Genetics |
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A recent study by Siris et al.30 of 788 cases and 387 spousal controls provides additional evidence of the familial nature of the disease. They found that the rate of PDB in first-degree relatives of patients was six times higher than in relatives of controls (12.3% vs 2.1%). They also reported that the cumulative incidence of the disease to age 90 reached 8.9% for relatives of patients and only 1.8% for relatives of controls. Cumulative risk to relatives was found to be highest when patients were diagnosed at an early age and had a bone deformity. Sofaer et al.'s Scottish study 60 reported a prevalence 10 times higher among parents and siblings of patients with PDB than among parents and siblings of spousal controls. The authors found differences in the age of onset of disease for familial cases versus isolated cases. They explained that the differences could be due to either different levels of genetic contribution or to the likelihood of earlier diagnosis in families with a previously affected member. The similarity of age of onset of the disease within families could be caused by common genes or by common environmental influences. However, Sofaer et al. suggested that "onset is more influenced by the length of time that has elapsed since birth than by any environmental factor of short duration affecting members of the same sibship together." Siris et al.30 reported that their study contributed a number of methodological advances over that of Sofaer et al.'s: adjustments were made for the years at risk of the relatives, validity of family history data was improved and estimates were provided of cumulative risk of PDB development for relatives at certain ages throughout life. Ethnic Origin / Race Although Paget's disease has been found to be rare among the black races on the African continent,63,65 a US study found the condition to be similarly prevalent among American blacks and whites.48 Overall, however, the racial and ethnic differences are striking. In earlier radiologic reports, a total of 10 cases were observed in South African blacks, 4 cases in Senegalese, 5 cases in Nigerians, 2 cases in African Jamaicans 65 and no cases in American Indians.66 This is very different from British and US autopsy and radiologic studies that have consistently shown a prevalence of about 3%. Two interesting studies by Guyer and Chamberlain compare the ethnic differences in prevalence in the US 48 and South Africa.67 In New York and Johannesburg, the prevalence of PDB was higher in whites than in blacks for both sexes, whereas in Atlanta, the rate for males only was higher in blacks (Table 7). |
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Sex Geographic Factors In Great Britain, the area of high prevalence in Lancashire seems to have no exclusive cultural, industrial, geological or climatic conditions that distinguish it from surrounding areas in England of much lower prevalence.47 There have been no explanations for the large differences in prevalence of Paget's disease between New York and Atlanta in the US.48 There are also interesting differences in the prevalence rates in Australia. The rates among Australian immigrants, specifically from Great Britain, are much higher than among the natives of Australia.69 Although the world distribution of Paget's disease compels speculation about a genetically determined disorder disseminated by migration, this general idea remains controversial and without substantial etiologic evidence to provide an explanation for the geographic distribution of the disease. Infections The immunologic data have demonstrated the presence of only two viral antigens, respiratory syncytial virus (RSV) or the measles virus,74 with the precise nature of the role of the viral infection in the etiology of PDB yet to be established. Researchers have suggested that Paget's disease shares the features of other proven slow-virus disorders: an extremely long incubation period and only one system (the skeletal system) selectively affected, much like kuru and Creutzfeldt-Jacob syndrome.54 The familial clustering and geographic variation may be further evidence of the slow-virus hypothesis.54 Barker 31 remains unconvinced of the slow-virus hypothesis. He suggests that confirmation of the periodicity of year of birth of cases would support an infectious etiology since various childhood infections show cyclic changes in incidence; measles outbreaks generally occur in three-year cycles and RSV usually occurs in infancy. However, Barker found no evidence of a correlation with childhood town environments or infectious disease prevalence during the childhood of the cases in the British towns he investigated. Gordon et al.77 investigated the presence of measles virus in PDB and could not find any measles virus ribonucleic acid (RNA) in either cases or controls. Similarly, Ralston et al.78 did not find any evidence of measles virus, RSV or related paramyxovirus RNA in the pagetic tissue they examined. Recent studies, such as that of Manolagas and Jilka,53 suggest that interleukin-6, a cytokine, helps regulate osteoclastic activity. Most investigators 53,79-81 now support the virus theory, believing that interleukins, particularly interleukin-6, and cytokines in bone marrow are important in controlling the virus infections of osteoclasts. Endocrinological Disorder An imbalance between parathyroid and adrenal glands, growth hormone and other pituitary gland secretions has also been blamed for triggering PDB.82 According to Hamdy,54 however, all the known hormones are within normal limits in patients with Paget's disease. Food Contact with Pets O'Driscoll and Anderson 84 suggested that a canine virus, possibly canine distemper, might be the primary infective agent in the disease. Gordon et al.77 investigated the presence of canine distemper in PDB. They found that, while 41% of cases showed canine distemper virus RNA in osteoclasts, osteoblasts and osteocytes, none could be detected in controls. More recently, Gordon et al.87 suggested that a number of paramyxoviruses can accelerate the development of PDB, one of which is canine distemper virus. On the other hand, Ralston et al.78 could not find any evidence of canine distemper virus RNA in the pagetic tissue they examined. Barker and Detheridge's 88 case-control studies in the high prevalence area of Lancashire, England, and the low prevalence area of Sienna, Italy, found no significant differences between cases and controls in exposure to any household pets-dogs, cats or birds. Piga et al.'s Madrid study 83 and Siris et al.'s US study,89 similarly did not support O'Driscoll and Anderson's Manchester findings. Vitamin D
Treatment Biochemical markers of bone turnover, in particular, serum alkaline phosphatase and urinary hydroxyproline, are often used to monitor the effects of treatment.91 In fact, serum alkaline phosphatase is the most commonly used marker of bone metabolism, and urinary hydroxyproline is the best established marker of bone resorption.92 Pyrophosphate bone scans, however, are the most sensitive method of follow-up to monitor treatment. At present, only two drugs are approved for treatment in the US, calcitonin and etidronate.6 Calcitonin has been successfully used as treatment for PDB for years.9,93 Several types of calcitonin are used in the treatment of PDB, although salmon calcitonin is the most common.10 It causes rapid bone pain relief and a decrease in excessive blood flow and fever over the affected area.6 It can also alleviate some of the chronic neurological problems associated with the disease in some people.6 Salmon calcitonin can decrease the serum alkaline phosphatase and urinary hydroxyproline levels by about 50%.6 The effectiveness of calcitonin, however, is dependent on its continued use; discontinuation of the drug will reactivate PDB.9 Calcitonin treatment is also expensive.93-95 There are no serious side effects associated with this treatment, although minor ones are common, including nausea, diarrhea, and pain and redness at injection site.6 Bisphosphonates are known to be effective in decreasing pagetic activity.6,9,96 They are anti-resorptive agents that seem to be more effective in reducing serum alkaline phosphatase and urinary hydroxyproline levels than calcitonin.6 Etidronate is the only bisphosphonate that is currently available in the US.6 It seems to produce prolonged results as compared to calcitonin,97 although it has limitations that include interference with the mineralization of newly formed bone 98,99 and minor side effects such as mild gastrointestinal problems and nausea.6 Pamidronate is another bisphosphonate that has been investigated,100-106 and results indicate that it is more effective and more rapid in producing results than etidronate. Recently, Watts et al.,107 Wimalawansa and Gunasekera,16 Bombassei et al.108 and Grauer et al.109 evaluated the treatment of PDB with pamidronate and found it to be very effective, in general. Bombassei et al.108 reported that the drug was most effective when used in mild cases of PDB. Side effects of this treatment include fever, rigours and malaise.110 It has been concluded that further investigation is required to determine optimal dosages of pamidronate, as well as the risks and benefits of more extensive therapy.16,107,108 Pepersack et al.'s 28 examination of the efficacy of five different regimens of pamidronate treatment in 64 cases of PDB resulted in the conclusion that the best dose and duration of treatment is intravenous infusion of pamidronate, 20 mg per day for 10 days. This treatment was found to be optimum in this study since it was simple, effective and produced minimal side effects. Tiludronate is a new bisphosphonate that is currently under investigation. Some recent uncontrolled studies have shown that oral tiludronate induces anti-osteoclastic activity.111,112 Reginster et al 113 tested three different doses on 18 patients and found that all three dose groups showed sharp and rapid reductions in both serum alkaline phosphatase and urinary hydroxyproline levels. Minimal side effects were observed with low doses of tiludronate, but very high doses produced gastrointestinal intolerance in half the subjects. The study authors reported that high dosages of tiludronate in a short period of time would result in reduced bone turnover for several months; however, due to the gastrointestinal problems associated with a 1200 mg per day dosage, it is inappropriate for clinical practice. The use of other new bisphosphonates, such as clodronate and alendronate, in the treatment of PDB has been gaining interest. Clodronate has shown to be very effective. Delmas' long-term placebo-controlled study 114 found that daily oral doses of clodronate (1600 mg) reduced both pathological fractures and osteoclastic activity. Plosker and Goa 115 reported that intravenous infusions of short-term (300 mg/day for five days) or longer-term oral treatment (1600 mg/day for six months) can reduce bone pain and improve mobility in most PDB patients. They also found the effectiveness to last up to 12 months after discontinuation. Filipponi et al.116 reported no adverse side effects of clodronate on patients receiving intravenous infusions of 300 mg per day on five consecutive days for one year. They found that urinary hydroxyproline and serum alkaline phosphatase were significantly reduced in 70% of patients. There are ongoing trials assessing the clinical and biochemical benefits of alendronate. Adami et al.117 investigated the effects of 20 mg and 40 mg daily doses of alendronate on 20 PDB patients for six months. They found that, while the 40 mg daily dose was more effective than the 20 mg dose, it produced gastric and esophageal difficulties in some patients. On the other hand, the 20 mg daily dose was well tolerated, but it did not produce very effective results. In another study, Adami et al.118 found that urinary hydroxyproline had significantly decreased within a few days of treatment with a single intravenous infusion of 5 mg of alendronate in 10 patients. This effect lasted for the entire six-month follow-up period. Serum alkaline phosphatase levels, however, fell significantly after four to six weeks. Mithramycin has been used in some patients due to its effectiveness.6,10 The results of this treatment have been good when given in small intermittent doses. This treatment can lead to remission and is good in controlling pain. It can, however, produce simultaneous platelet, renal and hepatic toxicity, and thus, it is only used in patients that do not respond to other therapies.6 Bockman and Weinerman 6 have stated that the use of mithramycin will become more and more infrequent with the appearance of newer anti-resorptive agents. Gallium nitrate has been shown to be an effective inhibitor of osteoclastic resorption. Matkovic et al.119 found that accelerated bone turnover ceased and normal bone function was restored for prolonged periods of time with gallium treatment. The Hospital for Special Surgery 120 and Bockman and Bosco 121 tested gallium nitrate as a treatment for PDB and found it to be quite effective in decreasing bone resorption. This therapy is not currently used in the treatment of PDB, since only preliminary results are available.9 In general, calcitonin treatment is recommended when rapid results are desired or if the patient is elderly and has a co-existing disease such as osteoporosis.6 Etidronate is recommended as a treatment in chronic situations.6
Conclusion Since PDB rarely occurs before age 40 4 and incidence and prevalence trends increase with age, it is obvious that PDB is aging-related. Although familial clustering has been found 60 and there are unusual geographic and ethnic variations, no definite genetic link has been established.11 In the past, pet ownership has shown some potential as a risk factor for PDB; however, recent studies have not supported this theory. The slow-viral infection hypothesis has been controversial for years; however, it has gained strong support, particularly with regard to the role of interleukin-6. Current treatments for PDB seem to be successful, but other therapies continue to be explored. The near future promises the availability of more effective treatments that will both provide long-term results and prevent the usual morbidity.6
References 1. Paget J. On a form of chronic inflammation of bones (osteitis deformans). Med Chir Trans 1877;60:37-64. 2. Merkow RL. Metabolic bone disease and Paget's disease in the elderly. Part II: Paget's disease. Clin Rheum Dis 1986;12:70-96. 3. Resnick D, Niwayama G. Paget's disease. In: Niwayama G, Resnick D, eds. Diagnosis of bone and joint disorders. 2nd ed. Philadelphia: Saunders, 1987:2127-70. 4. Kaplan FS, Singer F. Paget's disease of bone: pathophysiology and diagnosis. Instr Course Lect 1993;42:417-24. 5. Siris ES, Canfield RE. Paget's disease of bone. In: Becker KL, ed. Principles and practice of endocrinology and metabolism. Philadelphia: JB Lippincott, 1990:504-12. 6. Bockman RS, Weinerman S. Medical treatment for Paget's disease of bone. Instr Course Lect 1993;42:425-33. 7. Meunier PJ. Bone histomorphometry and skeletal distribution of Paget's disease of bone. Semin Arthritis Rheum 1994;23:219-21. 8. Fallon MD, Schwamm H. Paget's disease of bone. An update on the pathogenesis, pathophysiology and treatment of osteitis deformans. Pathology Annual 1989;24(Pt 1):115-59. 9. Bone HG, Kleerekoper M. Clinical review 39: Paget's disease of bone. J Clin Endocrinol Metab 1992;75:1179-82. 10. Thomas DW, Shepherd J. Paget's disease of bone: current concepts in pathogenesis and treatment. J Oral Pathol Med 1994;23:12-16. 11. Merkow RL, Lane J. Paget's disease of bone. Orthop Clin North Am 1990;21:171-89. 12. Deftos LJ, Wolfert RL, Hill CS. Bone alkaline phosphatase in Paget's disease. Horm Metab Res 1991;23:559-61. 13. Smith R. Paget's disease of bone [editorial]. BMJ 1992;305:1379-80. 14. Ziegler R, Holz G, Rotzler B, Minne H. Paget's disease of bone in West Germany. Prevalence and distribution. Clin Orthop 1985;194:199-204. 15. Singer FR, Krane S. Paget's disease of bone. In: Avioli L, Krane S, eds. Metabolic bone disease. Philadelphia: WB Saunders, 1990:546-615. 16. Wimalawansa SJ, Gunasekera R. Pamidronate is effective for Paget's disease of bone refractory to conventional therapy. Calcif Tissue Int 1993;53:237-41. 17. Avramides A. Salmon and calcitonin treatment of Paget's disease of the bone. Clin Orth Rel Res 1977;127:78-85. 18. Yates AJ. Paget's disease of bone. Baillieres Clin Endocrinol Metab 1988;2:267-85. 19. Rosenthal MJ, Hartnell J, Kaiser F, et al. Paget's disease of bone in older patients: UCLA grand rounds [clinical conference]. J Am Geriatr Soc 1989;37:639-50. 20. Hamdy RC. Paget's disease of bone. Hosp Prac 1990;10:33-4. 21. Kaplan FS. Paget's disease of bone: orthopedic complications. Semin Arthritis Rheum 1994;23:250-2. 22. Packard FA, Steele J, Kirkbridge J. Osteitis deformans. Am J Med Sci 1901;122:252. 23. Jaffe HL. Paget's disease of bone. Arch Path 1933;15:83. 24. Kay HD, Levy-Simpson S, Riddoch G, et al. Osteitis deformans with roentgenographic section. Arch Int Med 1934;53:208. 25. Dickson DD, Camp J, Ghormley R. Osteitis deformans: Paget's disease of the bone. Radiol 1945;44:449-70. 26. Newman FW. Paget's disease: a statistical study of 82 cases. J Bone Joint Surg 1946;28:798. 27. Goldenberg RR. The skeleton in Paget's disease. Bull Hosp Joint Dis 1951;12:229. 28. Pepersack T, Karmali R, Gillet C, et al. Paget's disease of bone: five regimens of pamidronate treatment. Clin Rheumatol 1994;13:39-44. 29. Nagant deDeuxchaisnes B, Krane S. Paget's disease of bone: clinical and medical observations. Medicine (Baltimore) 1964;43:233. 30. Siris ES, Ottman R, Flaster E, Kelsey J. Familial aggregation of Paget's disease of bone. J Bone Miner Res 1991;6:495-500. 31. Barker DJ. The epidemiology of Paget's disease of bone. Br Med Bull 1984;40:396-400. 32. Detheridge FM, Guyer PB, Barker DJ. European distribution of Paget's disease of bone. Br Med J (Clin Res) 1982;285:1005-8. 33. Schmorl G. Zur Kenntnis der Ostitis fibrosa Verh. Dtsch Ges Pathol 1926;21:71. 34. Schmorl G. Zur Kenntnis der Ostitis deformans Paget. Dtsch Ges Pathol 1930;25:205. 35. Rosenkrantz JA, Wolf J, Kaicher J. Paget's disease (osteitis deformans). Review of one hundred eleven cases. Arch Inter Med 1952;90:610-33. 36. Summey TJ, Pressly C. Sarcoma complicating Paget's disease of bone. Ann Surg 1946;123:135. 37. Campbell E, Whitfield R. Osteogenic sarcoma of vertebrae secondary to Paget's disease: report of 3 cases with compression of spinal cord and cauda equina. N Y J Med 1943;43:931. 38. Bird CE. Sarcoma complicating Paget's disease of the bone: report of 9 cases, 5 with pathologic verification. Arch Surg 1927;14:1187. 39. Hurwitz SH. Osteitis deformans, Paget's disease: a report of 6 cases. Bull Johns Hopkins Hosp 1913;24:263. 40. Codman EA. Registry of bone sarcoma. Surg Gynec Obst 1926;42:381. 41. Coley BL, Sharp G. Paget's disease: a predisposing factor to osteogenic sarcoma. Arch Surg 1931;23:918. 42. Da Costa JC, Funk E, Bergeim O, et al. Osteitis deformans: a report of 5 cases with complete metabolism studies in 2 instances and a review of the literature. Pub Jefferson M Coll & Hosp 1915;6:1. 43. Abel W, Hellwegen F. Sarkom auf dem boden einer ostitis deformans Paget. Rontgenpraxix 1938;10:93. 44. O'Reilly TJ, Race J. Osteitis deformans. Q J Med 1932;1:471. 45. Schmorl G. Uber ostitis deformans Paget. Arch Pathol Anat 1932;283:694. 46. Dalinka MK, Aronchick J, Haddad J. Paget's disease. Orthop Clin N Am 1983;14:3-19. 47. Barker DJ, Chamberlain A, Guyer P, et al. Paget's disease of bone: the Lancashire focus. Br Med J 1980;280:1105-7. 48. Guyer PB, Chamberlain A. Paget's disease of bone in two American cities. Br Med J 1980;280:985. 49. Gardner MJ, Guyer P, Barker D. Paget's disease of bone among British migrants to Australia [letter]. Br Med J 1978;2:1436-7. 50. Barry HC. Paget's disease of bone. Edinburgh: E & S Livingston Pub, 1969. 51. Barker DJ, Clough P, Guyer P, Gardner M. 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Author References Judith Seidman-Ripley, Consultants Miettinen & Seidman, 1515,
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