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
In Canada, for all three time periods (1974-1978, 1979-1983, 1984-1988) tabulated, the average annual mortality rate was about 1 per million for men and somewhat less than 1 per million for women. There was a slight decrease over the 15 years for both men and women (Table 1).

Age
Regardless of time period, Canadian age-specific death rates for Paget's disease show a sharp increase with age, the steepest increase occurring between those aged 80-84 and those aged 85 and over. Across the three time periods studied, mortality rates for Paget's disease seem to be declining for all age groups except for those 85 and over (Table 1).

Sex
In Canada, mortality due to Paget's disease is somewhat higher for men than for women. This difference is consistent with the higher prevalence of the disease among males found in other countries. In general, the male-to-female ratio for Paget's disease for all ages combined as well as for Canada as a whole has been increasing across the three time periods (Table 1).

Geographic distribution
There are large differences in mortality due to Paget's disease among regions in Canada. Similarly, marked geographic variations in the prevalence of this disease have been reported in European and US studies, the highest rates found occurring in some parts of England.32 In Canada, the highest death rates are found for men in Quebec (Table 2). It is difficult to judge whether the differences are artifacts of death certificate reporting or whether the regional variations are indicative of a higher risk of the disease in particular areas of the country. The variations between provinces should be interpreted with caution due to the small numbers involved.

Morbidity

Incidence
Of all metabolic diseases, PDB has the second highest incidence, after osteoporosis.6,10 Early investigations by Schmorl 33,34 found the overall incidence of PDB in Caucasians to be 2.9%. Other early studies reported the hospital admissions for PDB to range from 1 in 170 to 1 in 15,000.22,35-45

Dalinka et al.46 and Fallon and Schwamm 8 have reported that the incidence of PDB increases with aging.

Prevalence
All of the recent surveys conducted have been radiologic hospital surveys of patients over 55 years of age. Barker et al.'s British prevalence survey 47 was a comprehensive study of 31 towns, with the highest prevalence localized in the Lancashire area of England (8.3%). The prevalence in Aberdeen, Northern Scotland, was found to be 2.3%, whereas the prevalence in Glasgow, Southern Scotland, was found to be 5.4%.

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.

Morbidity in Canada
Average annual hospital separation rates for PDB in Canada are consistent with findings from radiographic surveys in Europe, though somewhat lower than findings in Britain and New York. Morbidity based on hospital separations includes only hospitalized patients whose primary diagnosis on discharge is Paget's disease. As the disease is largely asymptomatic, its frequency is no doubt underestimated.5

Age
Hospital separation rates for Paget's disease in Canada show that morbidity increases dramatically with age for both men and women. Across the three time periods studied, there were 5 or fewer hospitalizations per 100,000 person-years for those persons in the 45-64 age category and more than 20 per 100,000 person-years for those over age 85. From 1974-1978 to 1984-1988, hospital separation rates decreased steadily for all age categories. In the 85+ age group, the rate for men dropped from 41 per 100,000 in 1974-1978 to 31 in 1984-1988, and the rate for women dropped from 25 per 100,000 in 1974-1978 to 21 in 1984-1988 (Table 4).

Sex
Differences between sexes may reflect differences in the time of diagnosis of Paget's disease or some selective differential in diagnoses between men and women, rather than actual differences in the frequency of its occurrence. Canadian rates are consistent with radiographic studies that have found sex differences, the higher prevalence generally found for men. In all three time periods, the separation rate is higher for men than women aged 45-64 whereas the reverse is true for the 65-69 age group, suggesting an earlier onset for men (Table 4).

Geographic distribution
Geographic variation in Canadian hospital separation rates is marked in each of the three time periods observed, but it is inconsistent from one time period to the next, possibly reflecting the instability of small numbers. In 1974-1978, the highest morbidity among males was found in Quebec; the lowest, in British Columbia and Manitoba. The highest morbidity among females was found in Ontario, and the lowest was in Prince Edward Island. In 1979-1983, the morbidity for males ranged from 1.13 in New Brunswick to 3.72 in Newfoundland; for females, it ranged from 1.15 in Manitoba to 2.44 in Newfoundland. In 1984-1988, morbidity rates ranged from lows of 0.58 and 0.56 for males and females, respectively, in Prince Edward Island to highs of 2.65 for males and 1.84 for females in Nova Scotia (Table 5).

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
Radiologic and autopsy prevalence studies show that Paget's disease rarely occurs before middle age,54 and its frequency of occurrence has been found to increase steadily with age. This is supported by the Canadian mortality and hospital morbidity data. However, there is no evidence in the literature to suggest an etiology of biologic aging of body tissues, nor is there a proposed mechanism for this process.

Genetics
PDB could possibly be an autosomal dominant disorder.55 Several studies have found some degree of familial aggregation (Table 6) as well as the occurrence of PDB in multiple generations.55 According to Fotino et al.56 and Kaplan and Singer,4 there may be a genetic link between a PDB locus and the human leukocyte antigen (HLA) complex on chromosome 6.

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
There is ample evidence to support the role of ethnic origin or race in the etiology of PDB. Overall, PDB has been found most frequently in the United Kingdom, the US, Australia and New Zealand.8 PDB has been observed to be common in Caucasians and rare among blacks and Orientals.8,61-63 Barry 50 has found few reported cases of PDB in the Middle East, Japan and China. He has also suggested that the disease rarely occurs in Jews. Bloom et al.64 reported the prevalence of PDB to be about 1% in Israeli Jews, a rate that is similar to those in southern European countries. Bloom et al.64 also reported no findings of PDB cases among Arabic subjects.

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).

Sex
Although most studies have reported men to be more commonly affected by PDB than women,5,6,31,51,52 two clinical studies did not. Polednak's US hospital discharge study 68 and Ziegler et al.'s West German study 14 of physician practitioners both found the prevalence to be similar for males and females. Ziegler's survey concluded that the presentation and diagnosis of Paget's disease was made about one decade earlier in men than in women.

Geographic Factors
Epidemiologic studies of Paget's disease, in particular, description of its remarkable variation in geographic distribution, have led to many etiologic hypotheses including ethnic, genetic, viral and other environmental causes. To date, there have been no explanations for the striking variations in the frequency of occurrence of the disease both between countries and within countries. Paget's disease is more frequently encountered in Great Britain, the United States and Australia,4,31,50 and it is rarely seen in Scandinavia and Ireland.4,31 Few, if any, cases have been reported in some Asian and African populations,4,50 though Guyer and Chamberlain 67 have found rates higher than expected in South Africa. Ziegler et al.14 found the disease to be rare in West Germany.

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
Rebel et al.70 and Mills and Singer 71 were the first to suggest the possible role of a viral infection in the etiology of PDB. Some evidence exists to support this hypothesis;72-75 however, the presence of viral particles is not always found in PDB patients.75,76

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
The pathological similarities between PDB and hyperparathyroidism have led investigators to believe that a disordered parathyroid gland may be responsible for the disease. Mild cases have been found in some PDB patients; however, its significance in the etiology of this disease remains unknown.8,11

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
A prevalence study in Madrid, Spain,83 reported an association between the consumption of bovine meat without sanitary control and an increased risk of Paget's disease (odds ratio = 2.18, 95% confidence interval = 1.05-4.49). The authors suggest that the patients with Paget's disease, among whom the average age was 70, were likely exposed to a childhood diet of habitual consumption of bovine meat from animals killed prior to a Spanish law that enforced obligatory sanitary conditions in animal slaughterhouses only in 1920. Their results suggest that Paget's disease is possibly acquired by ingestion of an infectious agent from contaminated tissues of bovine meat. They report that this finding supports the hypothesis of a slow-virus infection and long latency period in the genesis of Paget's disease. There is no other evidence to date that confirms such a hypothesis.

Contact with Pets
Several case-control studies have examined the relationship between household pets and Paget's disease. O'Driscoll and Anderson 84 and O'Driscoll et al.85 reported that dog ownership was more common among patients with Paget's disease. O'Driscoll and Anderson cited odds ratios varying from 4 to 8, depending on the age of the patient when the dog was acquired. Holdaway et al.86 reported a significant increase in risk of Paget's disease associated with dog ownership for those under age 60; however, there was no significant association found for those over 60.

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
A deficiency of vitamin D in childhood has been suggested as a possible etiologic factor, on the basis of a broad geographic association between the current distribution of Paget's disease and that of rickets at the beginning of the century and as an explanation for the apparent decline in the incidence of the disease.90 There has been no further evidence to support the association between Paget's disease, childhood vitamin D deprivation and rickets, since it was first suggested by Barker in the mid-1970s.

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

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Author References

Judith Seidman-Ripley, Consultants Miettinen & Seidman, 1515, rue Docteur Penfield, Montréal (Québec) H3G 2R8
Julie Huang, Aging-related Diseases Division (affiliated with the Seniors Directorate, Health Programs and Services Branch), Bureau of Chronic Disease Epidemiology, L aboratory Centre for Disease Control, Health Canada, Tunney's Pasture, Postal locator: 0602E2, Ottawa, Ontario K1A 0L2

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