Paget's Disease in an Archeological Population

Pagets Disease in an Archeological Population

J. ROGERS,1,* D.R. JEFFREY,2 and I. WATT2

ABSTRACT

The aim of this investigation was to study the prevalence and distribution of Pagets disease in an archeologicalpopulation. Pagets disease, first described over 100 years ago, is a well-recognized chronic disorder involvingabnormal bone turnover with established radiological features. Prevalence within modern populations variesboth within individual countries and between them. Paleopathological examples are uncommon and sporad-ically reported both from Europe and the Americas and from many periods of history. A large skeletalassemblage (2770 individuals) from Barton on Humber, UK, provided an opportunity to examine theprevalence of Pagets disease in one area of the northern England over the period 900-1850 AD. All bones wereexamined visually for evidence of Pagets disease of the bone (PDB) and all abnormal bones were examinedfurther by plain radiography. Fifteen cases of probable Pagets disease were found. The overall prevalence was2.1% in those aged >40 years. The prevalence before 1500 AD was 1.7% and post-1500 AD was 3.1%. Thedistribution of disease mirrored modern disease, with the lumbar spine, pelvis, and proximal femur being thecommonest sites. The prevalence of Pagets disease in the United Kingdom over the last 1000 years has beenassessed. Although there is a trend of increasing prevalence, this did not reach statistical significance. This islikely caused by the small sample size, but this is by far the greatest number of cases of PDB described in asingle skeletal assemblage to date. The distribution of lesions within the skeleton is unchanged. (J Bone MinerRes 2002;17:11271134)Key words: Great Britain, human, osteitis deformans/epidemiology, paleopathology, time factors

INTRODUCTION

Pagets disease of bone (PDB) or osteitis deformans, whichwas first described and named after Sir James Paget in 1877,is a chronic disease involving disruption of the mechanismof normal bone turnover. It can be characterized as a local-ized disorder of bone remodeling with an increase in oste-oclastic mediated bone resorption and a compensatory in-crease in new bone formation. This results in a disorganizedstructure of woven and lamellar bone and, consequently,bone enlargement. The nature of the architecture of Pageticbone predisposes it to fragility. Vascularity is increased

also. The majority of cases is asymptomatic and is discov-ered incidentally by radiography or raised serum alkalinephosphatase. Bone pain may occur and joint pain and stiff-ness may result if the involved bone is adjacent to a joint.Symptoms due to complications of the disease include bow-ing deformities, fractures, cranial nerve compression, highoutput heart failure, and the development of primary bonetumors such as osteosarcoma. Pagetic bone has a pathogno-monic tile-like or mosaic pattern at histological examina-tion. The radiological appearances of PDB are characteristicand depend on the stage of the disease. Typically, an initiallytic phase commences in the subarticular region of a boneand extends distally, classically with a flame-shaped leadingedge. In subsequent phases, the development of new boneresults in, first, a mixed and, finally, a sclerotic appearance.

The authors have no conflict of interest.*This author is now deceased.

1Department of Rheumatology, Bristol Royal Infirmary, Bristol, United Kingdom.2Department of Clinical Radiology, Bristol Royal Infirmary, Bristol, United Kingdom.

JOURNAL OF BONE AND MINERAL RESEARCHVolume 17, Number 6, 2002 2002 American Society for Bone and Mineral Research

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Eventually, the bone becomes expanded with a coarse tra-becular pattern and bowing of long bones is a commonfeature.

The etiology of PDB is unknown. Various theories havebeen suggested, although no definitive proof exists for anyetiological agent to date. Any proposed etiology must ac-count for the striking variation in geographical prevalenceof PDB both throughout the world and within individualcountries. Longitudinal studies of how PDB has changedover time both in prevalence and in skeletal distributionprovide valuable information that may help to confirm orrefute etiological theories. The earliest reported case of PDBin archeological human remains was in the 20s,(1) in whicha femur from a French Neolithic site displayed the charac-teristic radiological changes. Wells and Woodhouse(2) laterreported an Anglo-Saxon example from Durham. Medievalexamples have been reported in Norwich(3) and a 16thcentury case was reported in Wells.(4)

This study examines the prevalence of PDB in a largepopulation of skeletons from the South Humberside regionderiving from the 10th to the 19th centuries. A comparisonis made between the prevalence during the period 10001500 and that during 15001900. The etiology of PDB inview of the findings of this study is discussed.

MATERIALS AND METHODS

The skeletons available for study were derived from anexcavation at St. Peters Church, Barton on Humber, UK,during the late 1970s and early 1980s (Fig. 1). Nearly 3000skeletons were recovered, approximately one-third beingchildren. Inclusion criteria for entry into the study were thatthe skeleton should be aged over 35 years (by standard

anthropological criteria)(5) and with at least 40% of skeletalparts present. Six hundred sixty-seven skeletons fulfilled theentry criteria. All bones were examined visually for signs ofPDB. Signs included increased size, thickness, or vascular-ity. All suspected bones were examined further by plainradiography, as were all other bones of any affected skele-tons. Because all bones with an abnormal appearance orshape were radiographed, two further cases of PDB wererecognized from the assemblage. One case was discoveredduring the radiological examination of fractures and anothercase was found during a study of the appearance and prev-alence of hyperostosis frontalis interna.

RESULTS

Fifteen cases of PDB were diagnosed at Barton, UK.About 40% of the cases were suspected on visual examina-tion. The Pagets cases came from all phases of the site withseven cases from before 1500 and eight cases after 1500.The male/female ratio was 11:3, which is a little higher thanmodern populations(6) (Table 1).

By definition, all the skeletons identified with PDB atBarton had at least 40% of skeletal parts present and allwere assessed as being over 35 years old. The prevalencefor the population as a whole was 2.2%. With a varyingnumber of individuals fulfilling the selection criteria withinthe different phases, it was decided to assess the prevalencein larger numbers by studying greater time intervals. Thus,the population was divided into two groups: pre-1500 and

FIG. 1. Map of the United Kingdom showing location of Barton onHumber and Lancashire towns with high prevalence rates.

TABLE 1. PDB CASES IDENTIFIED AT BARTON ON HUMBER

SexAge

(years) Centuries Affected bonesM 3944 18th19th Distal tibiaF Adult 18th19th Pelvis, ulna (with fracture),

and distal femurM Adult 18th19th Skull base and calcaneumM 45 18th19th Proximal humerus and tibiaM 3944 16th17th Pelvis, lumbar vertebra, and

sacrumF 50 16th17th Humerus, femur, and proximal

tibiaM 45 16th17th Humerus and femurM 4550 14th17th Pelvis, femur, sacrum, and

lumbar vertebraM 45 14th17th Humerus and proximal phalanxM 45 14th15th Radius (with fracture)? Adult 14th15th Distal tibiaF 45 12th13th Thoracic and lumbar vertebrae,

sacrum, and pelvisM 45 12th13th Proximal phalanx, pelvis, and

proximal humerusM 45 10th13th Femur and distal tibiaM 3539 10th13th Pelvis, lumbar vertebra, and

sacrum

1128 ROGERS ET AL.

post-1500. Two individuals were in phases straddling thedivideone was placed in the pre- and the other in thepost-1500 group. The denominator population likewise wasdivided equally. There were seven cases of PDB in the 409skeletons fulfilling the selection criteria in the pre-1500group, a prevalence of 1.7%. In the post-1500 group, therewere eight cases of PDB in 258 skeletons, a prevalence of3.1% (Table 2). Examples of Pagetic bones from severalskeletons are shown, together with corresponding plain ra-diographs (Figs. 2-5)

DISCUSSION

This study examines the prevalence of PDB in this part ofthe United Kingdom over the past 1000 years. The differ-ence in prevalence between the pre-1500 and post-1500populations shows a clear trend of increasing prevalencealthough not statistically significant by the 2 test. The smallnumber of cases of PDB found in the assemblage makesstatistical significance difficult to achieve. However, this isby far the greatest number of cases of PDB described in asingle skeletal assemblage to date. Therefore, the trend ofincreasing prevalence is an important finding, while notreaching levels of statistical significance.

A possible source of bias in these results reflects thedifficulty of accurately establishing those skeletons 45years of age at death. It is possible that there were moreelderly individuals in the post-1500 population group be-cause of increasing life expectancy. This may partly explainthe higher prevalence in the later population. However,there is no means of testing this hypothesis with currentlyavailable anthropological aging methods.

There was a significant amount of disarticulated skeletalmaterial recovered around the graves during the excavation.These bones were not included in the study because they didnot fulfill the entry criteria of at least 40% of skeletal partsbeing present. However, some of this material was exam-ined also and a definite identification of at least threePagetic bones was made. Two of these were sacra and onewas a femoral shaft. They displayed sufficient abnormalityon visual inspection to be selected for radiographic exami-nation. Very few of the disarticulated bones were so exam-ined. Thus, further unidentified cases of PDB may existamong this material. One of the sacra, from context 83, wasexamined microscopically, confirming the diagnosis.(4) Thedisarticulated bones were derived from locations suffi-ciently different from each other and the Pagetic skeletons

discussed previously to make it unlikely that they wereassociated.

The distribution of affected parts does not seem to differfrom that recognized today. The pelvis, sacrum, and lumbarvertebrae are the most frequently involved bones followed

TABLE 2. PREVALENCE OF PDB AT BARTON ON HUMBER

Number ofpopulation

Pagetscases Prevalence

Total populationobserved

667 15 2.2%

pre-1500 409 7 1.7%post-1500 258 8 3.1%

FIG. 2. (A) Distal femur of adult female dating from 18th19thcentury showing features of PDB (bone expansion and coarse trabec-ulation). (B) Corresponding plain radiograph of distal femur of adultfemale dating from the 18th19th century showing features of PDB(bone expansion and coarse trabeculation).

1129PAGETS DISEASE IN AN ARCHEOLOGICAL POPULATION

by the proximal femur. This pattern of anatomical distribu-tion is very similar to that described in large studies carriedout during the last 100 years(7,8) (Table 3). It is interestingthat 2 out of the 15 cases showed PDB in the phalanges.(7)According to a large study of 889 patients with PDB, thephalanges are involved in 2% of cases. This may relate tothe fact that the hand constitutes only 2% of the total

skeletal volume. However, the true frequency of phalangealinvolvement may be underestimated in the literature. Be-cause the majority of patients with PDB are asymptomatic,the diagnosis usually is an incidental finding and the pha-langes are less commonly imaged than the axial skeleton. Inaddition, the features may be subtle and more difficult todetect than in large bones.

FIG. 3. (A) Lumbar vertebrae of adult male dating from the 10th13th century showing features of PDB (bone expansion and coarsetrabeculation). (B) Proximal femora of the same adult male dating from the 10th13th century showing features of PDB on the right (boneexpansion and coarse trabeculation). (C) Corresponding plain radiograph of lumbar vertebrae of adult male dating from the 10th13th centuryshowing features of PDB (cortical thickening and coarse trabeculation).

1130 ROGERS ET AL.

The etiology of PDB is unknown. The main areas ofresearch have concentrated on the relative contribution ofgenetic and environmental factors. It has been shown that

12% of affected patients have a first-degree relative withPDB,(9) supporting a genetic basis for the etiology. How-ever, this does not exclude environmental factors. Several

FIG. 4. (A) Phalanx of adultmale dating from the 12th13thcentury showing features of PDB(bone expansion and trabecularcoarsening). (B) Correspondingplain radiograph of phalanx ofadult male dating from the 12th13th century showing features ofPDB (cortical thickening andcoarse trabeculation). (C) Normalphalanx of same adult male forcomparison. (D) Correspondingplain radiograph of normal pha-lanx of same adult male forcomparison.


studies have established linkage to a marker on chromo-some 18(10) and linkage to human leukocyte antigen (HLA)D antigens.(11) It has been suggested that there are twodistinct types of PDB, familial and sporadic, which can bedistinguished on their clinical features and may have dif-ferent etiologies.(9,12)

Numerous possible environmental agents may be in-volved in the etiology of PDB. Low levels of calcium intakein childhood as measured by milk consumption have beenshown to be associated with an increased risk of developingPDB.(9) An infectious agent is an attractive possibility that

may partly explain localized clusters of high prevalence.Evidence in favor of a viral etiology is conflicting. Viral-like inclusion bodies containing paramyxovirus antigenshave been identified by electron microscopy in Pageticosteoclasts.(13,14) However, these inclusion bodies are notonly found in Pagetic osteoclasts, but also in osteoclastsfrom diseases known not to have a viral origin such aspyknodysostosis(15) and oxalosis.(16) Therefore, their dis-covery in Pagetic osteoclasts may be purely incidental.Immunohistochemical studies have shown positive stainingfor a variety of viral antigens in Pagetic bone, including themeasles virus.(17) In situ hybridization studies using reverse-transcription polymerase chain reaction have shown bothmeasles and canine distemper virus in tissue from patientswith PDB.(18) However, other studies have failed to repli-cate these findings.(19) Serological tests do not show in-creased titers of antibodies to canine distemper or measlesvirus in patients with PDB.(20,21) Circumstantial evidence infavor of the canine distemper virus as an etiological agent inPDB has been proposed in studies showing an associationbetween past dog ownership and PDB(22,23) and betweenownership of dogs unvaccinated for canine distemper andPDB.(24) However, other studies have failed to replicatethese findings.(2527) Thus, the evidence for a viral etiologyin PDB is far from conclusive.

Therefore, to date, no consensus exists on genetic versusenvironmental etiological factors in PDB. Studies of bothgeographical variation and time trends in prevalence pro-vide valuable data that may help distinguish between ge-netic and environmental influences.

One of the earliest accurate studies of geographic varia-tion in prevalence of PDB was carried out in 14 towns in theUnited Kingdom in 1977.(28) They found overall prevalencerates of 5.4% in people aged55 years with a focus of highprevalence in three tightly clustered Lancashire towns, Pres-ton, Bolton, and Blackburn (Fig. 1). A follow-up study in1980(29) confirmed this high prevalence in three othernearby towns in the Lancashire region. Prevalence ratesthroughout the United Kingdom varied widely from 8.3% inLancaster to 2.3% in Aberdeen, but no obvious reason wasidentified for this. A further study of prevalence in 13 townsthroughout Europe(30) showed wide variation in prevalence.No country was found to have prevalence as high as that inthe United Kingdom. Highest rates were found in Frenchtowns (2.72.0%), intermediate rates in German towns(1.11.3%), and lowest rates in Scandinavian towns (0.40.5%). Other studies have shown low prevalence rates ofPDB in Ireland (0.71.7%)(31) and Norway.(32) Reports ofprevalence of PDB in Africa suggest that the disease isuncommon,(33) although there may be localized areas ofhigher prevalence.(34) It is possible that the prevalence ofPDB in Africa is underestimated because of the loweraverage age of patients in hospitals in comparison to thosein Europe and the relatively poorer access to radiologicalfacilities. However, studies of prevalence of PDB in Amer-ican blacks have shown that the rates are not significantlydifferent from the white population.(35) Similar findingshave been reported among the south African black popula-tion.(36) This lends support to an environmental etiology.

FIG. 5. (A) Os calcis of adult male dating from the 18th19th centuryshowing features of PDB (trabecular coarsening). (B) Correspondingplain radiograph of os calcis of adult male dating from the 18th19thcentury showing features of PDB (cortical thickening and coarsetrabeculation).

TABLE 3. ANATOMICAL DISTRIBUTION OF PDB

Area affectedPercentage in

Barton skeletonsPercentage

today

Pelvis and sacrum 38% 58%Lumbar spine 36% 37%Femur 30% 32%Tibia 21% 20%

1132 ROGERS ET AL.

Few studies have focused on possible time trends in theprevalence of PDB. A follow-up of the 1977 UK prevalencestudy found a dramatic decline in the prevalence of PDB in10 British towns between 1977 and 1999.(37) Indirect mea-sures of prevalence of PDB have been carried out by ex-amination of rates of mortality attributed to Pagets and toosteosarcoma. These figures suggest a decline in prevalenceof PDB between 1870 and 1915.(38) The severity of PDBmay be declining in New Zealand.(39) Patients are signifi-cantly older at diagnosis and have less severe disease asmeasured by serum alkaline phosphatase.

However, it is tempting to suggest that changes in prev-alence of PDB that have occurred during the last millen-nium may be attributed to the spread of an environmentalagent through a genetically susceptible population. Therapidity of the recent decline in prevalence in the UnitedKingdom particularly favors an environmental rather thangenetic etiology.

Therefore, current evidence points to a combination of agenetic predisposition and a superimposed environmentalfactor(s) in the etiology of PDB. This study supports thathypothesis. However, it is difficult to compare the preva-lence rates of this study with those in the literature. Many ofthe quoted studies assess prevalence in patients over 55years of age, whereas this study measures prevalence in theover 35-year age group. This is because of the difficulty inaccurately aging skeletons of an older age. It is tempting topropose that an environmental factor, most prevalent in theUnited Kingdom, was responsible for gradual changes in theprevalence of PDB over the last millennium. However,during the last 50 years a steep decline in prevalence of thedisease has occurred in the United Kingdom, perhaps be-cause of reduced exposure to or improved treatment of anenvironmental agent.

ACKNOWLEDGMENTSThis study was funded by the Arthritis and Research

Campaign and the English Heritage.

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Address reprint requests to:D.R. Jeffrey, F.R.C.R.

Department of Clinical RadiologyBristol Royal InfirmaryBristol BS2 8HW, UK

Received in original form June 14, 2001; in revised form January7, 2002; accepted January 16, 2002.

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Paget's Disease in an Archeological Population