paget's genetic studypaget's disease, e.g. deafness. were thirty-two patients who had...

Postgraduate Medical Journal (January 1977) 53, 33-39.

Paget's disease of bone-a clinical and genetic studyH.-J. B. GALBRAITH ENID C. EVANS

M.D., F.R.C.P. O.B.E., M.R.C.S., L.R.C.P.

J. LACEYM.D., F.R.C.P., F.R.C.Path.

Chelmsford Hospitals, Essex

SummaryAn unselected series of 285 patients with Paget'sdisease of bone has been studied, of whom 54% weremale and 46% female. The youngest was aged 25years at diagnosis and the oldest 95. Of the patients109 (38-2%) had never suffered serious symptoms.These diagnosed cases certainly represent only asmall proportion, perhaps 10-15%, of all those withPaget's disease in the community from which theycame. Few of the undiagnosed cases are likely to besuffering from serious symptoms or complications soit is apparent that the majority (probably over 80 or90%) of those with the pathological state are relativelyuntroubled by their disease.The most common complication (8.8%) was patho-

logical fracture. The fracture involved the shaft of thefemur in 62%, occurring in this section of the bonealmost seven times more frequently in the patients withPaget's disease than in the general population.

Because of the large number of undiagnosed casesin the community, the true incidence of pathologicalfracture and of sarcoma of bone in all patients withPaget's disease is probably only 1% and 0-1% re-spectively.

Simultaneous estimates of the serum alkalinephosphatase and ESR were made in 128 ofthe patients.It was shown that the ESR is valueless as a measure ofactivity or extent of the disease.

In many patients the level of the serum alkalinephosphatase changed very little over periods of severalyears.A history of the disease in one or more close relatives

was found in three families, a lower incidence than wasexpected from previously recorded studies. The ABOblood groups were determined in 215 of the patients;50% were of group A compared with 46% in a controlgroup. The difference in distribution of blood groupsin the two series of subjects is small and well withinchance limits. The secretor status of 138 patients wasinvestigated; 77% were secretors. This is similar tothe DroDortion in control series.

There is evidence to suggest that the degree ofseverity of Paget's disease does not vary, once it hasdeveloped in any particular individual, and that themore severe and extensive forms may have a strongergenetic basis.

OVER a period of 8 years an attempt has been madeto identify as many as possible of the patientsattending this District General Hospital Group inwhom Paget's disease of bone (osteitis deformans)was diagnosed. An analysis is now reported ofvarious aspects of these cases and it is shown thatthis disease is usually not ofmuch clinical significancebut that it may be possible to identify a group ofpatients with more extensive, and more active,symptomatic disease.

Identification of patientsThe patients studied were, for the most part, seen

as out-patients or in-patients in an acute medical anda geriatric unit of a district general hospital group.The others were studied after referral from surgical,orthopaedic and other specialist units in the samegroup of hospitals, sometimes following the demon-stration of the disease on X-rays taken for someother purpose.To ensure that the identification of the patients

with Paget's disease who were attending the hospitalswas as full as possible, the radiologists helped tomaintain a scrutiny of all X-rays taken during thesurvey period. A cross-check was also made usingthe in-patient diagnostic register. It is believed thatonly a small number of diagnosed cases have escapedinclusion and that these would, in the main, havebeen those without prominent clinical features. Inevery case the diagnosis of Paget's disease was basedon at least one of the following criteria:

(1) A firm radiological diagnosis supported by aserum alkaline phosphatase level of 15 King Arm-strong units (KAu) or more, in the absence of anyalternative explanation for the latter.

(2) Typical radiological changes in the opinion ofCorrespondence: Dr H.-J. B. Galbraith, Chelmsford &

Essex Hospital, London Road, Chelmsford, Essex CM2 OQH.

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34 H.-J. B. Galbraith, Enid C. Evans and J. Lacey

two consultant radiologists who viewed the filmsindependently.

(3) Typical clinical or radiological appearancesconfirmed by post-mortem examination.

(4) A combination of gross clinical and classicalradiological signs.

Clinical featuresA total of 285 patients were studied, of whom 154

(54°4) were male and 131 (46%Y) were female.Attention had been drawn to the possible diagnosisof Paget's disease by clinical features, such as pain,deformity or pathological fracture, in 152 (53 3%.)and by hitherto unsuspected bony abnormalities onX-rays carried out for other reasons in 127 patients(44-6%). The diagnosis was made in the remainingsix patients (2-1%) following the discovery of araised serum alkaline phosphatase level for whichthere was no other obvious explanation.The age at which the diagnosis was first made on

the basis of clinical or radiological examinationranged from 25 to 95 years. The distribution of theages on initial diagnosis, which was similar in eachsex, is illustrated in Table 1. In some patients withprominent symptoms or deformity the age at whichthe patient first became aware of these is known.Three patients noticed the first manifestation of theirdiseases before the age of 40: at 25, 32 and 39 yearsrespectively.

TABLE 1. Distribution of ages at initial diagnosis of 285patients with Paget's disease of bone

Age Male Female Total(years) Number (%) Number (%) Number (%°)

<40 2 (1 2) 1 (0 7) 3 (1-0)40-49 5 (3 2) 7 (5 3) 12 (4-2)50-59 17(11-0) 11 (8 3) 28 (9 8)60-69 39(25 3) 28(21-3) 67(23-5)70-79 40(25 9) 37(28 2) 77(27 0)80-89 44(28 6) 41(31-3) 85(29 8)90-99 7 (4 5) 6 (4 6) 13 (4 6)Totals 154 (100) 131 (100) 285 (100)

The case records of each patient were studied todiscover whether he or she had at any time sufferedsymptoms which could have been related to the bonedisease (Table 2). Pain related to bones involved inthe disease occurred in eighty-four. Of the seventeenwho presented with a pathological fracture, elevenappeared to have had no deformity or pain due to thePaget's disease beforehand. A further thirty-eightpatients had described discomforts apparentlyarising from degenerative changes affecting jointsadjacent to bones affected by Paget's disease, but notpain in the affected bones themselves. Obviousskeletal deformity without any other prominent localsymptoms was present in twenty-two patients. There

TABLE 2. Incidence of symptoms of the disease in 285patients with Paget's disease of bone

Percentageof all

Symptoms Male Female Total patients

Local pain* 41 43 84 29-5Related arthritic pains

only 15 23 38 13 3Obvious deformity alone 13 9 22 7-7Indeterminatet 13 19 32 11 3None 72 37 109 38-2

* Including seventeen with pathological fractures.t Symptoms possibly but not certainly attributable to

Paget's disease, e.g. deafness.

were thirty-two patients who had symptoms whichwere possibly but not definitely due to the Paget'sdisease. These symptoms included deafness, wide-spread discomforts in sufferers from polyarthritis,and impaired mobility. It appeared that 109 (38 2%)of the 285 patients had never suffered symptomsrelated to their Paget's disease which were seriousenough to be recorded in their notes and were alsofree of clinical deformity (Table 3).

TABLE 3. Distribution of ages of patients with apparentlysymptomless Paget's disease

Symptomless patientsAge All patients(years) Total number Number Percentage of

age group

<50 3 0 040-49 12 2 16 650-59 28 8 28*660-69 67 27 40 370-79 77 35 45*480-89 85 32 37-690-99 13 5 38*5

ComplicationsOne patient whose widespread Paget's disease had

apparently been previously symptomless presentedwith bone sarcoma and another such patient pre-sented with high output cardiac failure. The latterpatient, a woman of 78, was the only subject in thewhole series affected by this complication, for whichno other cause was apparent. Deafness of somedegree is a very common occurrence in people of theelderly age groups particularly affected by Paget'sdisease and it is not possible to say how many haddeveloped this disability as a result of bone disease.Involvement of the bone of the skull was recognizedin thirty (10-5%y) of the patients, eight of whom werenoted to be deaf.

Twenty-five patients (8 8%) suffered from patho-logical fractures of bones affected by Paget's disease.Incomplete fissure fractures have not been included.Four of these patients (all women) had pathological

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Paget's disease of bone 35

fractures on two separate occasions so that there wasa total of twenty-nine fractures (Table 4).

TABLE 4. Frequency and distribution of the pathologicalfractures occurring in 285 patients with Paget's disease of

bone

Site Total Male Female

All sites 29 9 20Femur 23Neck 5 0 5Shaft 18 6 12

Pelvis 3 2 1Tibia 3 1 2

The twenty-nine fractures occurred in twenty-five patients,four women having had repeated fractures.

As in the larger series of eighty-four cases ofpathological fracture in Paget's disease reported byGrundy (1970), the femur was the bone mostcommonly affected. The shaft or the subtrochantericregion was the site involved in 78% of the femoralfractures both in the series of Grundy (1970) and inthis one. Similarly in the ninety cases of femoralfractures in Paget's disease described by Barry (1969)the shaft or subtrochanteric area was affected inseventy-one (79%4). In contrast, in an unselectedpopulation over the age of 35, fractures of the shaftformed only 11 5y/ of all femoral fractures (Know-elden, Buhr and Dunbar, 1964).

In seventeen patients of the present study it was thepathological fracture which led to the diagnosis ofPaget's disease. The risk of fracture appeared greaterin the women but this increased risk may in part beaccounted for by the known predilection of womento fractures of the neck of the femur. Excludingfractures of this area there were eleven female andnine male patients who suffered pathological frac-tures.

In no instance was the fracture followed by asarcoma. Recent writers (Barry, 1969; McKennaet al., 1964) have discounted earlier suggestions that apathological fracture in Paget's disease predisposedto the development of sarcoma at the same site and,as Price and Goldie (1969) have said, 'fracture onlyserves to focus attention upon a bone alreadytumorous'.Sarcoma occurred in only two patients in this

series (0-7%). A man aged 77 presented with sar-comatous change in many bones. A woman aged 48with leontiasis ossea due to Paget's disease developedpain, ocular disturbance, and eventually localswelling in the temporo-mandibular region, due to asarcoma, 15 years after the first appearance of facialdeformity.One patient, a woman aged 81, suffered from

multiple myeloma. It has been suggested in the pastthat the association between Paget's disease and

myelomatosis is a significant one (Reich andBrodsky, 1948). The prevalence of both these con-ditions is much greater than was once thought andtheir coincidence is most likely to be due to chance.Patients in whom the diagnosis of either conditionhas been made are likely to have X-rays taken ofseveral bones. If, therefore, the second condition isalso present, it will probably be discovered.

Associated conditionsNo examples were seen of other diseases which

have been described in association with Paget'sdisease such as Hashimoto's disease (Luxton, 1957),malabsorption (Somayaji, 1968) and neurologicalstates. Details of the results of examination of thefundi by an ophthalmologist or another clinician hadbeen recorded in 133 patients of this series but therewere no cases of retinal angioid streaks despite therelationship between the two conditions reported byBatten (1931) and others. Similarly, no case ofpseudoxanthoma elasticum, which may provide thelink between Paget's disease and angioid streaks, wasidentified.

Sedimentation rate and serum alkaline phosphataseIt has been said that the erythrocyte sedimentation

rate (ESR) is usually raised in active Paget's disease(Hartung, 1955; Harris and Krane, 1968; AnyQuestions, 1958). Grainger and Laws (1957) foundthat the average Westergren ESR was significantlyhigher in a group of patients with active Paget'sdisease than in a group of quiescent cases. Since thedemonstration by Kay (1929) of an associationbetween a raised plasma phosphatase and Paget'sdisease of bone, general experience has shown thatthe serum alkaline phosphatase level is a reasonablyreliable measure of the extent and of the activity ofthe bone changes in Paget's disease (de Deuxchaisnesand Krane, 1964).

Simultaneous estimations, often on more than oneoccasion separated by months or years, of the serumalkaline phosphatase by the King-Armstrong tech-nique and of the ESR by the method of Westergrenwere carried out in 128 of the patients. Patients withother obvious disease of a type likely to influence thesedimentation rate were excluded. ESR readings of10 mm or less were found simultaneously with serumalkaline phosphatase levels of over 14 KAu (range15-103) in thirty-one patients. In those patients inwhom repeated simultaneous estimates were carriedout, no consistent relationship between the levels ofalkaline phosphatase and ESR could be recognized.Among patients whose disease involved three bonesor more there were nine in whom the ESR neverexceeded 10 mm. Figure 1 shows that there is no clearcorrelation between the serum alkaline phosphataseand the Westergren ESR.

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80 -

60

--aE40 - ..

* 4::20 -. .

.,^"..* * I .

0 20 40 60 80 100 120 140 160Serum alkaline phosphatase (KA units)

FIG. 1. Simultaneous measurements of serum alkalinephosphatase and ESR in 128 patients with Paget's disease.

It is clear, therefore, that the ESR is valueless as anindication of the activity or extent of Paget's diseaseof bone either in the group or in the individual case.

Serial serum alkaline phosphatase studiesRecords of serial estimations of the serum alkaline

phosphatase, extending over a period of at least 1year, were available for fifty-one patients. A clearpattern emerged of a group of patients (a smallmajority of the total) who had slightly, or moderately,raised phosphatase levels which varied little over theperiod of study. Figure 2a shows the individual serialphosphatase levels of all patients whose first recordedlevel was below 36 KAu. In only four of these thirty-six patients were values higher than 36 KAu everrecorded subsequently. Figure 2b refers to the fifteenpatients whose initial phosphatase values were over36 KAu. Their serial figures were much more erratic,many never showed a fall below their initial levels,and only a few showed a consistent fall. Apart fromone patient (who did not have a radiological surveyof the skeleton), all of these fifteen patients with highphosphatase levels had clinically manifest, multi-focal, and usually very extensive, disease of the bones.Pathological fractures were more than twice ascommon among the patients in this second group(five of fifteen) as in the first (five of thirty-six). Ifnot the initial, but all of the recorded phosphataselevels of each of the fifty-one patients are studied, theclearest separation into two groups of subjects occursat a level of 28 and 29 KAu. Twenty-seven (53%4) hadnever shown a serum alkaline phosphatase level ofover 28 KAu and ten (20%) had never shown a levelbelow 29 KAu.

Familial occurrenceThe causes of Paget's disease of bone (osteitis

deformans) are unknown. It is sometimes familialand has been reported in four generations (Dickson,Camp and Ghormley, 1945), in five siblings (Gal-braith, 1954), and in identical twins (Martin, 1947).Da Costa et al. (1915), reviewing all cases of Paget's

60-50:/40430

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. }%iA4{*;*- }200-:(b) : .i10190

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II150

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>JtJFIG. 2. Serial estimation of serum alkaline phosphataseover periods of 1 year or more in fifty-one patients withPaget's disease. (a) Patients with initial levels below36 KA units (b) patients with initial levels above 36 KAunits.

disease reported up to 1915, found that a familyhistory had been noticed in 7/. More recently, inseries recorded by Rosenkrantz, Wolf and Kaicher(1952) and by Galbraith (1954) a family history of thedisease was obtained in 64% and 7 7% respectivelyThe records of all 285 patients in the present study

were carefully scrutinized for any history of thedisease in close relatives and approximately 50% ofthe patients were also cross questioned on this matterThree examples of families with more than one firstdegree relative definitely affected by the disease werefound. These instances were of a brother and sister,two brothers, and a brother, sister and the latter's sonrespectively.

This frequency of familial occurrence of just over1% is at first surprising in view of the figure of

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approximately 7%4 mentioned earlier. One reasonmay be that series which include several apparentinstances of familial predisposition are more likely tobe reported. Two other possible factors are that insome studies the degree of relationship betweenaffected subjects is not defined, and that the numeri-cal size of the families being examined may varywidely.The explanation could alternatively lie in the type

of case included in the present study. Because thisstudy has been concerned with a relatively unselectedgroup this series has a very high proportion of symp-tomless and elderly patients, very many ofwhom havebeen diagnosed from X-rays carried out for otherpurposes. Most previous studies, on the other hand,were made at times when radiology was not so widelyemployed, and in places where comparatively few ofthe elderly were seen. Such studies, therefore, in-cluded a higher proportion of those with grossdeformities, pain and other complications.

All of the six patients with familial Paget's diseaseof bone ofwhom the details are to hand had sympto-matic and very widespread Paget's disease, three ofthem having serum alkaline phosphatase levels> 29 KAu (30, 69 and 132 KAu). It could be that theform of Paget's disease in which the genetic pre-disposition to the condition is strong tends to bemore severe and more extensive, and that symptom-less cases in which the disease is limited to one or twobones may have only a weak hereditary background.The possible genetic basis of the disease has been

investigated by analysing the distributions in patientswith osteitis deformans of the marker genes of ABOblood grouping and secretor status. Selection of thepatients for study of their blood groups and secretorstatus depended solely upon their availability for thenecessary blood and saliva tests.

ABO blood groupsABO blood grouping was carried out by the

standard tube method in 215 of the patients. Of these114 (53%°) were male and 101 (47°/) were female.The distribution ofABO blood groups found in these215 patients is compared in Table 5 with the distri-bution in the local population. The control figuresare based upon the blood group of voluntary blood

TABLE 5. Distribution ofABO blood groups in patients withPaget's disease of bone compared with a control group

Blood group Paget's Controls

0 94 43 *7% 533 43*1%A 107 49*8% 568 45*9%B 12 5*6% 98 799%AB 2 09%0 37 3 0%

Total number 215 1236

(X2 (3 d.f.) 4-819, P > 0-1).

donors (totalling 1236) in the five local postal areasfrom which the majority of the patients in the serieswere drawn. These data have been extracted from thecomprehensive national survey carried out during theyears 1952-1969 and reported by Kopec (1970).While there is an excess of blood group A among

the present patients with Paget's disease of bonecompared with controls from the same area, thisdifference is small and is not statistically significant.Murray (1961) studying 633 persons over 64 years ofage in Newcastle found that, while there was fairlyclose agreement between the distribution of bloodgroups in these elderly subjects as a whole and incontrols, there was a significant increase in group Asubjects in the apparently healthy elderly males. Thismight provide one explanation for the apparentexcess of group A subjects in the present series, as53%4 of the patients were male and over 33%4 of thetotal number were free of symptoms which couldhave been related to the bone disorder. It seems veryunlikely that, even with numerically much largerseries, an association between Paget's disease ofbone and group A will be established. Each of theseven patients examined who has a first degreerelative also affected by the disease was of bloodgroup A and the present studies do not exclude alinkage between the gene responsible for the ABOblood group and a gene bearing a predisposition toPaget's disease. However this also seems unlikely.

Secretor statusSaliva for examination for secretor capacity was

boiled in a water bath at once for 15 min, cooled andthen transferred to plastic tubes which were stop-pered and stored at - 200C until testing. Secretorstatus was determined by the isohaemagglutinationinhibition technique, using anti-H substance preparedfrom the seeds of Ulex europaeus (Race and Sanger,1968). The secretor status was investigated in 138cases (Table 6). The control data are those of Doll,Drane and Newell (1961), derived from a studyof 610 inhabitants of London, to which the area ofChelmsford is closely adjacent. Control series fromvarious other centres show similar figures.

TABLE 6. Distribution of secretor status inpatients with Paget's disease of bone compared

with a control group

Paget's Controls

Total 138 610Secretor 106 (77%) 481 (79%)Non Secretor 32 129

(X2 (1 d.f.) 0-276, P > 08).

The ability to secrete ABO blood group substancesin the mucous secretions is inherited as a Mendeliandominant. A higher incidence of non-secretors than

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in the normal population has been found in alcoholics(Camps and Dodd, 1967) and in cases of duodenalulcer (Clarke et al., 1956), rheumatic fever (GlynnGlynn and Holborow, 1959) and breast carcinoma(Bremner, 1961). This possible association betweenpossession of the recessive (non-secretor) gene and aparticular disease has been adduced as evidencefavouring a genetic factor in the aetiology of thedisease. The present studies provide no such evi-dence in the case of Paget's disease of bone, theincidence of secretor ability in 138 patients with thedisease (77°/) not being statistically different fromthat in the normal population (79%4).

DiscussionThis series of patients with Paget's disease of bone

differs somewhat from most similar series previouslyreported. Firstly, it probably includes more patientswhose disease only came to light as a consequence ofthe investigation of other conditions. Secondly, theseries is drawn from a group of hospitals providingall services for the whole of a community. Forgeographical, administrative and traditional reasons,the great majority of patients living in this (Chelms-ford) area who require specialist care or radiologicalor laboratory investigation are seen in the hospitalsof this group. Thirdly, with the increasing concern ofthe medical services for the elderly members of thecommunity, a larger proportion of patients in thelater age groups are investigated nowadays indistrict general hospitals than has been the practicein earlier years and in more specialized hospitalcentres.The population served by this group of hospitals

during the period of the investigation was approxi-mately 200,000 and the distribution of ages withinthis population is known. Using this distributionpattern and the figures of prevalence of the diseasesuggested by Collins (1956) and Schmorl (1932) it ispossible to calculate that there are about 2,900people with Paget's disease in the area. This studytherefore concerns only about 10%° of these. How-ever, it is likely, for the reasons which have beenexplained, that most patients in this area who wereseverely troubled by symptoms, or who sufferedfrom the complications of the disease, were examinedin these hospitals and were thus included in thepresent series. The true incidence of symptoms andcomplications in those with radiological or patho-logical evidence of Paget's disease is therefore verymuch lower than is usually stated. Pathologicalfractures thus perhaps affect only 1 00%, and sar-coma of bone only 0I1%, of patients with the disease.

Similarly, the true frequency of virtually symptom-less Paget's disease must be very much greater thanthe 38% which the present authors' figures at firstsuggest. Furthermore, the majority of the as yet

undiagnosed cases are probably among the oldermembers of the population (because even now theyare least likely to be investigated in any detail) and ithas been found that the incidence of symptomlesscases tends to increase as the age at diagnosis rises(Table 3). It seems, therefore, that the proportion ofpatients with Paget's disease (diagnosed or un-diagnosed) who are relatively untroubled by theircondition exceeds 80 or even 90%/.The records of the serum alkaline phosphatase

levels of individual patients extending over manymonths or years suggest that there may be a moreactive and more extensive form of Paget's disease.Progression from limited and relatively inactivedisease to the more widespread and highly activeform appears to occur rarely. There is some evidencefrom the familial cases that the more serious form ofthe disease may have a stronger hereditary basis.

AcknowledgmentsOur thanks are due to colleagues who allowed us to study

patients under their care, to Dr K. R. Aberdour, Dr F. A.Adcock and Dr J. M. Stewart for their willing help in theradiological assessment of our cases, to Professor G. A. Rosefor his advice and for his help with the statistical analyses,and to the Chelmsford Medical Education and ResearchTrust for facilities.

ReferencesANY QUESTIONS (1958) Sedimentation rate in Paget's disease.

British Medical Journal, 1, 1134.BARRY, H.C. (1969) Paget's Disease of Bone. Livingstone,

Edinburgh.BATTEN, R.D. (1931) Angioid streaks and their relation to aform of central choroidal disease. British Journal ofOphthalmology, 15, 279.

BREMNER, C.G. (1961) Secretor status in carcinoma of thebreast. Lancet, ii, 1338.

CAMPS, F.E. & DODD, B.E. (1967) Increase in the incidence ofnon-secretors of ABH blood group substances amongalcoholic patients. British Medical Journal, 1, 30.

CLARKE, C.A., EDWARDS, J.W., HADDOCK, D.R.W., HOWEL-EVANS, A.W., MCCONNELL, R.B. & SHEPPARD, P.M. (1956)ABO blood groups and secretor character in duodenalulcer. British Medical Journal, 2, 725.

COLLINS, D.H. (1956) Paget's disease of bone, incidence andsubclinical forms. Lancet, ii, 51.

DA COSTA, J.C., FUNK, E.H., BERGHEIM, 0. & HAWK, P.B.(1915) Osteitis deformans. A report of five cases withcomplete metabolism studies in two instances and a reviewof the literature. Publication of the Jefferson MedicalCollege, 6, 1.

DE DEUXCHAISNES, C.N. & KRANE, S.M. (1964) Paget'sdisease of bone. Clinical and metabolic observations.Medicine, 43, 233.

DICKSON, D.D., CAMP, J.D. & GHORMLEY, R.K. (1945)Osteitis deformans: Paget's disease of the bone. Radiology,44, 449.

DOLL, R., DRANE, H. & NEWELL, A.C. (1961) Secretion ofblood group substances in duodenal, gastric and stomalulcer, gastric carcinoma, and diabetes mellitus. Gut, 2, 352.

GALBRAITH, H.-J. B. (1954) Familial Paget's disease of bone.British Medical Journal, 2, 29.

GLYNN, A.A., GLYNN, L.E. & HOLBOROW, E.J. (1959)Secretion of blood-group substances in rheumatic fever.British Medical Journal, 2, 266.

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GRAINGER, R.G. & LAWS, J.W. (1957) Pagetrs disease-active or quiescent? British Journal of Radiology, 30, 120.

GRUNDY, M. (1970) Fractures of the femur in Paget's diseaseof bone. Journal of Bone and Joint Disease, 52B, 252.

HARRIS, E.D. & KRANE, S.M. (1968) Paget's disease of bone.Bulletin on Rheumatic Diseases, 18, 506.

HARTUNG, E.F. (1955) Paget's disease followed for twenty-one years. Arc-hives of Internal Medicine, 95, 869.

KAY, H.D. (1929) Plasma phosphatase in osteitis deformansand in other diseases of bone. British Journal of Experi-mental Pathology, 10, 253.

KNOWELDEN, J., BUHR, A.J. & DUNBAR, 0. (1964) Incidenceof fractures in persons over 35 years of age. British Joutrnialof Preventive and Social Medicine, 18, 130.

KOPEC, A.C. (1970) The Distribution of the Blood Groutps inthe United Kingdonm. Oxford University Press.

LUXTON, R.W. (1957) Paget's disease of bone associated withHashimoto's struma lymphomatosa. Lancet, i, 441.

MCKENNA, R.J., SCHWINN, C.P., SOONG, K.Y. and HIGIN-BOTHAM, N.L. (1964) Osteogenic sarcoma arising inPaget's disease. Cancer, New York, Philadelphia, 17, 42.

MARTIN, E. (1947) Considerations sur la maladie de Paget.Helvetica niedica acta, 14, 319.

MURRAY, S. (1961) ABO groups and Rh genotypes in theelderly. British Melical Journal, 2, 1472.

PRICE, C.H.G. & GOLDIE, W. (1969) Paget's sarcoma of bone.Journal of Bone and Joint Disease, 51B, 205.

RACE, R.R. & SANGER, R. (1968) Blood Grouips in Mlani, p. 298.Blackwell Scientific Publications, Oxford.

REICH, C. & BRODSKY, A.E. (1948) Coexisting multiplemyeloma and Paget's disease of bone treated by stilba-midine. Jouirnal of Bone and Joint Surgery, 304, 642.

ROSENKRANTZ, J.A., WOLF, J. & KAICHER, J.J. (1952) Paget'sdisease (osteitis deformans); review of Ill cases. Archivesof Internal Medicine, 90, 610.

SCHMORL, G. (1932) Uber ostitis deformans Paget. VirchoivsArchiv fiUr pathologische Anatonie iind PhYsiologie uind fiUrklinische Medizin, 283, 694.

SOMAYAJI, B.N. (1968) Malabsorption syndrome in Paget'sdisease of bone. British Alelical Journal, 4, 278.

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