The Mechanism Cardiovas- Paget's (Osteitis Deformans) …circ.ahajournals.org/content/6/5/711.full.pdf · C. FRANKLIN SORNBERGERANDMAGNUS I. SMEDAL ured the cardiac output and bone

The Mechanism and Incidence of Cardiovas-

cular Changes in Paget's Disease

(Osteitis Deformans)

A Critical Review of the Literature with Case StudiesBy C. FRANKLIN SORNBERGER, M.D., AND MAGNUS I. SMEDAL, M.D.

Although abundant evidence of concomitant cardiovascular disease is scattered throughout theliterature on osteitis deformans, appreciation of the etiologic relationship between the two dis-eases has been lacking. This paper shows that cardiovascular disease accompanying extensiveosteitis deformans may result from: (1) excessive demand on the heart from increased vascularityof affected bones; (2) the influence of concomitant arteriosclerosis apparently exceeding the formalfor the age concerned; (3) characteristic thoracic spine deformities which compromise cardio-respiratory function, and (4) hypertension. Fifty-four cases are presented. The incidence of cardio-vascular disease exceeds that in the general population of the same age and corresponds with theextent of skeletal involvement.

M ANY PHYSICIANS conversant withthe osseous characteristics of Paget'sdisease are not well acquainted with

concomitant changes in the heart and bloodvessels which occur in the same disease. In-controvertible evidence of such changes isscattered throughout the voluminous litera-ture on osteitis deformans that has accumu-lated since Sir James Paget's original paper,but to date little attempt has been made tocorrelate these various findings and opinions,nor has any extensive study on the incidence ofsuch changes been made. We have, therefore,reviewed the literature on Paget's disease withparticular reference to the nature and incidenceof the attendant cardiovascular changes, andpresented a series of consecutive cases in whichstudies of heart size and electrocardiographicexaminations have been made in an attempt tocorrelate previous observations and establishthe incidence of related cardiovascular diseasein osteitis deformans.

Occult,1-3 monophasici,4-0 monostotic,111-5and polyostotic or advanced classic forms ofthe disease have been described.'6-26 However,From the Department of Radiology, Lahey Clinic,

Boston, Mass.Editor's Note: This paper was awarded the 1950

prize of the Louis Lefkoe Memorial Foundation forthe best paper submitted on the subject of osteitisdeformans.

711

it is the vascular and cardiac changes that occurin the very extensive or classic form of thedisease with which we are primarily concerned.

RELATIONSHIP BETWEEN PAGET'S DISEASEAND THE CIRCULATORY SYSTEM

The characteristics of osteitis deformans,per se, have been thoroughly reported and dis-cussed in periodicals and texts,27-3' so that anattempt will not be made to elaborate on thisaspect of the problem. The appreciation of theinfluence of osteitis deformans and attendantconditions on the cardiovascular system hasbeen delayed and complicated by several fac-tors: (1) there is a high incidence of degenera-tive vascular changes in the "normal" elderlypopulation, which must serve as a basis forcomparison; (2) the marked limitation ofactivity that usually accompanies the classicform of Paget's disease tends to mask the pres-ence of cardiovascular changes in the groupin which they would otherwise be most likelyto manifest themselves; (3) the classic formof the disease is so uncommon (in contrast tothe localized disease)32' 33 that it is difficult toobtain a large series of cases for study; (4)deformities of the thoracic spine characteristicof the classic form of Paget's disease makethe determination of the presence of cardiac

Circulation, Volume VI, November 1952

by guest on April 19, 2018

http://circ.ahajournals.org/D

ownloaded from

http://circ.ahajournals.org/

CARDIOVASCULAR CHANGES IN PAGET'S DISEASE

enlargement difficult on roentgenologic andphysical examination.The following conditions, any one or all of

which may be present in a given case of osteitisdeformans, either increase the work of the heartor decrease the ability of that organ to performits function and, therefore, over a period oftime, diminish cardiac reserve and predisposeto enlargement and failure: (1) increased bloodflow in the bony lesions of osteitis deformans incertain phases of the disease; (2) arteriosclero-sis; (3) deformities of the thoracic spine andchest, and (4) hypertension.

INCREASED VASCULARITY AND HEMODYNAMICSIN OSTEITIs DEFORMANS

A. Incidence

Sir James Paget remarked the increased vas-cularity of affected bones, and described theappearance of the long bones in his first casewhich came to necropsy as follows: "The outersurface of the walls of the bones was irregularand finely nodular, as with external deposits oroutgrowths of bone, deeply grooved with chan-nels for the larger periosteal vessels, finely butvisibly perforated in every part for the trans-mission of the enlarged small vessels. Every-thing seemed to indicate a greatly increasedquantity of blood in the vessels of the bone."22

Increased heat over affected tibiae was re-corded in three of the seven additional casesreported by Paget in 1882.23Evidence of increased vascularity of affected

bone in the form of increased redness, warmth,or dilated overlying vessels was noted by manysubsequent observers,' 12, 15, 16, 34-44 and cameto be recognized as a clinical feature of thedisease.40' 45-47 The replacement of bone byfibrous and vascular tissue29' 48, 4 was observedto be accompanied by hyperemia, increasedvascularity and also by fibrosis of the bonemarrow. 1' 2, 6, 16, 17, 24, 32, 35, 44, 45, 50_55

Instances of excessive heat and rednesshave been observed in this series, and havebeen interpreted as clinical evidence of in-creased blood flow in affected bone.

It is usually difficult to accomplish satis-factory hemostasis when it is necessary tooperate on pagetic bone. Two patients in thisseries had surgical treatment and in both in-

stances there was excessive bleeding. Thisproblem has been encountered by others39, 40, 55, 56 and emphasizes the degree of ab-normal vascularity of bone affected by osteitisdeformans.Although the presence of excessive vascu-

larity in bones affected by osteitis deformanswas soon well established,36 39, 48, 54, 57, 58 thedegree of increased blood flowNr, its relationshipto the radiologic stage of the disease and in-fluence on the general circulation remained tobe determined.

In 1923, Sherwood Moore39 made the firstattempt to determine, quantitatively, the cir-culatory changes in Paget's disease by measur-ing the volume flow to the limbs. An averageof many observations showed the blood flowto the affected limb to be over twice that to thesound limb, and he concluded: "Increasedvascularity of bone in Paget's disease can beconsidered as established beyond doubt.... Itcertainly exceeds increased vascularity ob-served in infectious states of bone."

In view of the fact that recent experimentshave emphasized the difficulties encounteredin measuring the blood flow through extremitiesin human beings,59 the work of Moore should,perhaps, be accorded more qualitative thanquantitative significance, but it remains animportant early observation.Awareness of the effects of increased vas-

cularity due to Paget's disease developedslowly. One of our patients, a 68 year old man,had extensive Paget's disease of 20 years'duration and when last admitted to the hos-pital was in congestive heart failure. Thepossibility of a relationship between the ex-cessive blood flow due to Paget's disease andthe congestive heart failure was considered,as shown by the entry of Dr. L. M. Hurxthalon the hospital record of December 27, 1943:"The right leg is hot, probably indicatingmarked blood flow there due to Paget's disease.This added blood flow may be a factor in heartfailure."The most comprehensive study of the vas-

cular changes in bone affected by osteitis de-formans and their influence on the generalcirculation has been made by Edholm, Ho-warth. and McMichael.58 In 1945, they meas-

712



ownloaded from


C. FRANKLIN SORNBERGER AND MAGNUS I. SMEDAL

ured the cardiac output and bone blood flowin a 66 year old man who had advanced, ex-tensive osteitis deformans accompanied bycongestive heart failure of undetermined etiol-ogy. Left ventricular enlargement, markedcapillary pulsation in the nail beds and a highpulse pressure were present. An electrocardio-gram was normal. On venous catheterization,the right auricular pressure was elevated, andthe cardiac output was 13.3 liters per minute.Occlusion of the circulation to the lower ex-tremities (both of which were affected by ex-tensive osteitis deformans) caused a drop inthe right auricular pressure, pulse rate andcardiac output. Blood flow through the nutri-ent arteries of the affected bones was found tobe from 10 to 20 times the normal. Theyconcluded: "The data presented here indicatedthat there occurs in generalized* Paget's dis-ease an increase in bone blood flow of sufficientmagnitude to produce effects on the generalcirculation similar to those resulting from freearteriovenous communications. Further workis required to study the relationship betweenthe increased flow and the radiologic stage ofthe disease. The absence of significant in-creases in cardiac output in cases of localizedPaget's disease suggests that it is only whenthe disease becomes generalized that the circu-lation as a whole is greatly increased, and insuch cases the signs of heart failure may de-velop."58

Further studies by Edholm and Howarth57provide additional evidence of excessive vas-cularity and bone blood flow in osteitis de-formans. Two complete necropsies on casesthat had been followed and studied revealed"tremendous development of the bone vascularsystem in the affected limbs which we furtherdemonstrated by intra-arterial injections ofradiopaque material." These observations werefurther substantiated by biopsy specimensand studies on the effect of intravenousepinephrinie on skin temperature in the normallimb and in limbs affected by osteitis defor-mans. They concluded: "We have confirmedour previous findings that the total limb blood

* Since osteitis deformans is not a systemic dis-ease, "extensive" appears to be a preferable term.8

flow is very greatly increased whetl the bonesin the limb are affected by osteitis deformans."

B. EffectsThe increased vascularity that is charac-

teristic of the involved portions of the skeletonin osteitis deformans36 (at least in certainphases of the disease)58 has been shown to haveno significant effect ots the general circulationwhen the area of bony involvement is small.When a large proportion of the skeleton isinvolved, the attendant increase in blood flowmay be accompanied by elevation of the car-diac output37 58, 60 to several times the normalbasal rate of approximately 4 liters per min-ute61, 62

The factor of itscreased demand on the heartthus becomes an important consideration inextensive Paget's disease of long duration, inwhich case it reduces cardiac reserve, predis-posing to enlargement and failure.40' 63

ARTERIOSCLEROSIS AND CARDIOVASCULAR Dis-EASE IN OSTEITIS DEFORMANS AND THE

GENERAL POPULATION

A. IncidenceThe voluminous literature on the nature

and incidence of arteriosclerosis attests to thecontroversial nature of the subject.64 8 Statis-tics on the incidence of arteriosclerosis tend tobe unreliable, particularly in the living, sincethere is not an entirely satisfactory method forthe determination of its presence (once adefinition of the nature of the process has beenaccepted) and various observers report theirfindings on the basis of different methods andstandards.67 In addition, intimal lesions are ofmore clinical importance than medial calcifica-tion,68-70 and the problem is complicated by thefact that there are multiple causes of arterio-sclerosis when the term is used in its liberalsense. 64 68 , 71-80

Our interest in a possible relationship be-tween arteriosclerosis and osteitis deformanswas aroused from the observation that markedcalcification of the arteries is nearly alwaysfound on the roentgenograms of patients withextensive Paget's disease, and from the factthat since the time of Paget, clinicians have

713



ownloaded from



thought both the incidence and severity ofarteriosclerosis to be greater in patients withosteitis deformans than among the general pop-ulation of a similar age.9' 27, 29, 39, 81The question of a real increase in the severity

and incidence of arteriosclerosis in Paget'sdisease has not been adequately determinedbecause so many observers were inclined tostate their impression that the incidence andseverity were out of proportion to the agegroups concerned,9' 12, 14, 24, 31, 35, 39, 45, 47, 50, 51,55, 81-88 yet did not provide adequate statisticalevidence. Still others dismissed the questionwith the caveat that the advanced age ofthe patient was in itself sufficient explanationfor the severe arterioslcerosis,21' 27 while somepresented fairly sizable groups of cases support-ing the contention that the incidence of arterio-sclerosis is significant, the age of the patientnotwithstanding.16'20' 28, 83, 89, 90

For this reason, we have calculated the in-cidence of arterial calcification as seen in theroentgenograms of patients in our series withregard to the extent of bony involvement. Thefindings are, in turn, compared with the re-ported clinical and autopsy incidence of arterio-sclerosis in the general population of the sameage (fig. 1). Although our series is far too smallto be of statistical significance, the fact that inlocal Paget's disease the incidence of arterialcalcification on the roentgenograms is slightlyless than the clinical incidence of arteriosclero-sis in the general population of the same age,91yet in extensive Paget's disease, it exceeds theautopsy and clinical incidences for the ageconcerned,91, 92 lends support to those whobelieve that the severity and incidence ofarteriosclerosis in extensive Paget's diseaseexceed the normal, age notwithstanding.

B. Effects of Arteriosclerosis in Osteitis Deformans1. Heart. Locke stated that in osteitis de-

formans, cardiovascular disease is undoubtedlythe most common cause of death.27 As theetiologic role of arteriosclerosis in chroniccardiovascular disease is well recognized, itwill be alluded to only in broad outline.

Arteriosclerotic disease of the coronary ar-teries may lead to varying degrees of chronicmyocardial ischemia.82' 93-9 Decreased cardiac

reserve, angina pectoris, myocardial fibrosis,dilatation with or without hypertrophy and,finally, failure may result, depending upon thedegree of insult.96-'0' Coronary disease alsopredisposes to thrombosis, acute ischemia,conduction defects and infarction.55' 94, 102These may also result in dilatation, failure ordeath.'03Although the finding of increased incidence

of calcification in the aorta and peripheralvessels is not direct evidence of excessivecalcification of the coronary arteries, the ar-terial calcification in Paget's disease is not in-fluenced by the proximity to involved bones.90Since in the "heterochronic aging'6' 64, 78 ,104of the arterial tree the coronaries are known tobe ahead of the peripheral vessels,77 104 exces-sive coronary artery calcification may be ex-pected in Paget's disease.'05 Figure 2 shows theincidence of coronary artery disease in thegen-eral population in comparison with cardiacenlargement in osteitis deformans. Since notall cases of coronary disease have cardiac en-largement, it suggests that coronary disease inosteitis deformans must either exceed the nor-mal for the general population of the same ageor that other factors such as increased bloodflow and chest deformities also play a part. Webelieve the excessive cardiac enlargement inPaget's disease to be the result of the combina-tion of factors in most cases.

Arteriosclerosis and calcareous depositswhich chiefly involve the aortic and mitralvalves very often appear in advanced Paget'sdisease27' 88, 90, 106, 107 and the resulting stiffnessand deformity may impair the function of thesestructures.94' 96, 104, 108-111 The work of the heartis thereby increased, most likely at the verytime that the myocardium is deprived of anadequate blood supply by coronary artery dis-ease.A recent study by Harrison and Lennox"l2

in England revealed that calcification of themitral valve is more frequent in osteitis defor-mans than among the general population of asimilar age group. These workers stated thatintracardiac calcifications contribute to thehigh incidence of cardiovascular morbidityand mortality in Paget's disease.

In this connection, it is of interest that

714



ownloaded from



Paget's disease was present in 3 of 12 cases ofintracardiac calcification reported by Wind-holz and Grayson.3 This is a much higher in-cidence than could be expected in view of therelative infrequency of Paget's disease. Itshould be noted that they"3 considered thecalcifications to be unrelated to either rheu-matic fever or arteriosclerosis.

2. Other Organs. The effects of arteriosclerosisin osteitis deformans are not limited to theheart. Symptoms which are referable to anyorgan or portion of the body may result fromchanges in its blood supply.

Peripheral arteriosclerosis causes a loss ofelasticity in the vascular tree which results inbenign or senile hypertension, characterizedby a high systolic and more or less normal dias-tolic pressure, absence of progression or evi-dence of overt cardiac or renal damage andminimal retinal changes."4 This type of hyper-tension is usually thought to have little effecton the heart itself,68' 115 yet Burgess"14 hasshown that the most frequent cause of deathin these patients is cardiac failure, that theyare subject to cardiac hypertrophy and enjoysomewhat less than normal life expectancy.Other authors have also stated that systolicas well as diastolic hypertension adds a burdento the heart.60' 66

Arteriosclerosis of the renal vessels and con-sequent interference with the renal bloodsupply has been shown to be a cause of hyper-tension.66' 78, 116-120 Some authors consider hy-pertension to be associated with Paget'sdisease.'121 122

In the light of present knowledge it appearsthat a final decision cannot as yet be reachedwith regard to the relationship between ar-teriosclerosis that characteristically accom-panies extensive Paget's disease and the de-velopment of hypertension of a degree thatpredisposes to cardiac hypertrophy and dila-tation.The presence of a diabetic type of glucose

tolerance curve in Paget's disease has fre-quently been reported.44 46 83 89 123 124 Thesignificance of this observation has recentlybeen challenged but the mean age of the con-trol group in this experiment exceeded that ofthe group with Paget's disease by 14 years.125

Although a calculated correction was made forage discrepancy, the series was small and itappears likely that some degree of alterationin carbohydrate metabolism does occur inPaget's disease. The reason for such an altera-tion has not been demonstrated, but it hasbeen suggested that arteriosclerotic changesin the kidneys, accompanied by a high renalthreshold for glucose83 or variation in the activ-ity of the pituitary gland may play a part.89Although some competent observers believe

that arteriosclerosis is never a cause of dia-betes,126 other authorities state unequivocallythat arteriosclerosis of the pancreas may be acause of the milder type of diabetes whichoccurs in the aged.78 92 127-129 In support ofthis premise, it may be recalled that the ten-dency for diabetes to appear parallels the prog-ress of arteriosclerosis in Werner's syndrome.'30It, therefore, is possible that the tendencyfor a diabetic type of glucose tolerance curveto develop in Paget's disease may be explained,at least in part, on the basis of arteriosclerosisof the pancreas. This interpretation should betempered by the fact that glucose tolerancenormally diminishes with advanced age'25' 131

and with marked limitation of activity,'3' bothof which are often present in advanced osteitisdeformans.

DEFORMITIES OF THE DORSAL SPINEAND CHEST

A. Incidence

Severe cervicodorsal kyphosis accompaniedby marked deformity and restriction of move-ment of the thoracic cage is recognized ascharacteristic of the advanced, classic formof osteitis deformans.29' 31, 52, 54, 132 It was aprominent, feature in 7 of the 12 cases reportedby Paget up to 1882,22 23 and in 66 of 99"authentic cases"y in the literature up to 1900reviewed by Packard, Steele and Kirkbride.'4This association has subsequently been con-firmed by numerous authors,'' 4, 18-21, 24, 27, 52,55, 81, 85, 88, 124, 133-135 and was present to somedegree in two of the four cases of classic osteitisdeformans in the present series.

715



ownloaded from



B. EffectsAwareness of the direct and indirect effects

of severe deformities of the cervicodorsalspine and chest on the cardiorespiratory sys-tem has developed very slowly, and in so faras osteitis deformans is concerned, began withthe comments of Paget on his firstl case. Hestated that the spine was curved and rigid,while "the chest became contracted, narrow,flattened from before backwards, and themovements of the ribs w-ere lessened."22 Again,in case 4 of his original series,22 Paget notedthat, "about a year before death the generalhealth began to suffer from the thorax havingbecome implicated in the disease. Graduallythe chest became more contracted, and atlast quite fixed; the breathing became moredifficult until at last the respiratory apparatusaltogether ceased." After observing furtherexamples of respiratory embarrassment in hisadditional cases reported in 1882, Paget con-cluded that death "did not appear due inany degree to the disease of the bones unlessit were that the difficulty in breathing wasaggravated by the deformity of the chest."23

There are numerous references in the litera-ture to disease of the chest caused by deformityand restricted movement of the thorax inPaget's disease.'' 18, 24, 27, 40, 134 Occasionally,there has been further hindrance to respirationfrom paralysis of intercostal muscles as theresult of a bony overgrowth at the neuro-foramina.47' 56Although severe deformities of the dorsal

spine and chest became a recognized cause ofright heart failure'36 and a materially shortenedlife expectancy29' 111,137-146 as well as decreasedfunction of the lungs,147, 148 the various mecha-nisms involved were not clarified until ratherrecently. Earlier observers had inclined to theview that the cause of right heart failure inthese patients was mechanical, namely, lossof aid to the right heart from the normalrespiratory movements, increased resistancein the pulmonary circuit due to kinking orcompression of vessels and compression ofone lung and compensatory emphysema of theother. 133-149The advent of pneumonectomy and the sub-

sequent observation that obliteration of half

of the pulmonary circuit failed to precipitateright heart failure made it clear that theanatomic interference with the pulmonaryblood flow did not adequately explain theknown facts concerning pulmonocardiac failurein the hunc(hbacked. Chapmani, Dill and (GXray-biel made a step forward in the clarificationl ofthis problem by emphasizing the importanceof decreased oxygenation.139

Further elucidation has recently been pro-vided by the discovery of the fact that anlabnormally low oxygen saturation of the bloodhas a marked vasoconstrictive effect onl thepulmonary arterioles and precapillaries. Ex-perimental evidence of this vasoconstrictiveeffect stems from the observation that in thenormal individual, inhalation of half the nor-mal oxygen (onicentrationi will double the pul-monary arterial pressure without raising thecardiac output.'50-152 M~cAlichael pointed outthat the oxygen saturation of the blood inpatients with chronic emphysema is nearlyalways below 80 per cent, and may be as lowas 30 per cent.'5' He discussed these findingsin relation to right heart failure and em-phasized, along with others,'00 that a rise illpulmonary arterial pressure causes more em-barrassment to the right ventricle than a cor-responding rise in systemic pressure does tothe left ventricle. This is true because a risein systemic pressure automatically enhancesthe coronary flow, whereas, the right ventricleis not benefited as a result of its increased work.MeMichael summarized the effect of pul-monary vasoconstriction which results fromrelative anoxemia as follows: "Poor ventila-tion of the lungs may induce this vasoconstric-tive reaction and this may be the key to thepro', lem of many forms of pulmonary heartdisease. The difficulty of moving a kypho-scoliotic thoracic cage with consequent limitedventilation may have the same action on thepulmonary arterial pressure as the poor venti-lation of emphysematous lungs, or lungs inwhich the bronchioles and alveolar ducts arestrangled by peribronchial lymphatic car-cinoma.""'

It may be stated, therefore, that in classicosteitis deformans, the frequent, severe de-formities of the cervicodorsal spine and chest,

716



ownloaded from



accompanied by fixation of the thoracic cageand respiratory distress, occasionally aug-mented by paralysis of intercostal muscles,may predispose to right heart failure throughanatomic interference with pulmonary bloodflow, and as a result of spasm of the pulmonaryarterioles and precapillaries from the attendantlow oxygen saturation.

ANEMIA IN OSTEITIs DEFORMANS

On the basis of pathologic reports, a signifi-cant degree of anemia might be expected as acomplication in extensive Paget's disease be-cause of replacement of bone marrow by fibro-vascular tissue and encroachment on the mar-row cavity by bony overgrowth and osteoidtissue. MacCalluml53 stated that, "The mar-row actually loses its blood-forming elementsand becomes converted into a vascular fibroustissue which produces much soft, bone-liketissue." Numerous other authors have con-firmed the fact that metaplasia and fibrosis ofthe marrow and encroachment on the marrowcavity are common in advanced osteitis de-formans. 9, 14, 18, 21, 24, 31, 44, 49-52, 54, 154

These pathologic findings notwithstanding,marked anemia, attributable to osteitis de-formans, is a rare occurrence. Because Paget'sdisease progresses very slowly, if at all, theremay be time for compensatory phenomena tocounteract the effect of the gradual loss oferythropoietic tissue from the bone marrow sothat anemia, comparable to that found whenmarrow is replaced by neoplasm, is rarelyseen. Whatever may be the reason, we havenot found any cases of anemia due to Paget'sdisease in this series in which the red bloodcount and the hemoglobin reached less than50 per cent of normal, which is considerednecessary to cause cardiac enlargement fromanemia.'55 156 Moreover, we have been able tofind only one case in the literature in whichsevere anemia was attributed to Paget'sdisease.52 In this case, there was extensive re-placement of the red marrow by fibrous tissue,and death resulted from "osteosclerotic ane-mia which developed as a result of Paget'sdisease." In view of its demonstrated infre-quency, it appears that complicating anemiais not a significant cause of cardiac enlarge-

ment and heart failure in extensive osteitisdeformans.

REPORT OF CASES

This series is derived from the selection ofall cases of osteitis deformans which appearedin the files of the New England Baptist Hos-pital from January 1, 1941, to December 31,1947, and includes a detailed study of the rec-ords in each case. During this interval, therewere 106 patients for whom a definite diagnosisof Paget's disease was made. Eighty-eight ofthese patients had been studied at the LaheyClinic at some time before their hospitalization,and their outpatient records were also utilizedfor this study.The incidence of cardiac enlargement and

other studies are reported for 54 of the 106patients for whom standard 72 inch postero-anterior chest films were available. The 52patients for whom chest films were not taken,comprising a number in whom cardiac enlarge-ment was found on physical examination, werenot included in this series.

For the purpose of determining the influenceof the extent of the disease on the cardiovascu-lar system, the 54 cases were arbitrarily dividedinto three groups: (1) local disease, in whichosteitis deformans was confined to one bone oranatomic part such as the skull or pelvis,(2) moderately extensive disease, in which theprocess involved more than one long bone orpart, but less than the classic form, and (3)classic osteitis deformans, in which the skull,spine, pelvis and extremities were widelyinvolved.The mean age at examination was 58 years

for group 1 (36 cases), 63.4 years for group 2(14 cases) and 68.8 years for group 3 (fourcases).

Because of the high incidence of degenerativevascular disease in the general population ofthe sixth, seventh and eighth decades, the ageof the patients w^ho have Paget's disease is anobstacle to the demonstration of a relationshipbetween osteitis deformans and cardiovasculardisease. Figure 3 shows the incidence of cardiacenlargement in the general population of vari-ous age groups as determined by physical ex-amination. These findings were derived from

717



ownloaded from



the examination of 100,924 unselected lifeinsurance policy holders by one group'57and 10,000 similar unselected life insurancepolicy holders by another group.158 As the

100.

80

60zW0

40

201

0

decades concerned. Comparison of these figureswith the incidence of cardiac enlargement inlPaget's disease as shown in figure 3 revealsthe incidence in patients who had extensiveosteitis deformans to be many times that, of

IOOT

801

w 60-zW0o 40.z

_

S'e20

6 7AGE IN DECADES

8

.ARTERIOSCLEROSIS IN PAGET S DISEASE(SORNBERGER a SMEDAL)

- AUTOPSY INCIDENCE ARTERIOSCLEROSIS INGENERAL POPULATION (OPHULS, 1933)

--- CLINICAL INCIDENCE ARTERIOSCLEROSIS INGENERAL POPULATION (WRIGHT, 1948 ) *

A

BC

LOCAL PAGET'S DISEASE

MODERATELY EXTENSIVE PAGET'S DISEASE

CLASSIC PAGET'S DISEASE

FIG. 1. The clinical incidence of arteriosclerosis invarious stages of Paget's disease versus the incidence(clinical and autopsy) of arteriosclerosis in thegeneral population. Age on this and subsequentgraphs is by decade; thus, the seventh decade corre-

sponds to age 60, and so forth.Dotted line: Arteriosclerosis in Paget's disease

(Sornberger and Smedal).Solid line: Autopsy incidence of arteriosclerosis

in the general population (Ophiils, 1933).Dash line: Clinical incidence of arteriosclerosis in

the general population (Wright, 1948). (The authorstated the incidence by decades for each sex. Thisgraph represents the arithmetic mean of his figuresfor each decade.)

A: Local Paget's disease. B: Moderately exten-sive Paget's disease. C: Classic Paget's disease.

incidence in these groups was reported for eachsex, and in the latter group for five-yearperiods, the incidence shown in figure 3 was

derived by using the arithmetic mean for thetwo five-year groups and for each sex in the

o

...W B

I'~~~~~~~~.A- A

86 i7AGE IN DECADES

.CARDIAC ENLARGEMENT IN PAGET S DISEASE(SORNBERGER E SMEDAL)CORONARY HEART DISEASE(PAUL WHITE, 1947; BURCH and REASER, 1946)

CORONARY HEART DISEASE (CASSIDY, 1946)*A LOCAL PAGET'S DISEASE

B MODERATELY EXTENSIVE PAGET'S DISEASEC CLASSIC PAGET'S DISEASE

FIG. 2. The clinical incidence of coronary heartdisease in the general population versus cardiac en-largement in various stages of Paget's disease (seetext for explanation).

Dotted line: Cardiac enlargement in Paget's dis-ease (Sornberger and Smedal).

Solid line: Coronary heart disease (White, 1947;Burch and Reaser, 1946).

Dash line: Coronary heart disease (Cassidy,1946). (The author stated the incidence by decadesfor each sex. This graph represents the arithmeticmean of his figures for each decade.)

A: Local Paget's disease. B: Moderately exten-sive Paget's disease. C: Classic Paget's disease.

those in the general population of the sameage.

Figure 4 shows the relationship, betweencardiac enlargement and the extent of bonyinvolvement in osteitis deformans. There is amarked increase in the incidence of enlargementas the disease becomes more extensive, and as

718

....c0

s...."

> - - -- - - - - 49

":e

.,.I A

..I



ownloaded from



seen from figure 3, this increase is much greaterthan could be expected solely from the agegroups of the patients concerned. Of the caseswith localized disease, 28 per cent had cardiac

IOOT !0.

.

.

.

...

80+

r-' IWl fovzW

5 40.z

20

representative of the general population maybe questioned because they comprise a groupfrom which the lowest economic classes arelargely excluded, and since physical examina-tion is less accurate than the teleroentgenogramfor the determination of the size of the heart,further comparisons may be useful. Kretsch-mer and Butler'59 reported the incidence ofcardiac enlargement from all causes to be 15.3per cent in 314 patients who suffered fromprostatic disease. Patients who have prostaticdisease tend to fall in the same age group asthose with Paget's disease, and when it is re-called that for a given age, males are usually

CLASSICDISEASE

018

AGE IN DECADES8

.CARDIAC ENLARGEMENT IN PAGET'S DISEASE(SORNBERGER a SMEDAL)CLINICAL INCIDENCE CARDIAC ENLARGEMENTIN GENERAL POPULATION (SYDENSTRICKERond BRITTON, 1930)*

--- IDEM. (PROC. LIFE EXT. EXAMINERS, 1939)*A LOCAL PAGET'S DISEASE

B MODERATELY EXTENSIVE PAGET'S DISEASEC CLASSIC PAGET'S DISEASE

FIG. 3. The clinical incidence of cardiac enlarge-ment in the general population versus cardiac en-largement in various stages of Paget's disease (seetext for explanation).

Dotted line: Cardiac enlargement in Paget's dis-ease (Sornberger and Smedal).

Solid line: Clinical incidence of cardiac enlarge-ment in the general population (Sydenstricker andBritten, 1930). (The authors stated the incidence bydecades for each sex. This graph represents the arith-metic mean of their figures for each decade.)

Dash line: Idem. (Proc. Life Ext. Examiners,1939). (The incidence was stated by five-year periods.This graph represents the arithmetic mean for eachdecade.)

A: Local Paget's disease. B:-Moderately exten-sive Paget's disease. C: Classic Paget's disease.

enlargement, whereas the groups with moder-ately extensive and classic osteitis deformanshad 50 per cent and 100 per cent cardiac en-largement, respectively.

Since the use of life insurance examinees as

zW

( 0itrZ4 W_j Oz 2,WzU-o

0

MOD. EXTENSIVEDISEASE

LOCALDISEASE

AGE IN DECADES

FIG. 4. The relationship between cardiac enlarge-ment and the extent of bony involvement in Paget'sdisease.

more susceptible to coronary disease thanfemales,79' 99. 160 and that prostatic diseaseitself (when it causes obstruction) may be acause of cardiac enlargement, the contrastwith the incidence of cardiac enlargement inextensive osteitis deformans becomes evenmore significant.

There is further well documented evidencethat overt heart disease and cardiac enlarge-ment are not the rule in the aged generalpopulation. Willius'02 studied 700 patientswhose ages varied from 75 to 96 years, andcould not find clinical evidence of heart dis-ease in 45 per cent; however, the incidence ofcongestive failure was 12.1 per cent. Boas68

719

T

-- - - ----

0.- - - - - -- - -0

^ r



ownloaded from



discussed the aging of the cardiovascularsystem, and pointed out that in old age thebody demands less oxygen, the caloric intakeis less and the individuals in this group avoidextreme temperatures and physical activity.He concluded that such patients do not have aneed for the great cardiac reserves of youth,and that usually, the functions of the heartand arteries suffice to meet the needs of the

presumably the duration) of bony involve-ment (figs. 3 and 4). A summary of the re-ported incidence of cardiac enlargement andarteriosclerosis in Paget's disease may befound in table 1.

Electrocardiographic tracings were availablein 21 of the 54 cases in this series. The incidenceof normal tracings and those showing coronarydisease in the various stages of bony involve-

TABLE 1.-Summary of Incidence of Arteriosclerosis and Cardiac Enlargement in Paget's Disease

Author

Paget, 1877Hurwitz, 1913Smith, 1928Bortz, 1930Kay, Levy-Simpson, Riddochand Vilvandr6, 1934

Gutman and Kasabach, 1936Clegg, 1937Schwarz and Reback, 1939

Turner, 1940Wells and Holley, 1942Seligman and Nathanson, 1945Edholm, Howarth and McMi-

chael, 1945Burr, 1945Whalley, 1946Windholz and Grayson, 1947Rabiner and Hand, 1947Sornberger and Smedal, 1948

Arteriosclerosis

Number

1 of 1

2 of 214 of 1430 of 34

1 of 16 of 9

1 Of 11 of 1

1 of 1

5 of 537 of 544 of 4

12 of 1421 of 36

Per cent

100*

100loot88

10067

100§100

100

100691008658

Cardiac Enlargement

Number

1 of 12 of 62 of 29 of 1415 of 34

1 of 51 of 14 of 9

1 of 31 of 11 of 17 of 18

1 of 11 of 12 of 31 of 5

21 of 544 of 47 of 1410 of 36

Per cent

100*33.310064t44

2010044

33100§10039

100§10067t20391005028

Evidence

NecropsyClinicalNecropsyNecropsyClinical

ClinicalNecropsyClinicalNecropsyClinicalNecropsyNecropsy

ClinicalClinicalClinicalClinicalx-rayx-rayx-rayx-ray

Extent ofBone Disease

++ to +++++ to +++

+++ (1 case)

++ to +++

+++

+++ (1 case)+ to +++

±

Age(mean,Yrs.)

68

70

55

546458

555964

596677.55259.66563.458

Duration(mean,Yrs.)

22

9

65

613

5

10?

17.5

* Paget reported five cases, but only one in detail which came to autopsy.t Bortz reported 21 cases, but only 14 came to autopsy.1 While there were three cases of Paget's disease in the series of 12 cases of intracardiac calcification, only

two of the three were identified as examples of Paget's disease.§ This patient had rheumatic heart disease with congestive failure.

body under basal conditions in advanced oldage.A comparison of the incidence of cardiac

enlargement in extensive osteitis deformanswith that in the general population of the dec-ades concerned, therefore, refutes the factorof age per se as an explanation for the increasedincidence in Paget's disease. When age is dis-counted, it may readily be seen that the in-cidence of cardiac enlargement in osteitis de-formans is correlated with the extent (and

ment is consistent with the concept that car-diac disease is directly related to the proportionof the skeleton involved. A summary of theelectrocardiographic findings may be found intable 2.

Figure 2 shows the clinical incidence ofcoronary heart disease in the general popula-tion in comparison with the incidence of cardiacenlargement in the various stages of Paget'sdisease. The incidence of cardiac enlargementin osteitis deformans exceeds the clinical in-

720



ownloaded from



cidence of coronary artery disease in the gen-eral population when the bony involvement isextensive, in which ease it also exceeds theclinical and autopsy incidence of arteriosclero-sis in normal subjects for the ages concerned(fig. 1). This difference becomes more signifi-cant when the fact that marked coronary ar-tery disease may be present at autopsy with-out previous", 1c1clinical evidence is consi-dered, and when one considers that in 2,000consecutive autopsies only 69 per cent of thepatients who had significant coronary arterydisease showed cardiac enlargement."'1 It isapparent, therefore, that coronary sclerosis,per se, in the degree which is normal for theage concerned, could not account for the entireincidence of cardiac enlargement in Paget'sdisease. The other factors which help to bring

vanced and classic forms. In the meantime,these data may be accorded qualitative sig-nificance, and the determination of the preciseincidence of cardiovascular disease in exten-sive osteitis deformans must await the publi-cation of further studies.The cardiothoracic ratio as measured on pos-

tero-anterior chest films, taken in an uprightposition at a distance of 72 inches, has beenused as the index of cardiac enlargement inthis series. It is generally conceded that thisis an inexact method, although it is far moredependable than clinical findings.'62' 163 Thechief source of error attendant upon the use ofthe cardiothoracie ratio lies in the fact thatminimal enlargement may escape detection.'64Since error from the use of this method wouldtend to result in finding too few cases of cardiac

TABLE 2. Electrocardiographic Findings in Paget's Disease

Stage of Disease (bony involvement)

Localized.......... .....

Moderately extensive.........Classic .........................

Mean Agei of

(atiexami Electro-naio) cardiogram

58.063.468.8

1461

21

Normal Coronary ArteryDisease

Number Per cent

620

8

43330

Number

111

3

Per cent

717

100

LetVntiua

Left VentricularHypertrophy

Number Per cent

7 503 501* *

10

* The complication of bundle branch block prevented determination of presence of left ventricular hyper-trophy.

about this high incidence of enlargement inPaget's disease are thought to be the increasedcardiac output that often accompanies ex-tensive osteitis deformans,37' 40, 58 and moresevere arteriosclerosis than is warranted byage alone.'2, 29, 391 82, 89 90 Rarely, chest deform-ities and possibly hypertension related toarteriosclerosis may contribute to cardiovascu-lar morbidity and mortality in advancedPaget's disease.

METHODS AND SOURCES OF ERROR

It is realized that the figures presented on

the incidence of cardiovascular disease inosteitis deformans do not represent a serieslarge enough to be statistically significant.This will probably be true, however, of anyone series owing to the relative infrequencyof osteitis deformans in the moderately ad-

enlargement, employment of the cardiothoracicratio appears justified.The fact that chest films were made for all

of the patients in this series may distort theincidence of cardiac enlargement. While manychest films are taken routinely, or for col-ditions unrelated to the heart, an indetei'-minate error will result from the fact thatpatients who have symptoms referable to theheart are often selected for chest films, and theapparent incidence of cardiac enlargement maythereby be increased. This error can be elim-inated only by reporting a series in which chestfilms are taken routinely on all patients withextensive Paget's disease. However, this erroris compensated to some degree by the use of thecardiothoracic ratio which does not indicatecases with minimal eardiae enlargement.A possible source of error in the determilla-

721



ownloaded from



tion of the size of the heart in osteitis defor-mans is the deformity of the cervicodorsalspine and chest, commonly seen in the ad-vanced or classic form of the disease. Thesedeformities, when present, make the determina-tion of the size of the heart, by roentgenologicor physical examination, difficult. To date, noway has been found to obviate this problem,except by autopsy, although it did not have anyinfluence in this instance since only two casesin this series had marked cervicodorsal kypho-sis, and in each, the cardiac enlargement was sogreat as to be beyond question.

SUMMARY AND CONCLUSIONS

1. An appreciation of the influence of os-teitis deformans and concomitant conditionson the cardiovascular system has been retardedand complicated by several factors: (a) thehigh incidence of degenerative vascular changesin the normal elderly population, (b) the mask-ing effect of limited physical activity on thesymptoms of cardiovascular disease, and (c)the fact that the moderately advanced andclassic forms of osteitis deformans are too un-common to permit accumulation and study of asingle statistically significant series of cases.

2. The incidence of cardiovascular diseaseis appreciably greater in extensive Paget'sdisease than among the general population,age notwithstanding, and is manifested bycardiac enlargement and marked arteriosclero-S1S.

3. Cardiac enlargement and arteriosclerosisare related to the extent of the bony involve-ment, and are more pronounced when the lat-ter is extensive.

4. The mechanism of cardiac enlargement inextensive Paget's disease may be attributedto one, or more frequently, a combination ofthe following factors: (a) increased work of theheart as a consequence of the marked vascu-larity of bone in certain stages of osteitis de-formans; (b) more frequent and severe arterio-sclerosis than warranted by age alone, whichmay compromise the efficiency of the myocar-dium or valves, or both; (c) severe deform-ities of the cervicodorsal spine and chest whichdirectly or indirectly embarrass the pulmonarycirculation, and, on occasion, bring about right

heart failure; (d) in some cases, hypertensionwhich results from loss of elasticity in calcifiedvessels, or possibly from nephrosclerosis, maybe an added burden.

5. There is not convincing evidence of a sig-nificant increase in the incidence of cardiacenlargement in localized Paget's disease.

6. Anemia as a complication of Paget'sdisease does not appear to produce cardiacenlargement in an appreciable number of cases.

7. It is suggested that arteriosclerosis of thepancreas may contribute to the production of adiabetic type of glucose tolerance curve inosteitis deformans and that Paget's diseaseshould, in its extensive form, be added to theconditions (diabetes, myxedema, idiopathichypercholesterolemia and hypertension)68 69,77, 80, 116, 122, 160, 165, 166 which are considered to

be accelerators of arteriosclerosis.8. Patients in whom there is extensive ostei-

tis deformans should be classified as having"potential heart disease"'167 and should haveperiodic physical examinations, chest filmsand electrocardiographic studies.

9. The determination of the exact incidenceof cardiac enlargement and arteriosclerosis inextensive osteitis deformans must await furtherstudy of the subject and the compilation of astatistically significant number of cases.

ACKNOWLEDGMENTSWe are indebted to Louis I. Dublin, Second Vice-

President and Statistician, Metropolitan Life In-surance Company, for his assistance and to Dr.David I. Rutledge of the Department of InternalMedicine of the Lahey Clinic for his interpretationof the electrocardiograms.

REFERENCES1 JAFFE, H. L.: Paget's disease of bone. Arch.

Path. 15: 83,1933.2 SCHMORL, G.: Uber ostitis deformans Paget.

Virchows Arch. path. Anat., 283: 694, 1932.3SCHMORL, G.: Cited by H. L. Jaffe (ref. 1).4BRAILSFORD, J. F.: Paget's disease of bone; its

frequency, diagnosis and complications. Brit.J. Radiol. 11: 507, 1938.

-: The Radiology of Bones and Joints, ed. 4.Baltimore, Williams & Wilkins, 1948. Pp.326-328, 428-429, 600-615.

6 DICKSON, D. D., CAMP, J. D., AND GHORMLEY,R. K.: Osteitis deformans. Radiology, 44:449, 1945.

KASABACH, H. H., AND GUTMAN, A. B.: Osteo-

722



ownloaded from



porosis circumscripta of skull and Paget'sdisease; 15 new cases and review of literature.Am. J. Roentgenol. 37: 577, 1937.

8 REIFENSTEIN, E. C., JR., AND ALBRIGHT, F.:Paget's disease: Its pathologic physiology andthe importance of this in the complicationsarising from fracture and immobilization. NewEngland J. Med. 231: 343, 1944.

9 SANTE, L. R.: Principles of Roentgenological In-terpretation, ed. 7. Ann Arbor, Michigan,Edwards Bros., 1947. Pp. 116-117.

10 YOUNG, B. R.: The Skull, Sinuses and Mastoids:A Handbook of Roentgen Diagnosis. Chicago,Year Book Publishers, 1948. P. 82.

11 BOWLBY, A. J.: Cited by H. L. Jaffe (ref. 1).12 GROH, J. A.: Mono-osteitic Paget's disease as a

clinical entity: Roentgenologic observationsin nine cases. Am. J. Roentgenol. 50: 230,1943.

13 HURWITZ, S. H.: Osteitis deformans (Paget)involving a single bone. Am. J. M. Sc. 147:855, 1914.

14 MOORE, R. A.: A Textbook of Pathology. Phila-delphia, Saunders. 1947. Pp. 1234-1235.

15 SUGARBAKER, E. D.: Osteitis deformans, Paget'sdisease of bone: Review of 51 cases. Am. J.Surg. 48: 414, 1940.

16 BORTZ, E. L.: Osteitis deformans: A clinical andpathological survey. Internat. Clin. 2: 106,1930.

17 GRACE, E. J.: Osteitis deformans. S. Clin. NorthAmerica 7: 863, 1927.

18 DA COSTA, J. C.: Paget's disease of the bones(osteitis deformans). S. Clin. North America1: 47, 1921.

19 ELY, L. W.: Notes on five cases of Paget's de-forming osteomyelitis. Arch. Surg. 7: 532,1923.

20 KAY, H. D., LEVY-SIMPSON, S., RIDDOCH, G.,AND VILVANDR., G. E.: Osteitis deformans.Arch. Int. Med. 53: 208, 1934.

21 LEWIN, P.: Osteitis deformans (Paget's disease),with a report of 3 cases. J. Bone & JointSurg. 4: 45, 1922.

22 PAGET, J.: On a form of chronic inflammation ofbones (osteitis deformans). Tr. Med.-Chir.Soc. London 60: 37, 1877.

23 -: Additional cases of osteitis deformans.Mbed. Clas. 1: 61, 1936. (Original article inTr. Roy. Med.-Chir. Soc., Glasgow, 65: 225,1882)

24 ROBERTS, R. E., AND COHEN, WI. J.: Osteitisdeformans (Paget's disease of bone). Proc.Roy. Soc. Med. (Sect. Electro-Therap.) 19:13, 1926.

25 WILKS, S.: Cited by J. Paget (ref. 22).26 -: Osteitis deformans. Lancet 2: 1627, 1909.27 LOCKE, E. A.: In Christian, H. A., ed.: Oxford

Medicine. New York, Oxford UniversityPress, 1939. Vol. 4, pp. 421-446.

28 GUTMAN, A. B., AND KASABACH, H. H.: Paget'sdisease (osteitis deformans); Analysis of 116)cases. Am. J. M. Sc. 191: 361, 1936.

29 MUKHERJI, M.: Paget's disease of bones; con-plete survey. Indian J. Radiol. 1: 135, 1947.

30 NEWMAN, F. WV.: Paget's disease; a statisticalstudy of 82 cases. J. Bone & Joint Surg. 28:798, 1946.

31 SNAPPER, I.: Medical Clinics on Bone Diseases,a Text and Atlas. New York, IntersciencePublishers, 1943. Pp. 131-150.

32 NICHOLS, B. H., AND RAINES, J. R.: Paget'sdisease of bone (osteitis deformans), a reviewsof 48 cases. Cleveland Clin. Quart. 8: 139,1941.

33 HARRIS, H. E.: Paget's disease of skull compli-cated by mucocele of frontal sinuses. Cleve-land Clin. Quart. 11: 74, 1944.

34 BASCOURRET, M., AND DECOURT, J.: Les pous-sees 6volutives de la maladie osseuse de Paget.Rev. neurol. 1: 606, 1929.

3 BAUER, W.: In Cecil, R. L., ed.: Textbook ofMedicine, ed. 7. Philadelphia, Saunders, 1947.Pp. 1463-1466.

36 BOYD, W.: A Text-book of Pathology, ed. 5.Philadelphia, Lea & Febiger, 1947. Pp. 980-982.

37 EDITORIAL: The circulatory effects of osteitisdeformans. Am. J. Roentgenol. 57: 756, 1947.

38 KLIPPEL, M., AND WEIL, P.: Cited by I. Snapper(ref. 31). Also: Osteitis deformans and itspathogeny. Lancet 2: 1452, 1909.

31 MOORE, S.: Osteitis deformans. Am. J. Roent-genol. 10: 507, 1923.

40_: Osteitis deformans; a theory of its etiology.J. Bone & Joint Surg. 33-A: 421, 1951.

41 O'REILLY, A.: Paget's disease. South. AM. J. 21:815, 1928.

42 PASCAROLO, M., AND BERTOLOTTI, M.: Osteitisdeformans and its pathogeny. Lancet 2: 1452,1909.

4 SCHMIDT, B.: Cited by S. Moore (ref. 39) and byS. H. Hurwitz (ref. 13).

44 VAN HAZEL, W., AND ANDREWS, E.: Osteitisdeformans. Surg., Gynec. and Obst. 45: 54,1927.

45 KNAGGS, R. L.: Osteitis deformans (Paget'sdisease) and its relation to osteitis fibrosa andosteomalacia. Brit. J. Surg. 13: 206, 1925.

46 WAGNER, M.: Report of a case of Paget's dis-ease in an 18 year old male, with review ofliterature. Wisconsin M. J. 46: 1098, 1947.

4' WHALLEY, N.: Paget's disease of atlas and axis.J. Neurol., Neurosurg. & Psychiat. 9: 84,1946.

48 PANCOAST, H. K., PENDERGRASS, E. P., ANDSCHAEFFER, J. P.: The Head and Neck inRoentgen Diagnosis. Springfield, Ill., C. CThomas, 1940. P. 212.

19 GIAMPALMO, A.: Nuovo contributo sulla isto-

,:?3



ownloaded from



genesi della malattia osseas di Paget. Patho-logica 38: 1-4, 1946.

50 CONE, S. M.: The pathology of osteitis deformans,Paget's disease. J. Bone & Joint Surg. 4:751, 1922.

51 -: Paget's osteitis deformans in relation tocardiovascular disease. J. Bone & Joint Surg.15: 190, 1933.

52 DOLGOPOL, V. B.: Note on incidence, complica-tions and histopathology of Paget's disease ofthe bone. Bull. Russian M. Soc. New York.P. 37, 1939.

5 JAFFE, R. H.: Osteitis deformans (Paget's os-teitis, osteodystrophia fibrosa senilis [Chris-tellar-Frangenheim]). Tr. Chicago Path. Soc.12: 345, 1927.

54 PACKARD, F. A., STEELE, J. D., AND KIRKBRIDE,T. S.: Osteitis deformans. Am. J. M. Sc. 2:552, 1901.

5 SCHWARZ, G. A., AND REBACK, S.: Compressionof the spinal cord in osteitis deformans (Pa-get's disease) of the vertebrae. Am. J. Roent-genol. 42: 345, 1939.

56 TURNER, J. W. A.: The spinal complications ofPaget's disease (Osteitis deformans). Brain63: 321, 1940.

57 EDHOLM, 0. G., AND HOWARTH, S.: Personalcommunications, 1948, 1949.

58,-, AND MCMICHAEL, J.: Heart failure andbone blood flow in osteitis deformans. Clin.Sc. 5: 249, 1945.

59 BERRY, M. R., BALDES, E. J., ESSEX, H. E.,AND WAKIM, K. G.: A compensating plethys-mokymograph for measuring blood flow inhuman extremities. J. Lab. & Clin. Med. 33:101, 1948.

60 ZEMAN, F. D., AND SCHWARTZ, B. M.: The effectof arteriosclerosis on the dynamics of hyper-tension in the aged. J. Geront. 3: 40, 1948.

61 BEST, C. H., AND TAYLOR, N. B.: PhysiologicalBasis of Medical Practice, ed. 4. Baltimore,Williams & Wilkins, 1945. P. 225.

62 MOORE, R. A.: A Textbook of Pathology.Philadelphia, Saunders, 1947. P. 998.

3 GORDON, G. S.: Metabolic bone disease in prac-tice. Am. Pract. & Digest of Treat. 2: 113,1951.

64 HUEPER, W. C.: Arteriosclerosis. Arch. Path.38: 162, 245, 350, 1944; 39: 51, 117, 187, 1945.

65 COWDRY, E. V.: Arteriosclerosis. A Survey of theProblem. A publication of the Josiah Macy,Jr., Foundation. New York, Macmillan,1933.

66 MORGAN, H. J.: In Cecil, R. L., ed.: Textbookof Medicine, ed 7. Philadelphia, Saunders,1947. Pp. 1285-1290.

67 SYDENSTRICKER, E.: In Cowdry, E. V., ed.:Arteriosclerosis. New York, Macmillan, 1933.P. 151.

68 BOAS, E. P.: Aging of the cardiovascular system.Bull. New York Acad. Med. 16: 607, 1940.

69 MORRISON, L. M.: Arteriosclerosis. J. A. M. A.145: 1232, 1951.

70 WILENS, S. L.: Bearing of general nutritionalstate on atherosclerosis. Arch. Int. Med. 79:129, 1947.

71 ASCHOFF, L.: In Cowdry, E. V., ed.: Arteriosclero-sis. New York, Macmillan, 1933. P. 1.

72 HAUSE, W. A., AND ANTELL, G. J.: Arteriosclero-sis in infancy. Arch. Path. 44: 82, 1947.

73 IFF, M.: Cited by W. C. Hueper (ref. 64).74 STRYKER, W. A.: Arterial calcification in infancy

with special reference to the coronary arteries.Am. J. Path. 22: 1007, 1946.

71 DORMANNS, E., AND EMMINGER, E.: Cited byW. C. Hueper (ref. 64.).

76 TUTHILL, C. R.: Cited by W. C. Hueper (ref.64).

77 ULRICH, H. L.: Cardiovascular deterioration.Geriatrics 1: 152, 1946.

78 MOSCHOWITZ, E.: Vascular sclerosis. New York,Oxford University Press, 1942. Pp. 127-129,133, 139, 168-170.

79 GRECO, G. F.: Coronary artery disease in olderpatients. New York J. Med. 48: 1153, 1948.

80 MOORE, R. A.: A Textbook of Pathology. Phila-delphia, Saunders, 1947. P. 963.

81 DOCK, G.: In Nelson Loose Leaf Medicine. NewYork, Thos. Nelson & Sons. Vol. 5, pp.652-656.

82LEVINE, S. A.: Clinical Heart Disease, ed. 3.Philadelphia, Saunders, 1946. P. 81.

83 MOEHLIG, R. C., AND ABBOTT, H. L.: Carbohy-drate metabolism in osteoporosis and Paget'sdisease. J. Michigan M. Soc. 45: 642, 1946.

84 GILLAM, G. J.: Osteitis deformans (Paget's dis-ease). Canad. M. A. J. 17: 60, 1927.

85 GOLDSTEIN, A. E., AND ABESHOUSE, B. S.:Urinary calculi in Paget's disease (osteitisdeformans). Am. J. Surg. 30: 359, 1935.

86 MEAKINS, J. C.: The Practice of Medicine, ed.4. St. Louis, C. V. Mosby, 1944. P. 1143.

87 SELIGMAN, B., AND NATHANSON, L.: "Metastatic"calcification in soft tissues of legs in osteitisdeformans; case report. Ann. Int. Med. 23:82, 1945.

88 SMITH, L. H.: Two cases of Paget's disease (os-teitis deformans) associated with mentalsymptoms. J. Nerv. & Ment. Dis. 68: 578,1928.

89 MOEHLIG, R. C., AND ADLER, S.: Carbohydratemetabolism disturbance in osteoporosis andPaget's disease; associated soft tissue dis-turbances and results of various therapeuticprocedures. Surg., Gynec. & Obst. 64: 747,1937.

90 LOEPER, M., AND BACH, C.: La calcificationdes arteres dans la maladie de Paget. Progresm6d. 17: 295, 1942.

91 WR1GHT, I. S.: Vascular Diseases in ClinicalPractice. Chicago, Year Book Publishers,1948. P. 99.

724



ownloaded from



92 OPHCLS, W.: In Cowdry, E. V., ed.: Arteriosclero-sis. New York, Macmillan, 1933. Pp. 249-262.

93 MOSCHOWITZ, E.: Potential or latent congestivefailure in the aged. J. Mt. Sinai Hosp. 9: 663,1942.

94 NEW YORK HEART ASSOCIATION: Nomenclatureand Criteria for Diagnosis of Diseases of theHeart, ed. 4. New York, 1940. P. 18.

95 WHITE, P. D.: Heart Disease, ed. 3. New York,Macmillan, 1947. P. 487.

96 BURCH, G. E., AND REASER, P.: A Primer ofCardiology. Philadelphia, Lea & Febiger,1947. Pp. 166-174.

97 STROUD, W. D.: Diagnosis and Treatment ofCardiovascular Disease. Philadelphia, F. A.Davis, 1940. Vol. 1, Pp. 330-333.


19 DAvis, N. S.: Coronary disease. M. Clin. NorthAmerica 31: 153, 1947.

100 RATNOFF, 0. D., AND PLOTZ, M.: The coronarycirculation. Medicine 25: 285, 1946.

101 MCCLELLAN, W. S.: Physical medicine in thetreatment of the aged. J. A. M. A. 137: 130,1948.

102 WILLIUS, F. A.: The heart in old age. Am. J. M.Sc. 182: 1, 1931.

103 MASTER, A. M., JAFFE, H. L., AND DACK, J.:Incidence of various types of heart disease.Postmortem study. J. Mt. Sinai Hosp. 9:658, 1942.

104 COWDRY, E. V.: Problems of Aging, ed. 2. Balti-more, Williams & Wilkins, 1942. Pp. 116-129.

105 BURCH, G. E., AND REASER, P.: A Primer ofCardiology. Philadelphia, Lea & Febiger,1947. P. 41.

106 CLEGG, J. L.: Paget's disease. Lancet 2: 128,1937.

107 WELLS, H. G., AND HOLLEY, S. W.: Metastaticcalcification in osteitis deformans. Arch.Path. 34: 435, 1942.

108 ASHWORTH, C. T.: Atherosclerotic valvular dis-ease of the heart. Arch. Path. 42: 285, 1946.

109 NEW YORK HEART ASSOCIATION: Nomenclatureand Criteria for Diagnosis of Diseases of theHeart, ed. 4. New York, 1940. Pp. 51-52.

110 SUTTON, D. C.: Mitral stenosis. M. Clin. NorthAmerica 28: 47, 1944.

111 WARTMAN, W. B., AND HELLERSTEIN, H. K.:The incidence of heart disease in 2,000 consec-utive autopsies. Ann. Int. Med. 28: 41, 1948.

112 HARRISON, C. V., AND LENNOX, B.: Heart blockin osteitis deformans. Brit. Heart J. 10: 167,1948.

113 W1NDHOLZ, F., AND GRAYSON, C. E.: Roentgendemonstration of calcifications in the inter-ventricular septum in cases of heart block.Am. J. Roentgenol. 58: 411, 1947.

114 BURGESS, A. M.: Excessive hypertension of longduration. New England J. Med. 239: 75, 1948.

5LEVINE, S. A.: Clinical Heart Disease, ed. 3.Philadelphia, Saunders, 1946. Pp. 129-130.

116 BELL, E. T.: In Cowdry, E. V., ed.: Arteriosclero-sis. New York, Macmillan, 1933. P. 487.

117 GOLDBLATT, H.: Experimental renal hyperten-sion. Am. J. Med. 4: 100,1 948.

118 HYMAN, A.: Discussion. J. Urol. 42: 1000, 1939.19 SAsiN, H. S.: Hypertension in unilateral renal

disease. J. Urol. 59: 8, 1948.120 WEISS, S.: The clinical and physiologic charac-

teristics of arterial hypertension. Blood,Heart and Circulation, Science Press, Pub.Am. A. Adv. Sc., 1940. No. 13, pp. 295-302.

121 HADLEY, H. G.: Osteitis deformans. M. Rec.156: 93, 1943.

'2 MAHER, C. C.: Hypertension. M. Clin. NorthAmerica 28: 31, 1944.

123 APPERLY, F. L., AND CARY, M. K.: A note onglucose tolerance in Paget's disease (osteitisdeformans). Am. J. M. Sc. 192: 702, 1936.

124 HARE, H. F., AND SIMPSON, H. N.: Osteitis de-formans. Lahey Clin. Bull. 2: 93, 1941.

125 SCHNEEBERG, N. G.: Observations on the glucosetolerance test in Paget's disease (Osteitis de-formans). Am. J. M. Sc. 219: 664, 1950.

126 JOSLIN, E. P., ROOT, H. F., WHITE, P., MARBLE,A., AND BAILEY, C. C.: The treatment ofdiabetes mellitus, ed. 8. Philadelphia, Lea &Febiger, 1946. P. 219.

127 COLWELL, A. R.: Diabetes Mellitus in GeneralPractice. Chicago, Year Book Publishers,1947. P. 273.

129 LONG, E. R.: In Cowdry, E. V., ed.: Arteriosclero-sis. New York, Macmillan, 1933. P. 50.

129 MORGAN, H. J.: In Cecil, R. L., ed.: Textbook ofMedicine, ed. 7. Philadelphia, Saunders, 1947.P. 1290.

130 THANNHAUSER, S. J.: Werner's syndrome (pro-geria of the adult) and Rothmund's syndrome:Two types of closely related heredofamilialatrophic dermatoses with juvenile cataractsand endocrine features; a critical study withfive new cases. Ann. Int. Med. 23: 559, 1945.

131 JOSLIN, E. P., ROOT, H. F., WHITE, P., MARBLE,A., AND BAILEY, C. C.: The treatment of dia-betes mellitus, ed. 8. Philadelphia, Lea &Febiger, 1946. Pp. 165-166.

132 OSLER, W.: In Christian, H. A., ed.: Osler'sPrinciples and Practice of Medicine, ed. 14.New York, D. Appleton-Century, 1942. P.1203.

133 HARE, D. C., AND BERNARD, C. C.: Osteitis de-formans. Lancet 1: 371, 1921.

134 HURWITZ, S. H.: Osteitis deformans, Paget'sdisease. Bull. Johns Hopkins Hosp. 24: 263,1913.

135 PLATT, H.: Sarcoma in abnormal bones. Brit.J. Surg. 34: 232, 1947.

136 ZIMMERMAN, H. A.: Hemodynamics: studies ona group of patients who developed cor pul-

725



ownloaded from



monale following thoracoplasty. J. ThoracicSurg. 22: 94, 1951.

137 KARSNER, H. T.: In Cowdry, E. V., ed.: Arterio-sclerosis. New York, Macmillan, 1933. Pp.462-463.

138 FINLEY, F. G.: Spinal deformity as a cause ofcardiac hypertrophy and dilatation. Canad.MI. A. J. 11: 719, 1921.

39 CHAPMAN, E. M., DILL, D. B., AND GRAYBIEL,A.: The decrease in functional capacity of thelungs and heart resulting from deformitiesof the chest: Pulmoncardiac failure. Medicine18: 167, 1939.

140 EDEIKEN, J.: The effect of spinal deformities onthe heart. Am. J. M. Sc. 186: 99, 1933.

141 POLEVSKI, J.: The heart visible. Philadelphia,F. A. Davis, 1936. Pp. 22-23.

142 GOOD, C. A., AND DRY, T. J.: Conditions whichresult in increased pressure within the lessercirculation. Am. J. Roentgenol. 61: 26, 1949.

143REID, W. D.: Spinal deformity as cause ofcardiac hypertrophy. J. A. M. A. 94: 483,1930.

144 HERTZOG, A. J., AND MANZ, W. R.: Right-sidedheart failure (cor pulmonale) caused by chestdeformity. Am. Heart J. 25: 399, 1943.

141 NEW YORK HEART ASSOCIATION: Nomenclatureand Criteria for Diagnosis of Diseases of theHeart, ed. 4. New York, 1940. Pp. 24-25, 220.

146 WHITE, P. D.: Heart Disease, ed. 3. New York,Macmillan, 1947. Pp. 542-543

47 POWERS, S. R., JR., AND H1MMELSTEIN, A.:Late changes in ventilatory function followingthoracoplasty. J. Thoracic Surg. 22: 45, 1951.

148 W.TEST7 J. R., BALDWIN, E. D., COURNAND, A.,AND RICHARDS, D. W., JR.: Physiopathologicaspects of chronic pulmonary emphysema. Am.J. Med. 10: 481, 1951.

149 SPAIN, D. M., AND HANDLER, B. J.: Chroniccor pulmonale. Arch. Int. Med. 77: 37, 1946.

110 HOFF, H. E., AND SCOTT, H. J.: Physiology (con-cluded). New England J. Med. 239: 176, 1948.

1 MCMICHAEL, J.: Heart failure of pulmonary ori-gin. Edinburgh M. J. 55: 65, 1948.

112 HARVEY, R. M., FERRER, M. I., RICHARDS, D.W., JR., AND COURNAND, A.: Influence ofchronic pulmonary disease on the heart andcirculation. Am. J. Med. 10: 719, 1951.

5AMACCALLUM, W. G.: A Textbook of Pathology,ed. 7. Philadelphia, Saunders, 1940. Pp.1032-1033.

114 ARCHER, V. W: The Osseous System. A Hand-

book of Roentgen Diagnosis. Chicago, YearBook Publishers, 1945. Pp. 300-302.

155 BURCH, G. E., AND REASER, P.: A Primer ofCardiology. Philadelphia, Lea & Febiger, 1947.Pp. 156-158.


157 SYDENSTRICKER, E., AND BR1TTEN, R. H.: Thephysical impairments of adult life. Prevalenceat different ages, based on medical examina-tions by the Life Extension Institute of 100,924white male life insurance policy holders since1921. Am. J. HIyg. 11: 95, 1930.

15 PROC. LIFE EXTENSION EXAMINERS: A study ofimpairments found among 10,000 unselectedexaminees-cardiac enlargement and systolicmurmurs. 1: 112, 1939.

119 KRETSCHMER, H. L., AND BUTLER, S.: Prostaticsurgery and heart disease. J. A. MKI. A. 136:441, 1948.

160 UNDERDAHL, L. 0., AND SMITH, H. L.: Coronaryartery disease in women under the age offorty. Proc. Staff Meet., Mayo Clin. 22: 479,1947.

161 EGGLESTON, C.: In Cecil, R. L., ed.: Textbook ofMedicine, ed. 7. Philadelphia, Saunders, 1947.Pp. 1217-1230.

162 HODGES, P. C.: Heart size from routine chestfilms. Radiology 47: 355, 1946.

163 UNGERLEIDER, H. E.: Cardiac enlargement.Radiology 48: 129, 1947.

164 SHERMAN, C. F., AND DUCEY, E. F.: Cardiacmensuration. Am. J. Roentgenol. 51: 439, 1944.

161 PERERA, G. A.: Hypertension: A manifestationof hypertensive vascular disease. New YorkJ. Med. 48: 1724, 1948.

166 MORGAN, H. J.: In Cecil, R. L., ed.: Textbook ofMedicine, ed. 7. Philadelphia, Sauinders, 1947.P. 1289.


168 BURR, R. C.: Osteogenic sarcoma developing onPaget's disease. Canad. MI. A. J. 53: 262, 1945.

169 RABINER, A. M., AND HAND, AM. H.: Paget'sdisease and the central nervous system. NewYork J. Med. 47: 2689, 1947.

170 CASSIDY, M.: Coronary disease. Lancet 2: 587,1946.


726



ownloaded from


C. FRANKLIN SORNBERGER and MAGNUS I. SMEDALDeformans): A Critical Review of the Literature with Case Studies

The Mechanism and Incidence of Cardiovascular Changes in Paget's Disease (Osteitis

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1952 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.6.5.711

1952;6:711-726Circulation.

http://circ.ahajournals.org/content/6/5/711the World Wide Web at:

The online version of this article, along with updated information and services, is located on

http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions:

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

document.

Permissions and Rights Question and Answer Further information about this process is available in therequested is located, click Request Permissions in the middle column of the Web page under Services.the Editorial Office. Once the online version of the published article for which permission is being

can be obtained via RightsLink, a service of the Copyright Clearance Center, notCirculationpublished in Requests for permissions to reproduce figures, tables, or portions of articles originallyPermissions:



ownloaded from

http://circ.ahajournals.org/content/6/5/711

http://www.ahajournals.org/site/rights/

http://www.lww.com/reprints

http://circ.ahajournals.org//subscriptions/


Documents

The Mechanism Cardiovas- Paget's (Osteitis Deformans) …circ.ahajournals.org/content/6/5/711.full.pdf · C. FRANKLIN SORNBERGERANDMAGNUS I. SMEDAL ured the cardiac output and bone