Osteitis deformans (Paget's disease of bones)

OSTEITIS DEFORMANS

(PAGET’S DISEASE OF BONES)*

A REVIEW

OF FIFTY/ONE

EVERETT D.

SUGARBAKER,

CASES M.D.

CIinicaI Research FeIIow, MemoriaI HospitaI NEW YORK CITY

A

PPARENTLY

as oId as man himseIf yet comparativeIy new as a recognized cIinica1 entity, osteitis deformans can no Ionger be considered a rare condition. The NeanderthaI man has been suggested as a not unIikeIy example; it has been described in Egyptian mummies and in both its generaIized and monostotic varieties in the rather recentIy uncovered remains of prehistoric American Indians. Moreover, pathoIogicaIIy simiIar Iesions have been described in fow1, horses, and goats, and fairly typica cases have been described in monkeys, with convincing minera studies. Notwithstanding so deep a background and so wide a scope it remained for Sir James Paget in 1877 to give cIinica1 recognition to this disease, at f%-st considered a rarity but with the deveIopment of diagnostic aids no Ionger so regarded. Incidence. SchmorI, as a resuIt of a series of post-mortem studies, quotes an incidence of 3 per cent in persons over 40 years, and at the MemoriaI HospitaI, CoIey states that they now routineIy obtain skuI1 pIates on a11 patients over the age of go years seen in the Bone Tumor CIinic. At the Henry Ford HospitaI, from 1922 to 1937, in a tota of 224,676 admissions, fifty-one cases were recognized, or one case of Paget’s disease to every 4,500 admiscaIcuIations from other sions. SimiIar cIinics show an incidence of I :3,000 to I : 16,000. In our own series onIy seventeen cases (33% per cent) were recognized in the first haIf of the fifteen-year period and thirty-four cases (6695 per cent) in the remaining half. This is probabIy easiIy expIained on the basis of rapid deveIopment of the x-ray as an aid in the diagnosis

of whoIIy unreIated conditions (Paget’s disease being discovered onIy incidentaIIy) as we11 as its more frequent empIoyment in the differentia1 diagnosis of bone diseases. Kay, Simpson and Riddoch, in a series of ninety-six cases (sixty-two coIIected from the Iiterature and thirty-four of their own), give 55 years as the average age of diagnosis with a range of 3g to 78 years. They show a sex distribution of fifty-nine maIes and thirty-seven femaIes. Gutman and Kasabach, in an anaIysis of I 16 cases, show an equa1 number of each sex with a genera1 age range of 25 to 79 years. In the former group there were two sibIings and in the Iatter series four cases reported a famiIia1 incidence (four members in one case). In our own group there were thirty-one maIes, with an average age when diagnosed of femaIes with an 57 years, and twenty average age of 59.5 years, the tota average age being 57.7 years. However, the age of onset is diffIcuIt to determine because of the miIdness and indefiniteness of the earIy symptoms. (TabIe I.) None of our cases TABLE I DURATION OF SYMPTOMS (WHEN FIRST SEEN)

Duration

Lessthan I yr ................... I-5 yrs ......................... 6--royrs ........................ II yrs ..........................

7 ‘3 I0 5

60.7 60 58.7 57

gave a history of any other member of the famiIy having the disease. Our age range was 40 to 77 years. Cases occurring as earIy as the second decade of Iife (I 2 to I 6 years)

* From the Henry Ford HospitaI, Detroit. 414

KL\” SERIES VOL. XLVIII.

No. z

Sugarbaker-Osteitis

have been reported, Paget himseIf reporting one as earIy as 28 years of age. These should probabIy be regarded criticaIIy as they may well represent osteitis fibrosa. That Paget’s disease and osteitis fibrosa cystica may fortuitousIy occur together seems reasonabIe to suppose, and Aub has recentIy reported severa such cases. Symptoms. Pain seems to be the most distressing feature of the condition, confined usuaIIy to the Iower extremities, back, and head, and it is usuaIIy the first symptom to appear. The pain in the Iong bones is constant in type and is often marked Iong before any cIinica1 alteration can be detected. At first it may be due to periosteal stretching but Iater it is due to the new axes of strain and stress with the attendant Iigamentous stretching incident to the bending. This is confirmed by the observation that the pain is much more prone to occur in the bones of the Iower extremities than in those of the arms, the bending of course being more pronounced in the former. Back pain probabIy depends on the vertebral softening with compression (gravity) of the vertebra1 bodies, and on the postural deformity with the consequent stretching of the various groups of spina ligaments. That it not infrequentIy Ieads to a different type of pain, namely that due to nerve irritation, is shown by the fact that in severa of our cases there were periods of agonizing sciatica. One of our patients with spina invoIvement had several attacks of herpes zoster. Arthritis is often a compIicating factor. The headaches in patients with skuI1 invoIvement are difftcuit to evaIuate correctly due to the frequency of compIicating hypertension and arteriosclerosis. Bending of the Iong bones is the resuIt of softening, pIus gravity and muscIe puI1. Other Iess common and for the most part seIf-expIanatory signs and symptoms need not be commented upon and wiI1 mereIy be Iisted in the charts. (TabIe II.) Involvement. The skuI1, spine, peIvis, femur and tibia are the bones most frequentIy invoIved, in the order named. In

Deformans

American

Journal

ol’Surg:cry

4*j

the Iong bones the Iesions generaIIy first appear at the ends and Iater converge toward the midshaft. The periacetabuIar and sacroiIiac regions appear to show the first signs of int.oIvement in the peIvis. ApparentIy a sIight prediIection is shown by the disease for certain bones (i.e., ribs, scapuIae, cIavicIes, etc. ). This is slms AND I. Skeletal:

TABLE II SY~XPTOIIIS(WHEN

FIRST SEEN)

A. Long bones I. Deformity.. . z. Tenderness over or pain in. 3. Increase in local heat. 4. Overtying redness.. . . 5. AbnormaI gait.. B. Skull I. Deformity. . . 2. Nerve deafness. Conduction deafness. 3. Headaches. C. Miscellaneous I. Flaring of ribs and pelvis.. 2. SDinaI deformitv., 3 tiecrease in hefght or measurabIe shortening..

20

‘5 .2

4

5 2 2

6 bone

. .

8

aIso shown in groups of bones such as the vertebrae where the Iumbosacrai group predominates over the cervicodorsa1. However, undue emphasis seems to have been pIaced on this, for when reIative incidence is baIanced by reIative size of the bones this prediIection becomes somewhat more apparent than rea1 as an examination of most statistica tabIes, incIuding our own, wiI1 show. (TabIe III.) We are abIe to present an unusuaIIy high percentage of monostotic cases, tweIve in aI1, or 24 per cent. The average age of this group was 47.7 years. OnIy three of these had symptoms dating as Iong as five years; four cases were admitted as fractures and five cases were asymptomatic, the diagnosis being based entireIy on the roentgenoIogic picture. The tibia was invoIved in six cases, the skuI1 in two, the humerus in two, the sacroiIiac area in one, and the radius in one. With regard to the roentgenoIogic appearance of the lesions IittIe need be said. A heterogenous confluence of areas of osteoporosis and osteoscIerosis with a predominance of the former in the earIier

416

A m&can

Journal

Sugarbaker-Osteitis

of Surgery

and of the Iatter in the Iater stages, with a tendency toward overgrowth and thickening taking pIace as an integra1 part of the process, characterizes the x-ray picture. The pathoIogic appearance of the Iesions both grossIy and microscopicaIIy is so we11 known as to need no eIaboration. TABLE III

-

SkuII.

.

..

PeIvis . .. Spine. . Cervical DorsaI ..... . Lumbar Sacrum 1 Femur. . .. One .. . . Both 1 Tibia. . ... One Both 1 ’ FibuIa. . . One . . Both c PateIIa.‘. . ... One ... . Both i Humerus. . . . . One . ... . Both 1 ScapuIa. . . . . CIavicIes. . . . . . UIna ........... Radius. ......... Hands. ......... Ribs. ........... Sternum. ....... Face ............

-

BONES

INVOLVED

Totals

1uthor’ Series

154 136 I37

. 124

. . ro5

. . 20

... 13

.. 68

. 27 45 ‘9 29 II

F‘ackard SteeIe and Kirkbude

Jutman et a1.

23 25 24 5 9 I5 13

49

82

21

44 4 1 40 50 3 1 47 IO

34

8

I

IO

21

6

37

7 I4 6

S

21

II 1 IO 21

14 3

z

5 1 I 4 2 i 2

4 3

31

E

.. . .. ..

5 26

0

31

2

I2

3 2

19 8 16

29 7

5 0

IO

1

4

18 15 5 7 ;

7 9 -

Biochemistry. DecaIcification, new osteoid tissue formation and inorganic saIt deposition take pIace simuItaneousIy in Paget’s disease. The decaIcification is more apt to predominate in the earIier and more active stages of the disease, the inorganic saIt deposition in the Iater and Iess active stages. Hence it is inevitabIe that confficting reports concerning caIcium, phosphorus, magnesium, and suIfur baIances shouId

Deformans

MAY, row

have arisen (Locke, Hunter and DaCosta). The invoIved bones due to their Iarge size show an increase in the tota inorganic content, but the actua1 percentage inorganic content is Iess than normaI. BIood IeveIs of caIcium and phosphorus have quite generaIIy been found to be within norma Iimits (Kay et al. ; Gutman et aI.). In our own series the bIood caIcium range was 9.0 to 10.6 mg. per cent, the bIood phosphorus range was 1.72 to 4.54 mg. per cent with averages of 9.7 and 3.5 mg. per cent respectiveIy. Any constant variations in the serum caIcium depending on the stage of the disease (Belden and Bernheim) we were unabIe to observe. The most recent additions to our knowIedge of the biochemica1 changes taking pIace in Paget’s disease have come from a study of phosphatase activity, begun by Kay in 19x7. This substance, present in the pIasma and enzymic in nature, possesses the property of hydroIyzing phosphoric esters such as gIycerophosphate, hexosephosphate etc. The amount of this substance present is commonIy expressed in Bodansky units, the norma vaIue being r to 4 units. The enzyme, insofar as has been determined, is a product of body ceIIs in genera1 but is present in the greatest concentration in the intestina1 mucosa, kidney, and whoIe bone (Kay). In a few cases with a high pIasma phosphatase concentration studied by Kay, the urinary concentration remained Iow. The excretion of this substance has been incompIeteIy studied to date. Bone Iesions invoIving a fair portion of the skeIeton are accompanied by a rise in the phosphatase content of the pIasma. It has been found to be increased therefore in a number of conditions, incIuding infantiIe and adoIescent rickets (markedIy increased) renaI rickets, osteomaIacia, osteogenesis imperfecta (norma or sIightIy increased), muItipIe myeIoma (normaI or sIightIy increased), osteogenic sarcoma, carcinoma with bone metastases, hyperparathyroidism and Paget’s disease. Increased vaIues have aIso been noted in diseases with

Sugarbaker-Osteitis

NI-\r SI.RIL>Var. XLVIII, No. z

extensive liver damage. The highest vaIues ha1.e been obtained however, in Paget’s disease, they being higher than in osteitis fibrosa cystica for a comparabIe degree of bone involvement. It is evident therefore that an increase in pIasma phosphatase is the result rather than the cause of osteitis deformans, reflecting the celIuIar activity incident to osteogenesis. ConsequentIy it is in itseIf of no vaIue in differentiating Paget’s disease from other conditions in which bone formation occurs. Coupled with roentgenographic evidence, however, it is a distinct aid in the diagnosis. In Paget’s disease it may indicate the rate of deveIopment and is roughIy proportiona to the extent of invoIvement. Values as high as 120.6 units have been reported (Gutman) in patients with generalized bone invoIvement. In our own group of cases phosphatase studies were carried out in sixteen cases TABLE IV PHOSPHATASE

,

Age

57 53 48 42 0I

, Duration of Symp-

3.0* None* None*

6* None

51 57 52

/ Extent of InvoIvement

+

Phosphatase

7.48* 19,22* 8.98

1 + i li+ ++ ++ 1 +++ ’ +++++ +++

5.13* 2’62* (5-5-34) 5’49 (I-30-37). 8.21

7.35 4.06

None *

b-12-34) (12-12-36)

4.45 (12-2-35) 7.2 (2-9-37) 6.24 (10-9-36)

9.8 (I-25-37) 8.64 Il.9 II.3

5’

NOIIC

++++

43

+++

64

++++

* Fntcture.

20.4 14.3 31. ‘i 14.6

(l-7-35) (I-28-37) (8-14-35) (I 1-26-35)

35.6 (3-28-34) 24.7 (12-17-34) 35.05 (I I-2-34) 20.8 (3-3-37)

Deformans

A,~~cricxi~ Jour,lnldSurgcrr

_C17

av,eraged I 2.~4 units. (,‘l’abIe iv.) There were four monostotic cases in which the vaIues ranged from 2.62 to 19.22 units with an average of 8.97 units. The case in which the vaIue of 2.62 units was obtained three years later showed 5.49 units. The average of the polyostotic group was 13.9 units with a range of 5.83 to 30.13 units, somewhat Iow as compared with other series. Five of the sixteen cases were initiaIIy seen because of pathologic fractures. Contrary to what might be expected, it couId not be stated that the phosphatase readings in these cases were any higher than in others showing a comparable degree of bone invoIvement. The small size of this group however precludes an? dogmatism. Complications. Many of these patients present coincident neuropsychiatric conditions and numerous degenerative eye changes have aIso been reported, but one wouId be going a bit far afieId to attempt to pIace the bIame for these on the disease under discussion. It is generalIy feIt that these are due rather to coincident degenerative arterial changes. Knaggs, who has carefuIIy studied the skuI1 changes, states that the increase in the thickness of the skuI1 takes pIace almost entireIy outwards, and that the foramina are not seriously contracted, though the reguIarity of their margins (particuIarIy the foramen magnum) may be impaired. Crania1 nerve paIsies can occur from compression, however. The commoner resulting conditions are optic atrophy and nerve deafness. The Iatter is the more frequent. Lindsay and Perlman, in a review of this subject, concIude that Paget’s disease does not produce impairment in hearing except with extensive disease in the bones of the skull incIuding the temporal bone, and that though it is capabIe of producing conduction deafness, that of the inner ear type is much more characteristic. Fractures of the pathoIogic type occur in about 13 per cent of the cases. There were ten patients (20 per cent) presenting this comphcation in our series, one patient and

418

ofSurgery Sugarbaker-Osteitis Ame&anJournaI

having sustained two and another three separate fractures. It is common experience that with proper treatment these fractures heaI weI1, with abundant caI1u.s formation and usuaIIy within norma time Iimits. CaIcuIi were found in four cases, two biIiary and two urinary. GoIdstein and Abeshouse, who have reported six cases of urinary caIcuIi in Paget’s disease, state that it is an infrequent compIication. Aub states that the formation of urinary caIcuIi in Paget’s disease is Iess frequent than in osteitis fibrosa. MoehIig and Murphy in a recent pubIication report the high incidence of 15.6 per cent but in a series of onIy twenty-six cases. Sarcomatous degeneration in bones invoIved in the osteitic process occurred in two cases. In the first case the tibia aIone was invoIved and in the second, sarcoma appeared first in the femur and Iater in the radius. The incidence has been variousIy quoted at from 2 to 9.5 per cent (Speiser; Higbee and EIIis; Packard, SteeIe and Kirkbride; B. CoIey and Sharpe). Codman states that 14 per cent of a11 Paget’s disease patients succumb to osteogenic sarcoma. This association of the two conditions has not been found to occur under the age of 50 years. The average age of onset is 54 to 57 years, with maIes predominating. Our own two patients were 58 and 60 years of age respectiveIy and both were femaIes. CoIey and Sharpe state that the Paget’s is reported present one to twenty years before sarcoma deveIops. Due to the difflcuIty in rightIy determining the onset of Paget’s they feIt that an interva1 of ten to fifteen years is more IikeIy. The significance of this association is further emphasized by their statement that they know of no benign giant ceI1 tumor or endotheIia1 myeIoma occurring in a bone that was the site of a pregxisting Paget’s disease. In one of our cases there was a history of Paget’s for only nine months and in the other for ten years. In seventy-one cases of osteogenic sarcoma over 50 years of age which CoIey and Sharpe report (twenty of their own) there was an association with Paget’s in 28 per cent. KoIodny found that 5 per cent

Deformans

MAY, ,940

of a11 osseous sarcomas in the Bone Registry of the American CoIIege of Surgeons originated in bones invoIved in Paget’s. In a11 cases of sarcoma of the skuI1 there was preexisting Paget’s disease. Ochsner and Gage in thirty-one cases coIIected from the Iiterature found more than one bone to be invoIved in eight cases (CoIey and Sharpe in two cases). The sarcoma is sIightIy different histoIogicaIIy from the usua1 uncompIicated osteogenic sarcoma in that it shows more giant ceIIs and greater Iymphocytic infiItration. The degree of maIignancy is often greater aIso. CoIey and Sharpe were unabIe to find any record of a patient surviving more than five years and Ochsner states that in a11 of the cases but one which he investigated death occurred within a few months. Our two cases Iived onIy two and six months respectiveIy from the time the diagnosis was made. Etiology. Concerning the etioIogy of the disease IittIe is known of a positive nature. That Paget himseIf considered it inffammatory in origin is indicated by the name, osteitis deformans, which he gave to it. Since then a heterogeneous group of factors among which are chronic absorption of intestina1 toxins, Iues, trauma, gout, rheumatism, maIignant disease, trophic nervous disorders, heredity, and degenerative changes due to arterioscIerosis have been mentioned, a11 of which are probabIy incidenta1. The disturbances in minera baIance accompanying Paget’s disease, more particuIarIy that of caIcium, have been mentioned above. Whether they represent or are reIated to causes or to effects, however, can onIy be guessed at. The probIem is not a simpIe one. The factors inff uencing caIcium assimiIation (Wagoner), the inffuence of magnesium intake (Kruse, Schmidt and McCoIIum), and vitamin D intake (TayIor and WeId; Watchorn; PugsIey and Anderson) not onIy on the caIcium baIance but aIso on the route of eIimination deserve consideration. The effect of the parathyroids on caIcium metaboIism is too we11 known to require

NI u SF,HIER Vol..

XLVlII,

No.

z

Sugarbaker-Osteitis

elaboration. Selye has been abIe to produce interesting bone changes in rats, characterized first by osteoporosis and Iater by osteosclerosis, by feeding large doses of parathormone. Bauer, Aub and Albright, as a resuIt of their studies, suggest that hyperparathyroidism with its generahzed stimuIus for 0steocIastic activity may enhance the localized unknown factor sti tnuIating osteoclastic activity in Paget’s disease. The interreIationship of caIcium metabolism and thyroid function has aIso been estabIished (Aub et al.; HeIIwig; Klein; Pugsley and Anderson; Thompson; Hunter) and to complicate matters further the ability of thyroxin to sensitize the organism to parathormone might be mentioned (Stocker; Csepai and von PelIathy; Ask-Upmark). Moehlig, Murphy and Adler have attempted to correIate a high incidcnce of familiar diabetes, familial taI1ness and obesity, and a high incidence of diabetic glucose toIerance curves with pituitary dysfunction. However, in refutation it might be stated that patients with osteitis deformans generally exhibit norma appearing parathyroids; hyperthyroidism is an uncommon accompaniment of Paget’s disease (Boothby and Snndiford; Wakely), amounting to onIy 6 per cent in this series; and MoehIig et al. were unable to produce any picture comparabIe to Paget’s disease by the use of anterior pituitary extract in animaIs. In our own series only one case presented a famiIy history of diabetes and aIthough a family history of taIIness and obesity was not regurarly inquired into, these patients showed an average height and weight of 5 feet 6 inches and 152.4 pounds respectiveIy for the mares and 5 feet I inch and 1~5.5 pounds for the females, certainIy not unusual. Treatment. Treatment of a disorder as yet so IittIe understood can be carried out Lvith very IittIe rationaIe and for the most part is mereIy symptomatic and paIIiative. Parathyroidectomy as we11 as the administration of parathormone have been tried with equa1Iy poor resuIts. The administration of calcium, usuaIIy in combination

Deformans

American

Journal

of Surpcr:-

419

with vitamin D, in some form has been used with varying success, one of our own patients having folIowed such a regime for ten years with onIy indifferent resuIts. X-ray often relieves the bone pain and proper orthopedic treatment during the stage of softening prevents much of the otherwise ensuing deformity. RecentIy Gill and Stein have reported interesting results by using a diet low in calcium and phosphorus and high in magnesium, the magnesium being given in the- form of magnesium carbonate. They measure the efficiency of the treatment by a Iessening of the caIcium and phosphorous retention, by a decrease of the plasma phosphatase, by a decrease in the density and diameter of the long bones, and by a subsidence of symptoms. They state that it seems IikeIy that the magnesium exerts a favorable influence by increasing the soIubiIity of calcium and phosphorus and because it acts as a vasodilator. However, they neglect to state which phases of the disease have been benefited by this treatment nor do they present any numerica report of the progress of the phosphatase readings. Berman, postuIating that the first stage of Paget’s disease is due to a hyperfunctioning of the parathyroids in relation to a reIative deficiency of the adrena cortex, has tried administering extract of adrena cortex. Over a period of six to tweIve months he reports cessation of al1 symptoms with a recession of weakness and deformity. In tweIve cases phosphatase determinations at monthIy intervaIs showed a steady fall, usuaI1y to about one-fourth to one-seventh of the initial Ieve (never became normaI, however). We hav,e not as yet attempted this method of treatment but feel that it does merit a trial. SUMMAKY I. Fifty-one cases of Paget’s disease are presented, representing an incidence of one in 4,500 admissions. The proportion of males and femaIes was in the ratio of 3:~. The average age of onset was about 58 years with a range of 40 to ~7 years.

Sugarbaker-Osteitis

American Journal of Surgery

420

Pain is usuaIIy the first symptom to is usuaIIy the most distressing appear, feature of the disease and is IargeIy confined to the Iower extremities and back. 3. The skuI1, spine, peIvis, femur and tibia are the bones most frequentIy involved and in the order named. 4. The x-ray picture presents a heterogeneous confluence of areas of osteoporosis and osteoscIerosis with a predominence of the former in the earlier and of the Iatter in 2,

TABLE v INCIDENTALLABORATORYDATA

-

-

No. of

Chemistry

High

Cases

-~ N.P.N ............ Sugar. ............ Uric acid. ......... Urea. ............ P.S.P ............. Calcium. ......... Phosphorus. ....... Glucose tolerance. Increased. ...... Decreased. ...... NormaI. ........ B.M.R ........... Minus 10-15 PIus-minus 10. PIUS IO-15 ...... Phls30-40 ......

Average

_ 21 22

12.6

41.6 I 05

65 2.82 10.7 28

3.77 16.4 68 10.6

5 4 II

.

Low

29 29 7 I

9.0 I .72

4.52

32.5 74 3. 17 ‘3.7 57 9.7 3 s

5 I 14 r, 2 3

-

-

-

the Iater stages with a tendency toward bone overgrowth and thickening. 3. A negative caIcium and phosphorus baIance is generaIly present in the earIier and more active stages of the disease and a positive caIcium baIance in the Iater and Iess active phases, but the bIood caIcium and phosphorus IeveIs are normaI throughout. 6. The pIasma phosphatase is usuaIIy increased in Paget’s disease. It may indicate the rate of deveIopment and is roughIy proportiona to the extent of invoIvement. 7. Fractures occur in about 13 per cent of cases, but tend to hea we11 and within norma time Iimits. 8. CaIcuIi are not common, occurring in four of the present series. g. Sarcomatous degeneration is not uncommon, may occur in muItipIe foci and is PeneraIIv ci raoidIv I I/ fata1.

Deformans

MAY, ,gjo

IO. The etioIogy remains obscure. There is IittIe reason for implicating either the parathyroids, thyroid or pituitary. I I. The treatment is mainly symptomatic.

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