Bone scintigraphy in paget's disease treated with combined calcitonin and diphosphonate (EHDP)

Metab. Bone Dis. & Rel. Res.4, 103-I 11 Printed in the USA. All rights reserved.

0221-8748/82/020103-09$03.00/O Copyright 0 1982 Pergamon Press Ltd.

(1982)

BoneScintigraphy in Paget’sDiseaseTreatedwith Combined Catcitonin andDiphosphonate (EHDP) C.J.L.R.

‘Department “Department

VELLENGA,’

E.K.J.

PAUWELS,’

O.L.M.

BIJVOET,2

FRIJLINK’

of Diagnostic Radiology, Division of Nuclear Medicine, University Medical Center, Leiden, The Netherlands. of Endocrinology, Clinical investigation Unit, University Medml Center, Leiden, The Netherlands.

Address for correspondence and reprints: C.J.L.R. Vellenga, University Medical Center, 2333 AA Leiden, The Netherlands.

Department

Abstract

Key Words: Bone

Scintigraphy

-

Paget’s

Disease

of Diagnostic

Radiology,

Division of Nuclear Medicine,

obviates the disadvantages of both drugs, and the clinical therapeutic effect is promising (Bijvoet et al., 1978; Hosking et al., 1975). Thirty patients were treated with a combination of calcitonin and EHDP; patients, methods, and results were discussed in an earlier communication (Bijvoet et al., 1978). In this paper we wish to report the results of routine semiannual bone scintigraphy in these patients using a qualitative scoring system. Moreover, the study has been updated since the group of patients has been followed for an additional year. During this year a few more recurrences were seen. The only methods of investigation that provide information on localizations of Paget’s disease are radiography and bone scintigraphy. Whereas radiography shows the macroscopic architecture of bone, uptake of bone scintigraphic agents is dependent on multiple factors, such as vascularity, bone metabolism, exchangeable bone pool, amount of osteoid, and microscopic architecture. Because the main feature of Paget’s disease is excessive focal remodeling by disorganized osteoclasts and osteoblasts, we were especially interested in bone scintigraphy during treatment. In this paper special attention will be given to the following problems:

Bone scintigraphic results for 28 patients with Paget’s disease treated with a combination of EHDP and calcitonin are reported. The uptake of the bone scintigraphic agent decreased considerably during the first year of treatment. There was good correlation between scintigraphic and biochemical changes, but most of the 22 patients who attained normal biochemical values still had one or more active lesions scintigraphically. Remission of disease does not therefore mean normalization of the bone scintigram. All affected bones showed a distinct drop in activity, but lesions with a higher initial activity remained more active than lesions with a lower initial activity. One third of the affected bones normalized completely, although radiographic anomalies persisted. There were slight differences in scintigraphic activity depending on the anatomical site. The success of treatment, however, could not be predicted from the pretreatment scintigram. A recurrence of disease was often visible on the scintigram, in certain cases 6 months prior to the biochemical decline. This could be of importance in the therapeutic management of the recurrence. Combined

D.J. HOSKING,2andW.B.

Is the scintigraphic pattern of Paget’s disease similar in every bone or is it dependent on the anatomical site in the skeleton? Does the bone scintigram have any prognostic significance for the therapeutic success to be expected? How does the bone scintigram change during and after treatment? What is the relationship between changes in the bone scintigram and other parameters used for the evaluation of therapeutic success? Are local effects of therapy constant, or do individual lesions react differently? Does remission of Paget’s disease mean normalization of local scintigraphic activity? Is bone scintigraphy capable of detecting a recurrence of the disease and, if so, sooner or later than other parameters?

-

Treatment.

Introduction One century after the first description by Sir James Paget, the etiology of Paget’s disease still remains unclear. This impeded effective therapy for a long time, and only in the past IO years have symptomatic, biochemical, and histological improvements been achieved (Bijvoet et al., 1968). The available therapeutic agents, calcitonin and the diphosphonate EHDP, both have their limitations. It seems that a combination of calcitonin and EHDP largely 103

104

C.J.L.R. Vellenga et al.: Bone scintigraphy

Patients and Methods Thirty consecutive patients referred to the clinical investigation unit of the Department of Clinical Endocrinology and Metabolism for treatment of Paget’s disease were studied scintigraphically. The patients were treated with a combination of EHDP and calcitonin. EHDP was given’ orally (7.5 mglkg body weight/day) and calcitonin (50 or 100 MRC units/day) by self-administered subcutaneous injection. All patients noted subjective improvement, being able to walk further or work longer before pain developed. Iliac crest biopsies showed a decrease in the volume percentage of osteoid as well as the number of osteoclasts. At 6 months, calcium balances had become more positive, consistent with continued mineralization of previously formed bone. Further details and clinical and biochemical methods and results have been described elsewhere (Bijvoet et al., 1978). The patients are numbered as in our previous paper. In this paper, two patients (numbers 3 and 15) are excluded, because serial scintigrams were not available. Therefore, the total number of patients in the present study is 28. The follow-up of these 28 patients. which was longer than in our previous paper, ranged from 1 to 4 years; 19 patients were followed for at least 2 years, 9 of these for 3 years or more. The patients have been divided into three groups: I. Lasting remission:remission was defined as normalization of the biochemical parameters of disease activity, paralleled by clinical improvement. Remission was considered to have occurred when 6 consecutive monthly alkaline phosphatase and hydroxyproline determinations were normal (treatment was then stopped). Patients with lasting remission are those patients who to date have shown no signs of recurrence. Remission occurred in 22 out of 28 patients. However, seven of these suffered a recurrence of the disease, so that group I consists of 15 patients. Six of these patients were followed for 1 M years, three for 2-2X years, and six for 3-4 years. II, Plateau phenomenon: the other six patients (numbers 5, 8, 12, 13, 17, 23) showed an incomplete remission after 8 months of treatment whereby the alkaline phosphatase values were less than twice the upper limit of normal (50-90% decrease). In five of these patients (numbers 5, 12, 13, 17, 23) the disease later progressed. Ill. Recurrence: Seven patients were excluded from group I because remission was followed by progression of the disease (numbers 4, 10, 11, 18, 20, 25, 28). Three of these patients were followed for 2 years, one for 2’12 years, and three for 3-4 years. Bone scintigraphy was performed 3 hours after the intravenous using a Toshiba large-field injection of 20 mCi ““Tc-Sn-EHDP, 202 gamma camera. Pictures were taken of the scope, using a Polaroid@ camera with a triple-lens optical system. Routinely the entire bodywasscreened. Foreachsubsequentexaminationthe patient was positioned in the same way, and identical views were obtained, gathering a fixed number of counts. At first an attempt was made to obtain a quantitative ratio of count rates in pagetoid and normal bone (Vellenga et al., 1976). Since at that time no computer was available and, hence, no regions of interest could be chosen, this method was not very accurate. Therefore a subjective, but in our opinion quite satisfactory scoring method was designed, The scores range from 6 to 1 and are assigned as follows: Score 6: very high uptake

in pagetoid bone; the surrounding normal bone is not visualized due to the high count rate and short exposure time. Score 5: very high uptake in pagetoid bone, but some activity is seen in normal bone. moderately high uptake in the pathological area; normal bone is clearly visualized. Score 3: the uptake in pagetoid bone is only slightly elevated, but it is still distinctly demarcated from normal bone. Score 4:

in Paget’s disease under treatment.

Score 2: the pagetoid bone can hardly be differentiated normal bone; normalization is almost reached. Score 7: normal.

from

The scintigraphic evaluation was carried out simultaneously by two observers, C.J.L.R. V. and E.K.J.P., without knowledge of other data. Of course, this method is subject to personal appreciation of the images, but the scores agreed or at most deviated 1 point in 90% of the cases, while the intra-observer accuracy in the same respect was 93% and 87%, respectively. The judgment as to whether there was improvement, no change, or deterioration agreed in 85% of the cases, whereas here the intra-observeraccuracywas88%and81%. Incaseofconflicting scoring% the photographs were discussed until consensus was achieved.

Results Figure 1 a, b, c illustrates

that the three groups repreremission, plateau, and recurrence, respectively, no differences in the average scintigraphic for the affected bones before treatment was Every group contained both higher and lower Furthermore, the anatomical distribution of the was essentially the same. Table I demonstrates that there is a small variation in the distribution of scores among the most commonly affected bones and that high scores are encountered particularly in bones such as the skull. The mean scores, before treatment was started, show that there are significant differences among the various bones (chi-square test, p c 0.05). In all three groups a distinct drop in the average scintigraphic score for the affected bones was seen during the first year of treatment in all patients (Fig. 1). The greatest changes occurred in the first half-year. During this period 75% of the total decrease in scintigraphic score was attained. If one considers the change from the pretreatment score to normalization (score 1) as 1 OOVo, the total decrease in the scintigraphic score was 75% for group I (remission) and only 40% for group II (plateau). Group III (recurrence) showed a 52% decrease in scintigraphic score. Apart from this slight difference in the decrease in the average scintigraphic score, the appearance of the scintigraphiccurvesforthethreegroupswasverysimilar. However, it must be stressed again that our method was not a quantitative one, so that these figures must be handled with care. After 1 year of treatment, almost no further scintigraphic improvement was seen, although the average scintigraphic score had not yet reached unity. This means that one or more bones in each patient were still abnormal scintigraphically (Fig. 1). Figure 2 shows the average scintigraphic scores together with the different pretreatment scores. The curves are roughly parallel and become horizontal after 12 months, This means that bones with a higher initial score remain more active than bones with a lower initial score. It also means that bones with a high initial score do not normalize, whereas bones with a lower initial score may normalize. For example, normalization of bones with score 6 was never seen, whereas 25% of the bones with score 5 and 75% of the bones with score 3 normalized. Thirty-six affected bones out of a total of 100 affected bones (36%) normalized. In Figure 3 the scintigraphic curves for the different parts of the skeleton are shown. Here, too, the curves are parallel, and there are significant differences in the scintisenting showed scores started. scores. lesions

C.J.L.R.

Vellenga et al.: Bone sclntigraphy

105

In Paget’s disease under treatment.

6.0

graphic scores at all times. In addition the tendency toward normalization for the various bones also differs markedly. Normalization of the skull is less likely to occur than normalization of affected vertebrae. For some patients the scintigraphic score began to rise again after the period of decrease, suggesting that there was recurrence of the disease. In group III, the group with clinical recurrence, six out of the seven patients showed an increase in the scintigraphic score for one or more bones (Fig. 1 c). Bone scintigraphy in patient 11 failed to show such changes because further scintigraphic followup has not yet been performed. In group II, five patients suffered an increase in disease activity (Fig. 1 b). This was apparent scintigraphically in four patients, but not in patient 13, which possibly can be attributed to the very high activity in the monostotic lesion on the tibia, which hampered proper evaluation of minor changes. In group I we saw a rise in scintigraphic score in three patients who are still in remission biochemically (Fig. la). Follow-up after these scintigraphic changes was very short, so it is still possible that these patients will show biochemical recurrence later. Table II shows the relationship between scintigraphic and biochemical deterioration. In five patients scintigraphic deterioration preceded biochemical recurrence by 6 months or more, in three patients the changes

5.8 5.6

L.6 b.2 3.8 3.1,

2.6

1.8 1.6

6

12

6.0

18

30

21

6.0,

months

5.8 5.8 n 5.6

B

5.1

:::‘i, , , , , 6

12

16 months

2b

30

1 1

7

36

6

12

16

2b

30

months

Fig. 1. The average scintigraphic score for the affected bones in each individual patient ISgiven on the vertical axis; the time in months after start of treatment on the horizontal axis. Dashed lines indicate that treatment was discontinued. (A) The average scintigraphic scoresfor the affected bones in 15 patients with lasting remission (group I). There is a rapid decrease in scintigraphicactivity during the

first year of treatment, followed by stabilization. In 3 patients a rise in scintigraphic activity has been seen recently, which has not (yet) been reflected by a clinical deterioration. (B) The average scintigraphic scores for the affected bones in 6 patients with a plateau phenomenon (group II). The scintigraphic activity decreases somewhat more slowly. In 5 patients (marked with 0) a clinical relapse was encountered. Only patient 13 showed no scintigraphic deterioration. In patient 12 the average score continued to decrease but one bone showed reactivation. (C) The average scintigraphic scores for the affected bones in 7 patients with a relapse of Paget’s disease after initial improvement (group Ill). The scintigraphic deterioration is evident in most patients. Patient 11 has not been examined scintigraphically since deterioration. In patient lOone bone deteriorated, but the average score did not rise.

106

C.J.L.R. Vellenga et al.: Bone scintigraphy

in Paget’s disease under treatment.

2.6

1.6 -

6

0

6

12

18

months

Fig. 2. The average of the scintigraphic scores during treatment of bones with a pretreatment score of 6, 5, 4, and 3, respectively. Above each curve the number of bones included is indicated. The curves are roughly parallel, and bones with a higher initial score remain more active than bones with a lower initial score. (almost) coincided, in three patients the recurrence has not (yet) been confirmed biochemically. In two patients the biochemical deterioration was seen first. In two patients the progression of the disease was not seen scintigraphically.

Discussion The advent of effective therapy for Paget’s disease necessitated appropriate and reliable parameters for monitoring the activity of this disease. Of course, one of the most important parameters should be the symptomatology. Unfortunately, however, assessment of pain and incapacitation is difficult and unreliable, and the few studies employing a double-blind approach reported contradictory findings (Altman et al., 1973; Canfield et al., 1977). A very objective parameter is biochemistry, especially the serum alkaline phosphatase and urine hydroxyproline levels, and these values are in fact commonly used as the main index of activity of the disease (Bijvoet et al., 1978). However, these values reflect an average level in the entire body and give only indirect information about local activity of the disease in different lesions. The

12

18

months Fig. 3. Scintigraphic scores for different parts of the skeleton during treatment. Bones with an initial score of 1 were omitted. Thus only bones which were affected by Paget’s disease are included in this figure. There is a significant difference in the pretreatment scores for the skull, pelvis, tibia, and spine, which persists after 6, 12, and 18 months of treatment. same is true for 47Ca kinetics. Bone biopsies provide information about only one site in the skeleton. Therefore, radiography and bone scintigraphy remain as the only methods which reveal the status in individual localizations in the skeleton. Radiographic changes during treatment of Paget’s disease have been described several times (De Rose et al., 1974; Doyle et al., 1974; Nagant de Deuxchaisnes et al., 1977; Woodhouse et al., 1977), and indeed we saw slight changes in some of our patients and definite improvement in three patients (Fig. 4). However, standardization of the radiographic technique and positioning of the patient are critical and, when done properly, timeconsuming (Doyle et al., 1974). Moreover, since the pattern of Paget’s disease is highly variable, those changes indicating regression and those reflecting the natural evolution of disease must be defined (Frost, 1973). The role of bone scintigraphy in the diagnosis of Paget’s disease and in establishing the extent and activity of the disease is well documented (Canfield et al., 1977; Hadjipavlou et al., 1977; Khairi et al., 1973; Klein and Lund, 1964; Merrick, 1975; Serafini, 1976; Shirazi et al., 1974; Vellenga et al., 1976). In our study the levels of pretreatment alkaline phosphatase and urinary hydroxyproline could not be used to predict the chance of remission, plateau, or recurrence (Bijvoet et al., 1978).

C.J.L.R. Vellenga et al.: Bone scintigraphy

107

In Paget’s disease under treatment.

Table 1. Relationship between anatomical site and scintigraphic activity before treatment was started.’ Pelvis

Spine

Tibia

Femur

Skull

Cervical Score Score Score Score Score Score

6 5 4 3 2 1

5 6 3 1 0 13

(normal) Mean score

0 0 0 2 0 26

3.1

1.1

‘The incidence for the most commonly p < 0.05).

Does the bone scintigram significance

DoA

Lumbar

0 3 1 2 0 22

0 2 2 3 0 21

1.7

Left

1.7

success to be

Figure 1, the answer age pretreatment scores did not groups, nor did the anatomical groups, the degree of involvement the number of bones involved (not Considering

is negative. The averdiffer for the various distribution in these of individual bones, or shown in the figures).

of Paget’s

every bone, or is it dependent

disease similar in

on the anatomicalsite

in

the skeleton? Table I shows that the pretreatment scores were almost randomly distributed among the different localizations but that higher scores occur more often in the skull and the pelvis than in the spine. The average scores for the various parts of the skeleton show significant differences (chi-square, p < 0.05). Thus, it appears that the scintigraphic activity of Paget’s disease depends to a certain extent on localization in the skeleton, as we have noticed before(Vellengaet al., 1978; Vellengaet al., 1979). In this Table II. Relationship between scintigraphic and biochemical deterioration. Increase in Patient Number scintigraphlc score after 1 4 5 7 10 11 12 13 14 17 18 20 23 25 28

23 18 25 30 6 18 30 24 24 30 18 18 18

months’ months” months* months* months’ None months” None months months’ months months’ months months* months”

* During treatment t New lesion, originating treatment. + 2 new lesions.

Clinical and/or biochemical relapse after None 25 months 24 months None 20 months 26 months 25 months 21 months’ None 18 months” 18 months 26 months 38 months 27 months 20 months

0 6 6 1 1 14

2.5

2.6

Right

Left

Right

1 2 0 2 0 23

3 1 2 1 0 21

1 0 2 1 0 24

2 3 2 1 0 20

1.6

2.0

Number of deteriorating bones I+ 2 5 3 1+ 1’ 2 2

8: 3 3

1.5

2.1

different (chi-square test,

context, one must bear in mind that the geometry of the various bones, e.g., the skull and vertebra, istotally different. This may account partly for these differences in activity on the bone scintigram.

have any prognostic

for the therapeutic

pattern

0 6 4 3 0 15

Left

affected bones is given. The initial scores of the skull, spine, and pelvis are signlflcantly

expected?

Is the scintigraphic

Right

Total number of affected bones

1 9 12 5 2 2 9 1 4 2 2 3 4 4 3

in formerly healthy bone after the start of the

Bone scintigraphy

in the follow-up

of Paget’s disease

during treatment The question arises as to whether the scintigraphic changes during treatment should not be attributed to the natural fluctuations in the activity of Paget’s disease, which are known to occur (Dickson et al., 1945; Nagant de Deuxchaisnes and Krane, 1964). In two control patients followed without treatment for 18 and 24 months, respectively, we did not see a similar drop in scintigraphic activity. Both showed marked improvement of the bone scintigram after the initiation of treatment. Goldman et al. (1975) and Altman et al. (1973) confirmed that the scintigraphic changes during therapy were sufficiently different from changes in patients who received a placebo to be considered real. An important question is whether the therapeutically administered EHDP interferes wjth
change during and after

treatment? Many authors mention bone scintigraphy as an index of the activity of Paget’s disease during treatment (Burckhardt, 1978), and in all studies a distinct decrease in radionuclide uptake was seen in the diseased areas in most patients treated with calcitonin (Hadjipavlou et al., 1977; Lavender et al., 1977; Waxman et al., 1977), mithramycin (Hadjipavlou et al., 1977; Lentle et al., 1976) or EHDP (Altman et al., 1973; Canfield et al., 1977; Khairi and Johnston, 1977; Finerman et al., 1976; Wellman et al., 1977). Some authors used quantitative measurements of the uptake of scintigraphic agents (Lentle et al.,

108

C.J.L.R. Vellenga et al.: Bone scintigraphy

in Paget’s disease under treatment.

Fig. 4. (A) Before treatment the characteristic V-shaped front of Paget’s disease, with osteolytic spaces interspersed with more sclerotic bone, thickening of the corticalis, and coarsening of the trabeculation, is apparent. (B) After 1 year of treatment, there is the semblance of a corticalis with a more clearly defined endosteal surface. The osteolytic spaces have become filled with well-mineralized bone. The border between pagetoid bone and normal bone is becoming obscured. (C) One year later there is further blurring of the boundary between pathologic and normal bone. The pagetoid bone has assumed a normal trabecular structure. The corticalis is even more clearly defined, with an increase in mineralization.1976; Lavender et’al., 1977; Serafini et al., 1973; Miller et al., 1974; Vellenga et al., 1976), while Goldman et al. (1975) stressed the superiority of quantitative measurement over qualitative scintigraphy. In our study, the bone scintigraphic changes during treatment were striking: all patients showed a distinct decrease in radionuclide uptake in the diseased area during the first year of treatment (Fig. 5). Changes during the first half-year exceeded those during the second half-year (Fig. 1). What is the relationship

between

scintigram

and otherparameters

evaluation

of therapeutic

changes

in the bone

used for the

success?

Most observers reported a rather good correlation between scintigraphic and biochemical improvement (Altman et al., 1973; Goldman et al., 1975; Finerman et al., 1976), although in some patients the courses of the biochemical values and scintigraphic activity were different (Lavender et al., 1977; Waxman et al., 1977; Russell et al., 1979). Our study was not designed to make a quantitative comparison of these two parameters, but it shows a good correlation between scintigraphic and biochemi-

cal improvement. The tendency toward improvement during treatment is the same (Fig. 1 a), as is the tendency toward later deterioration (Fig. 1 c). In addition, the lesser tendency toward improvement observed in group II is reflected in the scintigraphic curves (Fig. 1 b). There are, however, two differences between the biochemical and scintigraphic response in general. In the first place, the decrease in biochemical values was steeper and exponential, with a half-time of 1% months (Bijvoet et al., 1978), whereas the scintigraphic improvement, although impressive, was more gradual and linear (Fig. 1). In the second place, biochemical values were much more likely to reach normal levels (in 22 out of 28 patients) than scintigraphic activity (26 patients retained pathological uptake in one or more bones) (Fig. 1). Does remission

of Paget’s disease mean normalization

of localscintigraphic

activity?

A possible explanation for the difference in the responses of biochemical and scintigraphic activity is that alkaline phosphatase is, roughly speaking, an index of osteoblastic activity (Nagant de Deuxchaisnes and Krane, 1964), which in turn presumably is a factor in ““Tc-Sn-EHDP

C.J.L.R. Vellenga et al:

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109

in Paget’s disease under treatment.

Fig. 5. Patient number 30 showed very high uptake of 99mTc-Sn-EHDP in the left femur (score 5), matching gross radiological deformity. After 18 months of therapy, the femur was quite normal, although the radiological anomaly persisted. The patient was in clinical remission

but not the major determinant (Genant et al., 1974; Jones et al., 1976; King et al., 1977). It is believed that the most important factors for this uptake are vascularity (Genant et al., 1974; Jones et al., 1976; King et al., 1977; Siegel et al., 1976), the exchangeable bone pool (Jones et al., 1976; King et al., 1977), and extracellular fluid in bone (Charkes et al., 1978), while also the amount of osteoid (Rosenthal1 and Kaye, 1975; Tilden et al., 1973; van Langevelde et al., 1977) and the concentration of enzymes in the bone (Zimmer et al., 1975) should play a role. All of these faotors are disturbed in Paget’s disease, and every one of them showed a substantial decrease during treatment of our patients (Bijvoet et al., 1978). We feel that the steep drop in scintigraphic activity can be explained in this way and that a year of treatment produces a steady state in which the residual scintigraphic activity is mainly caused by permanent changes in the micro- and macro-architecture of the bone, as demonstrated by histology and radiography. This could also explain why bones with serious scintigraphic involvement and gross radiological abnormality - probably as a result of long-standing Paget’s disease - remain highly active after treatment, although biochemical normalization often was achieved. Our conclusion from this paragraph is that remission of Paget’s disease does not mean normalization of local scintigraphic activity. uptake,

Are local effects of therapy constant,

or do individual

lesions react differently? Lavender et al. (1977) reported identical decreases in the pathological uptake in pagetoid lesions in the same patient. In our patients, all lesions showed a distinct gradual decrease in scintigraphic activity, but during and after therapy the initially most active lesions retained more activity than lesions with lower initial scores (Fig. 2). Thus

the rate of scintigraphic improvement in the various lesions in our patients was fairly constant, leaving a variable resting state after 1 year. This resting state may appear normal on the scintigram if the initial score was not too high. Even as many as one third of all affected bones became normal scintigraphically while the outstanding radiographic anomalies persisted. Similarly there were small differences in the scintigraphic scores for the individual bones after 6 and 12 months, indicating a somewhat higher activity in the skull and pelvis than elsewhere (Fig. 3). Is bone scintigraphy of the disease and -

capable

of detecting

a recurrence

if so - sooner or later than other

parameters? Deterioration of the scintigram following initial improvement was noticed by some authors (Khairi and Johnston, 1977; Shirazi et al., 1974). Although many of our patients maintained total biochemical and clinical remission for periods ranging from l/z to 2 years after termination of combined treatment, a recurrence of the disease was seen in some patients (group III and five patients in group II). Scintigraphically the recurrence was often apparent because a rise in scintigraphic activity was seen in one or more bones, either diffuse or, not infrequently, as circumscript active foci in the affected bone (Fig. 6) or, occasionally, as progression of disease into adjacent normal bone. In approximately one third of our patients with a recurrence, the scintigraphic changes preceded the biochemical deterioration by 6 months or more (Table II), This illustrates the possibly important role of bone scintigraphy in the early detection of a recurrence of Paget’s disease, the more so because this recurrence has been shown to be reversible (Khairi and Johnston, 1977). Detailed information on this subject was provided by us in an earlier paper (Vellenga et al., 1981).

110

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Vellenga et al.: Bone scintigraphy

in Paget’s disease under treatment

Fig. 6. Patient number 18 showed a very high uptake of bone scintigraphic

agent in the sacrum (score 5). Within 1 year biochemical values had returned to normal, and the scintigraphic activity was almost normal (score 2). Treatment was stopped, but 1 year later a focal increase in scintigraphic activity was seen; 24 months marked the relapse of the disease, which becameapparentclinically 1 year later. At this time (41 months) scintigraphic deterioration has progressed even further.

References Acknowledgemenf: We wish to thank C. Ruygrok for the excellent reproduction of the illustrationsand Mrs. J. Vellenga-Kaptein and Mrs. Y.E.J. Soons for their assistance in the preparation of the manuscript. Statistical evaluation was carried out by Dr. J. Hermans; the English text was corrected by Mrs. G. BiegerSmith. We are grateful to the technicians of the Department of Nuclear Medicine for their cooperation and the careful engineering required to obtain good images. This work was partly supported by the Foundation for Medical Research (FUNGO) which is subsidized by the Netherlands Organization for the Advancement of Pure Research (ZWO). EHDP was kindly donated by Henkel KGaA, Dusseldorf, West Germany.

Altman R.D.. Johnston C.C., Khairi M.R.A., Wellman H., Serafini A.N. and Sankey RF.: Influence of disodium etidronate on clinical and laboratory manifestations of Paget’s disease of bone (osteitis demormans). N. Engl. J. Med. 289: 1379-l 384, 1973. Bijvoet O.L.M., Hosking D.J., Frijlink W.B., te Velde J. and Vellenga C.J.L.R.: Treatment of Paget’s disease with combined calcitonin and diphosphonate(EHDP). Metab. BoneDis. Rel. Res. 1:251-261,1978. BijvoetO.L.M.,SluysVeerJvander, JanssenA.P.: Effectsofcalcitoninon patients with Paget’s disease, thyrotoxicosis or hypercalcaemia. Lancer 1:876-881, 1968. Burckhardt P.: Die Behandlung des Morbus Paget mit menschlichem

CJ

L.R. Vellenga

et al.:

Bone scintigraphy

In Paget’s disease under treatment.

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Received: December 3, 1980 Revised: October 5, 1981 Accepted: November 2, 198 1

RESUME Les auteurs rapportent les effets sur la scintigraphie osseuse de I’association EHDP-Calcitonine cher 28 malades atteints de maladie de Paget. La rbtention du marqueur osseux diminua considtkablement pendant la premibre annbe du traitement. On obtient une bonne corr&ation entre les variations biochimiques et scintigraphiques, mais la plupati des 22 malades dont la biochimie s’btait normalisbe avait encore une ou deux l&sions actives ii la scintigraphie. La r6mission de la maladie ne signifie done pas une normalisation de la scintigraphie. Tousles OS atteints montraient une nette diminution de I’activitb mais les I&ions ayant une activitib initiale haute restaient plus actives que celles ayant une activith plus basse. Un tiers des OS atteints se normalisPrent complktement malgrb la persistance des anomalies sur la radiographie. On observa de petites differences dans I’activitb scintigraphique en fonction du site anatomique. La scintigraphie prealable au traitement ne permet pas de prddire cependant le succc?s du traitement. Une rkidive de la maladie a &r riv&e souvent d’apr&s la scintigraphie, dans certains cas six mois avant la rechute biochimique. Ceci peut Otre t&s important dans la conduite thhrapeutique & I’dgard des rechutes.