BONE HISTOMORPHOMETRY IN PAGET’S DISEASE
Quantitative and Dynamic Analysis of Pagetic and Nonpagetic Bone Tissue
PIERRE J. MEUNIER, JEAN M. COINDRE, CLAUDE M. EDOUARD, and MONIQUE E. ARLOT
Transiliac bone biopsies from 136 untreated pa- getic patients, taken from both pagetic (72 cases) and nonpagetic bone (64 cases), were quantitatively ana- lyzed. Tetracycline double labeling analysis demon- strated that osteosclerosis of pagetic bone results from an overproduction of woven bone by the osteoblasts. In- creased bone cell populations appeared as the con- sequence of an increased birthrate of the basic multi- cellular units. In 45% of patients biopsied in nonpagetic bone, there were prints of an increased bone remodeling attributed to a hyperparathyroidism secondary to the high calcium demand of pagetic bones.
Past studies devoted to the pathology of Paget’s disease of bone were based on a qualitative and static analysis of the lesions on decalcified sections (1). But, as previously shown by others (24), it seems more inter- esting to analyze the lesions on undecalcified sections in a quantitative and dynamic perspective, because this is more likely to increase understanding of the clinical, ra- diologic, and biochemical signs of the disease and to clarify interpretation of the bone scans. This approach also permits a more precise determination of the histo- logic bone effects of therapeutics, particularly of new compounds such as the diphosphonates.
By using bone histomorphometry and double la- beling with tetracycline as applied to the analysis of
From FRA Inserm 44, Pathologie des Tissus Calcifies, Fac- Supported in part by grant of Faculte Alexis Carrel.
Pierre J. Meunier, MD; Jean M. Coindre, MD; Claude M.
Address reprint requests to Pierre J. Meunier, FRA Inserm ulte Alexis Carrel, Rue G. Paradin, 69008 Lyon, France.
Edouard, DSC; Monique Arlot, MD: Inserm Research Fellow.
44. Faculte Alexis Carrel, Rue G. Paradin, 69008 Lyon, France.
iliac bone biopsies, we attempted to specify the main disturbances in the morphology and dynamics of the re- modeling process in pagetic bone that we described ini- tially (5,6). In addition, we also quantatively analyzed nonpagetic iliac bone from pagetic patients. This bone must be considered, not only because it represents an interesting receptor for all metabolic and endocrine dis- turbances observed in Paget’s disease but also because it is an involuntary target for the therapeutic agents.
MATERIALS AND METHODS
A transfixing iliac bone biopsy was performed in 72 patients with a pagetic involvement of the iliac crest, and in 64 patients without radiologic evidence of Paget’s disease in iliac bone. The biopsy was taken with a trephine having an 8 mm inner diameter. In 63 patients biopsied in pagetic bone (P) and in 57 biopsied in nonpagetic bone (NP), a double labeling with demethylchlortetracycline had been given before the bone biopsy: the patieats received 600 mg per day of declomy- cin for 2 days, and after 12 days without tetracycline, they again received declomycin for 4 days.
The specimens were fixed in 75% alcohol and embed- ded in Ward’s Bioplastic. They were cut in 14 longitudinal nonconsecutive serial sections with a Jung K microtome. Four 20p thick unstained sections were used for tetracycline double labeling analysis under fluorescence.
Of the other 10 sections, 8p thick, four were stained with solochrome cyanin R, which permits a clear distinction between osteoid seams and calcified bone (7), and were used for the measurement of the amount of bone and of the osteoid parameters; four were stained with Goldner’s process modi- fied by Schenk and used for the measurement of resorption surfaces and osteoclasts count; two were stained with toluidine blue at pH 4.3 for cell analysis.
In 7 0 cases (33 in pagetic and 27 in nonpagetic bone), another iliac sample was obtained, fixed in Bouin’s fluid, de- calcified, and embedded in wax. These were used for the mea- surement of the periosteocytic lacunae size, on 5p thick sec- tions.
Arthritis and Rheumatism, Vol. 23, No. 10 (October 1980)
The various histomorphometric parameters measured in this study were:
1. Trabecular bone volume (TBV) which represents the percentage of a given bone volume occupied by trabeculae, excluding the medullary space, but including the calcified and osteoid tissue. This parameter is measurable either manually by a point-counting method or automatically by using an im- age analyzing computer (8).
2. Trabecular osteoid surfaces (TOS). This parameter represents the percent of the total trabecular surface covered by osteoid (7).
3. Trabecular osteoid volume (TOV). This parameter represents the percentage of a given volume of the trabecular bone occupied by osteoid (7).
4. Thickness index ofthe osteoid seams (TIO). This in- dex is calculated by the ratio TOV/TOS X 100 (7).
5. Total resorption surfaces (TRS). This parameter rep- resents the percent of the total trabecular bone surface where osteoclastic resorption is occurring or where the resorption is finished but where the osteoblasts have not yet begun the re- filling of the lacuna (9).
6. Number of osteoclasts (NOcl) per square millimeter of bone section.
7. Calcification rate (CR). This parameter represents the rate of progression of the calcification front labeled twice by tetracycline. CR is obtained by measuring the mean dis- tance between the two fluorescent labels and dividing this length by the number of days separating the two intakes of tetracycline (10). CR is expressed in microns per day. When the thickness index of the osteoid seams is normal (7), CR and the osteoblastic appositional rate are identical.
IAB. BONt VOlUMt
20 4 0 60 80
8 . Periosteocytic lacunae size (PLS). This parameter represents the mean surface area of the cross-section of 50 periosteocytic lacunae measured on decalcified sections, either manually or with an image analyzing computer (1 1).
RESULTS Pagetic bone
Increased density and hypertrophy of the bones.
The two main morphologic characteristic5 of Paget's disease of bone are the increased density of bone tissue inside the periosteal envelope and the hypertrophy of the skeletal bone pieces. Both are the result of an abnor- mally positive bone tissue balance.
The increased density is obvious in most cases where the trabeculae are thick and numerous, and the boundary between the cortical and the spongy bone is poorly defined. This osteocondensation may also be quantitatively demonstrated by the measurement of the trabecular bone volume (Figure 1). In pagetic samples the TBV is markedly increased in both sexes, in com- parison with a group of 285 control subjects, who had all suffered violent deaths. The magnitude of the in- creased density is about the same in males (number: 34;
mean TBV: 41.7 f 14.5%) and females (number: 29;
mean TBV: 41.5
*14.8%), and the ratio of the mean
F E M A L E S 1:29
20 40 60 80
Figure 1. Values of iliac trabecular bone volume in 63 biopsies taken in pagetic bone. These values are compared to mean values (& 1 SD) from 285 autopsied control subjects.
BONE HISTOMORPHOMETRY 1097
value for TBV in patients with Paget’s disease over the mean value in age-matched controls is close to 2.2 in both sexes. This increased density has little clinical con- sequence and a poor radiologic specificity for the diag- nosis.
The hypertrophy of the skeletal pieces is cer- tainly one of the more characteristic and specific mor- phologic abnormalities of pagetic bone. It explains most of the clinical signs of the disease and has a high value for the radiologic diagnosis.
Disorganization of bone architecture and lamel- lar texture. In normal bone tissue the osteonic systems are cylindrical in compact bone and form regular arches or packets in spongy bone. Their lamellar texture has a regular ordination, well revealed by polarized light.
In pagetic bone one finds few complete regular osteonic systems. Most of the pagetic tissue is composed of small patches, having scalloped contours and inter- locked together by polycyclic cement lines. They pro- duce the classic structure of a puzzle.
In most of these tissue patches the texture is an- archic and the collagen fibers form a woven bone, but in the other areas the lamellar texture persists. In pagetic bone there are always two distinct tissue components:
one with lamellar bone, the other with woven bone. As shown by Bordier (12), the percentages of these two components vary with the patient and the site of the sample, but the presence of few zones with a regular la- mellar texture is very common in pagetic bone tissue from untreated patients.
At the level of the osteocytes, the presence of these two different tissue components in pagetic bone is again easily demonstrated. By using polarized light, we measured separately the size of the periosteocytic la- cunae (POL) in woven and lamellar zones on 27 pagetic samples and noted a significant difference between both osteocytic populations. A mean cross-section surface area of the lacunae was significantly larger in the woven zones (76.9 & 13.9 pm’) than in the lamellar zones (54.1 f 9.2 pm’; P < 0.001). In the woven zones periosteocytic lacunae are the same size as in any fibrous bone.
The large size of the periosteocytic lacunae in pagetic bone had been previously noted by Belanger (13) and Duriez (14). However, this increased size does not represent a periosteocytic “osteolysis” similar to the periosteocytic enlargement noted in primary hyper- parathyroidism (1 1) but is merely a constitutional char- acteristic of the woven bone.
Prints of the disturbed remodeling process. The prints consist mainly of a marked hyperosteoclastosis associated with fibrosis and a marked hyper-
osteoblastosis associated with an extension of the osteoid borders.
Osteoclasia is qualitatively and quantitatively ab- normal in pagetic bone tissue. Most of the osteoclasts have a very large size and demonstrate numerous nu- clei. These nuclei contain viral inclusions first described in electron microscopy by Rebel (1 5). These large osteo- clasts drill deeply and scallop lacunae on the edges of the trabeculae. Besides these giant osteoclasts, few nor- mal-sized osteoclasts are noted; this is additional evi- dence for the survival of a normal remodeling process alongside the abnormal one in pagetic bone tissue.
Quantitatively, the total resorption surfaces are markedly increased in pagetic bone (Figure 2), with a mean value for 72 patients of 23.1 k 8.3% which is about seven times the mean value in 130 controls (3.6 &
1.1 %), and three times the mean obtained in a series of 147 cases of primary hyperparathyroidism confirmed by
n : 7 2
Figure 2. Mean values (-t 1 SD) for total resorption surfaces in 72 pa- getic patients biopsied in pagetic bone and in 130 control subjects.
surgery (8.2 f 1.7%) (16). Mean values for TRS are not significantly different in females than males.
If we compare the number of osteoclasts per square millimeter of section of bone tissue in iliac biopsies performed in pagetic zones and in biopsies per- formed in nonpagetic iliac crests of pagetic patients, we note also a significant increase of the osteoclastic popu- lation in pagetic areas (Figure 3), NOcl/mm2 equals 3.18 f 2.30 in pagetic areas (number: 57) and 0.33 0.23 in nonpagetic areas (number: 47). This hyper- osteoclastosis explains the increase of total urinary hy- droxyproline in Paget's disease.
Incidentally, the discovery on the sections of osteoclasts drilling a resorption cavity in a doubly la- beled trabecular edge may permit direct measurement of the resorption rate of the pagetic osteoclasts. If the dates of tetracycline administration and the bone biopsy
P A G E T I C P A T I E N T S
n : 4 7 n : 57
Lp c 0.001
Figure 3. Mean values (2 1 SD) for number of osteoclasts per mmz of iliac bone in nonpagetic and pagetic bone.
P C 0 0 1 P ' O O I P < O 0 1 P ' 0 0 1 F o o l
T 2 T
Figure 4. Mean values (k 1 SD) for osteoid parameters in pagetic bone (P) as compared to control subjects' normal values (N).
are known, the erosion rate of the osteoclasts can be cal- culated in micrometers per day. This rate, evaluated in 2 cases, was 9 and 15 pm/day.
Hyperosteoblastosis is also accentuated, with nu- merous and thick osteoblasts lining the bone edges. Bor- dier (4) and Guncaga (17) who measured the osteo- blastic surfaces found them considerably increased.
This hyperosteoblastosis induces marked changes in the amount and distribution of osteoid tissue (Figure 4), and it explains the increase in serum alkaline phospha- tase.
Osteoid volume is moderately but significantly increased in pagetic bone of both sexes by comparison with normal control subjects. In 66 control males mean TOV was 3.1 k 1.8% versus 7.8 f 3.2 in 40 pagetic pa- tients (biopsied in pagetic iliac crest). In 42 control fe- males mean TOV was 2.0 f 1.2% versus 8.3 k 3.6% in pagetic bone (32 cases).
Osteoid surfaces are more markedly increased, with means reaching about four times the normal val- ues: in males mean TOS was 15.9 f 7.9% in control sub- jects, 50.4 & 12.0% in pagetic patients. In females mean TOS was 10.7 +- 6.3% in control subjects versus 53.0 f 13.7 in pagetic bone.
Conversely, the thickness index of the osteoid borders was significantly lower in pagetic bone than in normal bone in both sexes: in males mean T I 0 was 18.8 f 4.7 in control subjects, 15.2 f 3.6 in pagetic patients;
in females: 18.2 f 3.0 in control subjects, 15.4 r+ 4.2 in pagetic patients.
BONE HISTOMORPHOMETRY 1099
C A L C I F I C A T I O N R A T E ( micron/day )
n:12 n : 1 6 n:29 n :63
CONTROLS OMALACIA NORM. BONE P A C
ET in Paget's dis.
Figure 5. Mean value (f I SD) for calcification rate in pagetic bone, as compared to mean values in control subjects, osteomalacic patients and nonpagetic bone from pagetic patients.
Thus, in pagetic bone the osteoid borders are ex- tended but thin. This morphologic abnormality means that dynamically the calcification rate is slightly faster than the osteoblastic appositional rate. Such a situation is exactly the reverse of that noted in osteomalacia, where the thickness of the osteoid seams is increased and the CR is slower than the OAR.
Osteoblastic appositional rate in pagetic bone. We found in pagetic bone tissue a markedly increased calci- fication rate with a mean value of 1.36 & .27 pm/day (number: 6 3 ) , as compared with 0.72 & 0.12 in control subjects (Figure 5). That O A R is even higher than C R indicates that O A R is itself notably increased; the pa- getic osteoblasts produce an excess of collagen matrix which is quickly synthesized in an anarchic fashion to produce a woven bone and is subsequently rapidly min- eralized.
The tetracycline labeled surfaces (Table I), singly and doubly, measured in 25 cases, occupy about 80% of the total trabecular osteoid surfaces, with doubly labeled surfaces representing about 75% of the total la- beled surfaces. Doubly labeled surfaces are always ob- served along an osteoblastic layer (Figure 6). These ex- tended labeled surfaces where the calcification process is active, combined with the acceleration of the osteo- blastic appositional rate, explain the marked increase of the bone tissue anabolism and the calcium accretion in pagetic bone. There is a high bone demand for calcium.
This also explains the increased uptake of the tracers on the bone scans.
If we measure separately the calcification rate in the rare zones having a regular lamellar organization and in the woven zones, it appears that the appositional rate is increased only in the woven areas and is normal in the lamellar areas. This observation demonstrates again the persistence of a normal appositional process along with the pathologic apposition, and thus the asso- ciation of both systems of remodeling in pagetic bone.
The acceleration of the appositional process and the histologic turnover induces an incomplete mineral- ization of many bone packets which have insufficient time to complete their slow calcification before they are resorbed by osteoclasts. This condition is clearly visible on microradiographs where undermineralized zones are easily detectable (2).
Medullary fibrosis and hypervascularization.
These conditions are evident on simple qualitative ex- amination of pagetic bone. Fibrosis is difficult to ana- lyze morphometrically and may be total or may affect only the periphery of the alveolar cavities of pagetic bone, with adipous tissue persisting in their centers. The marrow fibrosis is certainly directly related to the hyper- osteoclastosis. This is proved by the effects of high doses of ethane-1 hydroxy 1, 1 diphosphonate which induce a dramatic decrease of the osteoclast numbers and at the same time a total disappearance of the marrow fibrosis
Table 1. Doubly and singly tetracycline labeled bone surfaces in pagetic bone tissue
Bone surface Males (16) Females (9)
9% trabecular osteoid surfaces 47.8 f 11.5 56.3 f 10.4
% doubly labeled surfaces 9% singly labeled surfaces
+SL* 0.72 iz 0.07 0.76 f 0.06
27.1 k 8.5 10.8 f 4.8
34.6 f 5. I 10.9 f 4.0
+SL/TOS* 0.79 f 0.14 0.82 f 0. I I
* DL = doubly labeled surfaces; S L = singly labeled surfaces; TOS
= trabecular osteoid surfaces.
Figure 6. A, Extended tetracycline doubly labeled surfaces in pagetic bone. B, The distance separating the two labels is wide.
(18,19). Bone marrow returns to a normal state with a normal hematopoietic population.
Hypervascularization has been quantified by Demmler (20) who found abnormally numerous capil- laries in the marrow. This is likely to be the con- sequence and not the cause of pagetic hyperremodeling.
In 5 of the 64 patients biopsied in noninvolved iliac bone, well-defined histologic signs of Paget’s dis- ease were found in spite of normal x-rays of the iliac crest. Cavities of endhaversian resorption filled with multinucleated osteoclasts and areas of woven bone with increased calcification rate were observed. These abnormalities were present only in cortical bone in 2 cases but in both cortical and spongy bone in the other 3 patients. In these 5 cases trabecular bone volume was still normal, which in all likelihood explains the absence of radiologic evidence of Paget’s disease on the x-rays.
In the remaining 59 biopsies there was no evi- dence of Paget’s disease.
Trabecular bone volume. The comparison be- tween pagetic patients (24 males and 35 females) and age and sex-matched controls (21) did not show a signif- icant difference of TBV values between the groups.
Resorption parameters. In nonpagetic samples, we noted a significant increase of trabecular resorption surfaces, with a mean value of 5.8 f 2.5% (number: 56), which must be compared with a normal mean of 3.6 f
1.1% in 130 controls (P < 0.01) (Figure 7). The number of osteoclasts was 0.33 & 0.23/mmz of bone section,
greater than the normal range, which is usually lower than 0.20/mm2. Unfortunately we have no valid group of control subjects for this parameter because the post- mortem cytolysis altered the cellularity on samples from autopsied control subjects who had suffered violent deaths.
We also noted a significant periosteocytic en- largement in nonpagetic bone (mean value: 55.0 f 6.0 pm2; number: 37) when compared with control subjects (50.7 +- 5.5 pm2; number: 92) (P < 0.02).
Osteoid parameters. Mean osteoid volume was 3.0 k 2.3% in nonpagetic bone from male patients (number: 23) and 3.3 f 3.1% from females (number:
33). When compared with mean values from control subjects (3.1 & 1.9 in 66 males and 2.0 f 1.2 in 42 fe- males), a significant increase was noted only in females Though mean osteoid surfaces were increased in males (17.8 f 9.8%) as well as females (20.8 f 12.3%), a significant increase was found only in females (P <
0.001) (Figure 8).
Mean thickness index of osteoid seams was sig- nificantly lower in pagetic patients than in controls in both sexes (15.4 f 5.5 in males versus 18.8 f 4.7 in con- trols; 14.7 f 5.7% in females versus 18.2 k 3.0 in con- trols; P < 0.001).
Calcification rate. CR was not significantly dif- ferent in nonpagetic bone (0.68 & 0.16 pm/day in 57 pa- tients) from control values (0.72 f 0.12).
On the whole, in nonpagetic bone from patients with Paget’s disease, trabecular bone volume is normal, (P < 0.01).
resorption surfaces and periosteocytic lacunae size are increased, osteoid surfaces are increased (in females), thickness of osteoid seams is reduced, and calcification rate is normal. These characteristics are those of a hy- perremodeling, and in 43% of our patients resorption surfaces are higher than the mean normal value plus two standard deviations.
Histopathogenesis of the pagetic lesions as non- pagetic bone. It is possible to study the etiology of pa- getic lesions by using the concept of a basic multi- cellular unit (BMU) proposed by Frost (22) where osteoclastic resorption always precedes osteoblastic ap- position.
In pagetic bone tissue the marked extent of osteoclastic and osteoid surfaces and the great number
C O N T R O L S N O N P A G E T I C B O N E
I I z I 3 0 i l Z 5 s
L - -
,.<0 1 _ _ - 1
Figure 7. Mean value (+ I SD) for resorption surfaces in biopsies taken in nonpagetic bone in 58 pagetic patients, as compared to mean value in 130 control subjects. The individual values for the 58 patients are on the right part of the figure.
i p N *1
C O N T R O L S N O N P A C B O N E C O N T H O L S N O N P A G B O N E
,/ 6 6 / / 2 3 / / 4 2 I I 3 5
Figure 8. Mean value for osteoid surfaces (+ 1 SD) and individual values for this parameter in biopsies taken in nonpagetic bone in 58 pagetic patients. Comparison to mean value in control subjects of both sexes.
of the osteoclasts and osteoblasts can be explained theo- retically by:
A marked increase in the “birthrate” of the BMU
An increase in the “lifespan” of the BMU 1.
The acceleration of the osteoblastic apposi- tional rate noted previously demonstrated that the parcels of new bone are formed in pagetic bone, not in a slower but in a faster manner than in normal bone. This finding is thus contrary to the second hypothesis. Con- versely, a marked increase in the birthrate of the BMU is in agreement with all the data collected and pub- lished.
In addition to this increased birthrate of the BMU, that is, the increased frequency of occurrence of the new bone cell differentiation foci, there are prob- ably changes in the relative duration of the two con- secutive phases of activity in the pagetic BMU. The ra- tio of apposition surfaces to resorption surfaces, normally a value of about 4, is only about 2 in pagetic tissue. This suggests either a shortened phase of forma- tion or a prolonged phase of resorption, or both. Be- cause it is well demonstrated that the osteoblastic ap- positional rate is approximately doubled in pagetic bone, we can assume that the formation phase is ap- proximatively halved in pagetic bone, when compared with normal bone. These data are in close agreement with the fact that the ratio of TOS in normals to TOS in pagetic patients is about 3.5 and the ratio of TRS in
normals to TRS in pagetic patients is about 7, i.e. twice as much.
All of these abnormalities of the remodeling process of pagetic bone suggest a disturbance in the nu- clear code of the bone cells, probably by means of a so- matic mutation which invades the bone tissue gradually and could result from a viral agent.
Three hypotheses can be suggested to explain the hyperremodeling of bone tissue in noninvolved areas of pagetic patients:
1. A possible influence of disuse in patients suf- fering partial disability from bone pain or articular con- sequences of Paget’s disease of bone. This hypothesis is unlikely because none of our patients was resting in bed or unable to stand up and walk a few meters before bone biopsy.
2. A possible “prepagetic” state of the whole skeleton. This is also unlikely because the tissue or cel- lular abnormalities noted in nonpagetic areas are radi- cally different from those of pagetic tissue.
3. A possible hypersecretion of parathormone, as evidenced by the prints in nonpagetic bone tissue. Sev- eral observations are consistent with this hypothesis.
First, the histomorphometric profile of nonpagetic bone is very similar to that noted in bone of hyper- parathyroid states: increase in resorption surfaces, peri- osteocytic lacunae size, and osteoid surfaces (16). Sec- ondly, the serum immunoreactive parathormone level was found to be increased in 13 of 109 untreated pagetic patients with normal renal function, and serum calcium was found significantly lower in high iPTH pagetic pa- tients than in those with a normal PTH (23). This in- crease in PTH thus appears as a secondary hyper- parathyroidism, probably resulting from an increased demand for calcium by pagetic bone, and noninvolved bone is capable of registering the cumulate prints of this parathyroid hypersecretion which may fluctuate with time. In pagetic patients treated with dichloromethylene diphosphonate (C1,MDP) which markedly reduces the osteoclastic population without changing calcium depo- sition in bone, the dysequilibrium between bone cal- cium efflux (decreased) and bone calcium influx (un- changed) is accentuated and the parathormone level was increased in 13 of 19 C1,MDP treated pagetic pa- tients (24).
In spite of the histomorphometric study and iPTH assay conducted in two different groups of pagetic patients, the most likely hypothesis to explain bone hy- perremodeling noted in noninvolved areas is the influ-
ence of a parathyroid stimulation due to a lack of cal- cium in patients who have to provide enough calcium to mineralize more and more dense and hypertrophic bone.
The main histologic characteristics of pagetic bone, as defined by static and dynamic bone histo- morphometry, are thus densification of bone tissue in- side the periosteal envelope and hypertrophy of the skeletal pieces. Both conditions result from an abnormal tissue balance which requires a large amount of calcium and may stimulate parathyroid function.
Both hyperosteoclastosis and hyperosteoblastosis seem to depend on a marked increase in the birthrate of the basic multicellular units which remodel bone tissue.
Pagetic bone not only reflects a disease but also repre- sents an ideal model of bone hyperremodeling useful in rapidly determining, by dynamic histomorphometry, the effects of any therapeutic agent on bone tissue and bone cells.
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Dr. MacIntyre: What causes the parathyroid to produce increased parathyroid hormone in Paget’s disease?
Dr. Meunier: A low serum calcium level probably tells the parathyroid gland to produce more parathyroid hormone. Twelve percent of our patients have a sig- nificantly increased serum iPTH. Serum a n d urine calcium are significantly lower in high iPTH pagetic bone than in those with a normal iPTH.
Dr. Wallach The patient with severe Paget’s disease has to deposit a n average of 2-4 grams of calcium per day to produce new bone and it is reasonable that some parathyroid hyperplasia would result from these accelerated processes.
Dr. Bijvoet: We have had patients o n combination ther- apy in remission u p to 5 years. However, the fibrosis of pagetic bone has remained although it is said t o disappear with either calcitonin or EHDP. Why the difference with the combination?
Dr. Meunier: We have seen tremendous reduction of fi-
brosis after 6 months in patients on either E H D P or dichloromethylene diphosphonate.
Dr. Bijvoet: There is a discrepancy in our experiences.
Dr. Meunier: T h e reduction of fibrosis seems to be pro- portional to the reduction of osteoclasts.
Dr. Canfield I agree that the pagetic patient is not like the normal patient nor like a patient with hyper- parathyroidism. We examined the effect of mith- ramycin therapy o n vitamin D. When therapy was started, the parathyroid hormone levels were at the upper limit of normal or above, as were the urinary cyclic AMP, GMP, and vitamin D levels. T h e pa- tients had been on vitamin D and calcium before treatment. This is not just a vitamin D lack, there is something more operating here.
Dr. Meunier: I agree that this is not just a vitamin D lack. When mean serum 250HD levels were measured in 57 untreated pagetic patients, there was n o signifi- cant difference between patients with high serum iPTH and those with normal iPTH.