Pre- and postoperative bone metabolism of primary hyperparathyroidism

Biomed & Pharmacother 2000 ; 54 Suppl 1 : 90-6 © 2000 l~ditions scientifiques et m6dicales Elsevier SAS. All rights reserved

Short article

Pre- and postoperative bone metabolism of primary hyperparathyroidism S. Suzuki, T. Fukushima, H. Ami, S. Asahi, H. Onogi, I. Nakamura, A. Tsuchiya, S. Takenoshita Department o f Surgery 1I, Fukushima Medical University School o f Medicine, 1 Hikarigaoka, Fukushima, 960-1295, Japan

Summary - Primary hyperparathyroidism (PHPT) is a well-known indicator of severe bone loss. However, the recovery process of bone mineral density after surgery in PHPT patients is not sufficiently clear. We examined postoperative bone metabolism in 24 PHPT patients. Patients and methods - Subjects were 24 patients with PHPT upon whom we performed parathyroidectomy in the Department of Surgery II, Fukushima Medical University. Mean age was 54.2 years and the male-to-female ratio was 10:14; mean time of follow-up was 27.3 months. Patients were divided histopathologically into 16 adenomas and eight hyperplasias, and classified by heredity into seven familial (six, MEN 1; one, MEN 2) and 17 sporadic types. Bone mineral density was measured by dual energy X-ray absorptometry (DXA) and digital image processing (DIP). Age-matched values of these parameters were obtained. Serum bone metabolic parameters; ionized calcium (CaF), phosphorus, intact PTH (iPTH), c-PTH, ALP, osteocalcin (OC) and PTHrP were measured. Results - PHPT patient preoperative bone mineral densities were significantly lower than those of healthy controls. Those by DIP method were lower than those by DXA. High CaF, iPTH, OC and ALP levels were indicated before surgery, but all parameters immediately became normal. Longitudinal bone mineral density changes of asymptomatic cases increased more than those of patients with renal stone and/or ostitis fibrosa. In adenoma cases, tumor weights were significantly inversely, which correlated with preoperative DIP bone density measurements. Conclusion - Preoperative PHPT patients showed decreased bone density; bone loss in symptomatic cases was especially prominent compared to asymptomatic cases. Most PHPT patients had not completed the BMD recovery after surgery, so even asymptomatic and mild PHPT patients should undergo parathyroidectomy to minimize irreversible bone loss. © 2000 Editions scientifiques et m6dicales Elsevier SAS bone mineral density / DIP / DXA / osteopenia / primary hyperparathyroidism

P r i m a r y h y p e r p a r a t h y r o i d i s m ( P H P T ) is a w e l l - k n o w n i n d i c a t o r o f severe b o n e loss as ' h u n g r y b o n e synd r o m e ' [1, 2], but r e c o v e r y o f b o n e mineral density after surgery in P H P T patients is not sufficiently clear. B o n e r e d u c t i o n in P H P T patients is not rare; osteopenia is a c o m m o n p r o b l e m even in patients with a s y m p t o m a t i c H P T [3, 4]. B o n e mass r e c o v e r y after surgery in P H P T p a t i e n t s was c o n t r o v e r s i a l , s i g n i f i c a n t l y d e c r e a s e d [5, 6], or not d e c r e a s e d [7, 8]. Martin, et al. [9] and Parfitt [10] d e s c r i b e d bone loss in P H P T as o n l y partially irreversible. T h e r e w e r e variable methods in r a d i o l o g i c e x a m i n a t i o n o f bone mineral content; w e have m e a s u r e d pre- and p o s t o p e r a t i v e bone m i n e r a l density ( B M D ) o f 24 P H P T patients by two m e t h o d s in t w o sites ( l u m b a r spine and s e c o n d m e t a c a r p a l bone). Also, s o m e b o n e m e t a b o l i c markers w e r e e x a m i n e d in relation to these B M D before and after surgery.

PATIENTS AND METHODS Patients We studied all 24 PHPT patients who underwent parathyroidectomy in the Dept. of Surgery II, Fukushima Medical University Hospital. Mean _+ standard deviation (SD) of ages in PHPT patients was 54.2 _+ 17.6 years (range 12-79 years). Male-to-female ratio was 10:14. Mean duration of follow-up after operation was 27.3 months (range 1-33 months). Three types were classified for those PHPT by predominant clinical symptoms. Type I patients complained of some symptoms due to ostitis fibrosa, while type II complained of renal calculus, and type Ill showed no symptoms other than hypercalcemia and/or high levels of PTH (parathyroid hormone). There was one type I patient, 14 type II patients, and nine type III patients. In our cases, seven were hereditary (six multiple endocrine

Bone metabolismof primary hyperparathyroidism neoplasia [MEN] type 1 and one case of type 2) and 17 were sporadic cases. Histopathologically, there were 18 cases with parathyroid adenoma and six cases with hyperplasia. These methods of surgical procedures were single parathyroidectomy (PTx) in five cases, double PTx in ten cases, triple PTx in six cases and quadruple PTx in three cases.

Methods D X A method

Bone mineral density (BMD) of the L2-L4 vertebrae of each patient was measured by dual-energy X-ray absorptometry (DXA) performed by an XR-26 DXA system (Norland Co., Fort Atkinson, WI, USA). Age-matched BMD values were calculated as patient BMD/mean BMD where the mean was that of a number of healthy control Japanese men or women of the same age provided by the Japanese Society for Bone and Mineral Research [11].

91 S

Tokyo, Japan) (normal range: 1.00-1.215 mM/L). Serum alkaline phosphatase (ALP) was measured by the BesseryLowry method (normal range: 125-335 IU/L). Intact parathyroid hormone (iPTH) was measured by an immunoradiometric assay (IRMA) method, using an Allegro intact PTH immunoassay kit (Mediphysics Co., Tokyo) (normal range: 5-60 pg/mL). Serum osteocalcin (OC), so-called bone Gla protein (BGP), was measured by an IRMA method with a BGP IRMA kit (Mitsubishi Medical Co., Tokyo) (normal range: 3.1-12.7 ng/mL).

Statistical analyses Student's t-test and Wilcoxon rank sum test (for coefficient of correlation) were used for statistical analyses. Significance level was decided at P < 0.05. RESULTS

Preoperative bone metabolic markers

D I P method

X-ray film of the hand was obtained with an aluminum wedge as standard on the same film. Bone mass was then assessed from the image by a digital imaging processing (DIP) technique described by Hayashi et al. [12, 13]. In this method, the second metacarpal bone in the non-working hand is assessed for bone mass. A region of 6 to 8 mm long and covering 10% of the length on the shaft in the X-ray film is transversely scanned at 30 to 40 lines. Obtained DIP values represent average luminosity of the image on the lines used for the image processor, a Bone Analyzer DIP-1000 (Hamamatsu Photonix Co., Ltd., Japan). This method obtains BMD for the value of ZGS/D. Age-matched ZGS/D was found as patients ZGS/D/mean ZGS/D of a number of healthy Japanese men and women controls of similar age, provided by the Japanese Society for Bone and Mineral Research [I 1]. We classified four groups in preoperative DXA and DIP indices: group A (DNA index > 1), group B (0.90-0.99), group C (0.80-0.89) and group D (< 0.8 0).

Biochemical markers The concentration of ionized calcium (CaF) was measured with an ionized calcium analyzer (Chiba-Corning Co.,

Clinical bone metabolic markers in preoperative patients are shown in table I. All parameters indicated high values. There was no significant correlation in CaF, iPTH, OC and ALP among type I, II and III because type I was only one case. Still, these parameters (excepting OC) had a tendency to be higher for type II than for type III, and higher for type II than for type I.

Parathyroid gland weights Mean weight of resected type I parathyroid glands was higher than for type II glands, and type II were higher than type III ( t a b l e I). However, there was no significant difference among these three groups because there was only one case of type I.

Preoperative bone mineral density Through DXA and DIP methods, type I patients showed the greatest decrease in bone mineral density (BMD) compared to types II and III. Mean D X A and DIP indices in type III were significantly higher than those

Table I. Variable factors of preoperative bone metabolismand weights of parathyroidtumors. Factors

Ca F (mMfl) iPTH (pg/ml) OC (ng/ml) ALP (I/L) Weight of gland (mg)

Type I (N = 1)

2 780 15.8 2,845 4,900

Type H (N = 9)

1.56 - 0.33 402.5 _+772.9 18.1 _+11.1 633.2 _+1,154.7 1,723.2 _+3,187.8

Type I11 (N = 14)

1.38 _+0.16 95.8 -+52.7 12.8 _+6.4 254.7 _+112.6 619.5 _+632.3

Overall (N = 24)

1.49 + 0.27 264.8 ___533.1 14.8 _+8.2 536.1 _ 909.6 1,303.7 -+2,295.9

92S

S. Suzuki et al.

Index 1.2

Group A, conversely, decreased transiently for three to six months after the operation (figure 2b).

./¢ I

I

1

Longitudinal changes in bone mineral densities in postoperative PHPT (DIP method)

0.8

DIP

0.6

Longitudinal BMD change by DIP method is shown in patients showed increased BMD after surgery. Still, many cases had not completed recovery to index ' l ' , which was the normal control mean. Even one or two years later, these cases had not increased to DIP index 1. In two type II patients, those DIP indices were below 0.8 even after more than 48 months (figure 3a). Most groups, excepting C, indicated increased BMD after surgery, especially group D, which showed severe bone loss with prominently increased BMD. Though group C showed decreased BMD after surgery up to 12 months, it began to increase at 24 months. Group B also showed transient decrease over a three- to six-month post-surgery period.

figure 3a. Most PHPT

0.4 0.2 0

'

'

'

Type II (N=l 4)

Type I (N=I)

Type III (N=9)

*: P=0.048

Overall (N=24)

**:P=O.OO75

Figure 1. Preoperative bone mineral density. The type I patient had the greatest decrease in BMD than those with type II and III using both methods. The means of DXA and DIP index in type III were significantlyhigher than those in type II (P = 0.0075, 0.048). in type II (P = 0.0075, 0.048): mean of the DXA index in type III was similar to 1.0 - the normal control baseline. There was no significant difference between DXA and DIP indices of overall cases and every subtype

Postoperative changes of ionized calcium (CaF) in PHPT patients

(figure 1).

Longitudinal changes in bone mineral densities in postoperative PHPT patients (DXA method) Longitudinal BMD change after surgery with PHPT patients is shown in figure 2. Most patients had not completed BMD recovery yet (figure 2a). Three groups, excepting A, had shown gradually increasing BMD correlating with the interval after surgery (figure 2b).

Postoperative changes of CaF in PHPT patients are indicated in figure 4. Postoperative CaF in all patients (except one with super-numeral parathyroid gland despite four resected glands) reached normal levels (figure 4a). Mean average time for normalized CaF was 1.1 + 2.6 months: 15 patients (62.5%) became normocalcemic within one week after operation (figure 4b). Some total PTx cases showed hypocalcemia due to calcium and/or vitamin D3 supplements.

A D X A index

(%)

1.6

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- Type 1

1.4

....... T y p e I I

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1.2

~

• ~

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• ~

......................

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15'

u

[] 0.8~)89: Group C

i

o~

..~

0.2

~-5' 0

• l: Group A [] 0.9~0,99: Group B

~ 5

°..°°'~

0.6 0.8 I 0.4 0

Preoperative DXA index

[10

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I

I

I

i

i

I

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24

36

48

60

72

84

[ ] <08: Group D

1

3

16

|

12

24

Postoperative t i m e ( m )

-10

postoperative time (m)

Figure2. A: Longitudinalchanges of bone mineral densities in postoperative PHPT patients (DXA method). Most of patients have not completed recovery of BMD yet. B: Changes of postoperative bone metabolismin PHPT patients (DXA method). Three groups except A were shown with gradually increasingBMD, which correlated with the interval after surgery.

Bone metabolism of primary hyperparathyroidism

DIP index 1.4 ~

(%) 40

.

1.2

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~ 30

1

0.8 0.6

- • Type I ...... Type II m Type lII

0.4 0.2

.

0 0

12

.

. 24

.

.

36

.

48

lO 0

°_ m.J. lJ

[] <0.8: GroupD

Post operative time (m)

~ -20 72

[] 0.84.89: Group C

! -10

. 60

[ -~

Preoperative DIP index • 1: GroupA [] 0 9 ~ . 9 9 : Group B

84

(M)

-ao

Figure 3. A: Longitudinal changes of bone mineral densities in postoperative PHPT patients (DIP method). Most PHPT patients showed an increase of BMD after surgery. But many cases have not completed recovery to index '1 '. B: Changes of postoperative bone metabolism in PHPT patients (DIP method). Most groups except C had increased BMD after surgery; group D was especially prominent.

A

B

CaF

(mM/I)

No. of cases

2.5

16 14 l.l ± 2.6 m o n t h s

Average

12 10

1.5

8 6 4

o/ 0

A)

2 I

I

I

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I

12

24

36

48

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72 84 Postoperativetime(m)

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"

l

B)

C)

2

3

12

--

0.25

0.5

0.75

1

Postoperative time (m)

Persistenl of hypercalcemia

Figure 4. A: Changes of postoperative ionized calcium (CaF) in PHPT patients. Postoperative CaF in all patients except one fell immediately after surgery. B: Interval until normalized ionized calcium levels in postoperative PHPT patients. Mean average time which normalized CaF was 1.1 _+2.6 months, 15 patients (62.5%) became normocalcemic within one week after surgery. A) These two cases were performed total PTx. B) Giant adenoma with a weight of 11 g (type II). C) Giant adenoma, with weight of 4 g (type I). D) This patient was shown to have persistent hypercalcemia because of super-numeral gland.

Postoperative intact P T H (iPTH) changes

Postoperative OC changes in PHPT patients

Postoperative i P T H changes showed similar trends to CaF, so only one patient exhibited persistent high i P T H levels due to the super-numeral gland. M e a n average o f interval to i P T H normalization was 5.1 _+ 12.5 months (figure 5b), but i P T H w i t h m o s t patients d e c r e a s e d below the upper limit of normal range within one w e e k after surgery (figure 5b ).

P r e o p e r a t i v e O C w e r e h i g h in o n e - t h i r d o f P H P T patients. These cases showed nearly normal OC. However, two cases of giant adenomas exhibited t r a n s i e n t h i g h O C at six a n d 20 m o n t h s a f t e r s u r g e r y (figure 6a-b). O n e - f o u r t h m a i n t a i n e d h i g h O C up to 12 m o n t h s a f t e r t h e o p e r a t i o n

(figure 6b).

94s

s. Suzuki et al.

A i-PTH (pg/ml)

3,000[ 2,500 2'0001/ 1'500I/ 1'000I/

No. of cases

14 12

Average 5.1 + 12.5 months

10

8

4|

6

2

c) A)

B)

1

D)

6

16

59

E)

0 0

12

24

36

48

60

0.25

72 84 Postoperative time (m)

5

Persistent of

high iPTH

Postoperative time (m)

Figure 5. A: Changes of postoperative intact PTH in PHPT patients. Postoperative iPTH in all patients except one fell immediately after surgery. B: Interval until normalized intact PTH levels in postoperative PHPT patients. Mean average of interval until normalized iPTH was 5. l _+ 12.5 months. A) type III adenoma, B) and C) type II adenomas, D) This patient had residual gland because of super-numeral gland. A

B

OC (ng/ml)

50

No, of cases

3040

/

Type II adenoma (llg)

25-

35 30 25 15 10 5 0

Osteocalcin levels [] normalized

15, .

.

.

.

.

.

.

• high level

10-

[] transient

50

12

24

36

48

60

72

' 84

increasing

0'

Pre op.

12 Postoperative time (m)

Postoperativetime (m)

Figure 6. A: Postoperative serum osteocalcin (OC) changes in PHPT patients. Preoperative OC were high in 33% of PHPT patients, but two giant adenomas showed transient high OC. B: Postoperative serum osteocalcin changes in PHPT patients. One-fourth showed high OC 12 months after operation.

Postoperative ALP changes in PHPT patients P r e o p e r a t i v e A L P was e l e v a t e d in six P H P T cases (25%). Two cases (33%) had high A L P six months after operation: these cases were large (11 g and 4 g) adenomas. The type II a d e n o m a case showed normal A L P 12 months after operation, but the type I a d e n o m a case was not e x a m i n e d until 60 months after operation. U p o n the patient's hospital visit 60 months after operation, A L P levels were normal (figure 7 a-b).

Preoperative parameters and bone mineral density correlation T h e r e w e r e no s i g n i f i c a n t c o r r e l a t i o n s b e t w e e n D X A index, DIP index and CaF, ALP, iPTH, O C before surgery. There were no significant associations between D X A index, DIP index, and gland weight. In adenoma cases, there was s i g n i f i c a n t n e g a t i v e c o r r e l a t i o n b e t w e e n DIP index and gland weight (coefficient value r = - 0 . 5 5 4 , P = 0.017). There was slight correlation

Bone metabolism of primary hyperparathyroidism A

95s B

ALP

(IU/L) 5,000

No. of cases

30 4,000

25 3,000

20

i i ilii ::

2,000

15

::::::: :

I'q normalized

10

i((::::i

k~high level

1,000 0

•. . . . . . . . .

0

12

24

36

48

60

72 84 Postoperativetime(m)

0

........

Pre op.

I

6M

12M

Postoperative t i m e ( m )

Figure 7. A: Postoperative ALP changes in PHPT patients.

Postoperative ALP fell immediately after surgery except for two giant adenoma. A) type II adenoma (11 g), B) type I adenoma (4 g). B" Postoperative serum ALP changes in PHPT patients. Preoperative ALP was elevated in six PHPT cases (25%). Two cases (33%) had high ALP six months after operation; these cases were large adenomas, with weights of 11 g and 4 g.

Table II. Correlation between preoperative parameters and bone mineral density (Coefficient values). Parameters

Age Weight of gland CaF ALP 1-PTH OC

DXA index

0.243 0.166 -0.104 -0.503 -0.104 -0.434

DIP index

0.587* -0.130"* -0.120 -0.482 -0.081 -0.257

between age and preoperative DIP index (r = 0.587, P = 0.067) (table II). DISCUSSION The present study shows preoperative bone loss in PHPT patients. The DIP indicated the cortical bone BMD, while the D X A method mainly shows that of the trabecular bone in the lumbar spine. Some authors assert that the cortical bone was more affected than the trabecular bone in PHPT [14-16], but our results showed no difference between D X A and DIP methods. Our results indicate that preoperative bone loss was most prominent in type I, then in type II, and that bone loss in type III was slight compared with normal controis. Most of the type III cases may include asymptomatic cases. Seibel et al. suggested that osteopenia was a common problem, even in patients with asymptomatic PHPT [4]. Longitudinal changes in B M D measured by two methods after surgery were not great. All cases except

group A in DXA, with no osteopenia, and group B in DIP, with slight osteopenia before surgery, showed gradually increased BMD up to 24 months after surgery. M o s t patients c o m p l e t e d B M D recovery in several years. These results agree with those of Tisell et al. [ 17], who described skeleton remineralization after PHPT surgery, but differ from those of Abugassa and colleagues [18], who suggested recovery phase completion within six months o f surgery. Remineralization is incomplete: only a poor bone mineral gain can be expected over one year [19]. Silverberg et al. [8] suggested that the BMD increase occurred over at least four years. Most iPTH, CaF, OC and ALP fell immediately after surgery in the present study. Rebound PTH increase was shown from ten days to three months after. These patients' PTx and CaF were significantly lower: these patients had higher PTH and CaF, which could have led to greater depletion of bone mass [17]. Our data indicated PTH and CaF in cases with late normalization had severe bone loss because of large adenomas. Preoperative OC was high in 33% of our cases, but Takami et al. [20] indicated 77.7%. Preoperative A L P was high in 25% of our cases, but Brasier et al. [2], and Martin et al. [9] indicated 42% and 50%, respectively. Our results suggested that iPTH, OC and A L P in patients with d e l a y e d n o r m a l i z a t i o n were a s s o c i a t e d with large adenoma and/or symptomatic (type I or II) cases or residual glands. These might be difficult for immediately recovering BMD. Still, preoperative biochemical parameters were not significantly associated with BMD

96s

s. Suzuki et al.

in o v e r a l l c a s e s . O u r d a t a s h o w e d s i g n i f i c a n t c o r r e l a tion between adenoma weight and preoperative DIP i n d e x , w h i c h r e s u l t w a s s u p p o r t e d in B r a s i e r et al. [2], in t h a t t h e m o s t i m p o r t a n t p r e d i c t i v e f a c t o r w a s t h e resected parathyroid adenoma volume. These sugg e s t e d that t h e a m o u n t o f b o n e lost at t h e t i m e o f s u r g e r y depends more on disease duration than on bone t u r n o v e r rate a l t e r a t i o n s [9]. V e r t e b r a l c r u s h f r a c t u r e s in P H P T w e r e m o r e p r e v a l e n t t h a n in t h e c o n t r o l g r o u p [9]. In t h e p r e s e n t study, this w a s u n c l e a r . C o n c l u s i v e l y , most PHPT had not completed BMD recovery after surgery, so even asymptomatic and mild PHPT patients s h o u l d u n d e r g o p a r a t h y r o i d e c t o m y to m i n i m i z e irrev e r s i b l e b o n e loss.

9

10 11 12

13

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