Klinische Wochenschrift

Klin Wochenschr (1991) 69: 351-353 002321739100085M

9 Springer-Verlag 1991

Serum Osteoealein Levels in Primary Hyperparathyroidism P. Pietschmann, B. Niederle, A. Anvari, and W. Woloszczuk 2. Medizinische Universit/itsklinik, 1. Chirurgische Universit/itsklinik, Ludwig Boltzmann Institut f/ir Klinische Endokrinologie, Wien, Osterreich

Summary. The serum levels of osteocalcin, a 49amino-acid bone-matrix protein, have been found to be a specific biochemical parameter of bone formation. The aim of our study was to compare the sensitivity of serum osteocalcin levels with that of alkaline phosphatase in the evaluation of patients with primary hyperparathyroidism. In 40 patients with biochemically and histologically confirmed primary hyperparathyroidism, the serum levels of osteocalcin, intact parathyroid hormone, alkaline phosphatase, calcium, phosphorus, and creatinine were determined preoperatively. The serum levels of osteocalcin were elevated in 22 patients (55%), whereas the serum levels of alkaline phosphatase were increased in 18 patients (45%). In 10 patients (25%) the serum levels of osteocalcin, but not those of alkaline phosphatase, were increased, whereas in six patients the activity of alkaline phosphatase was high, but the serum osteocalcin levels were normal. When the biochemical data of the patients with increased serum osteocalcin levels were compared with those of the patients with serum osteocalcin levels within the normal range, the serum levels of intact parathyroid hormone and alkaline phosphatase were significantly increased in the group of patients wi~h elevated serum osteocalcin levels. Our data indicate that serum osteocalcin levels might be a clinically useful additional parameter in the evaluation of patients with primary hyperparathyroidism. Key words: Osteocalcin - Bone GLA protein Parathyroid hormone - Alkaline phosphatase Primary hyperparathyroidism Abbreviations: AP = Alkaline phosphatase; CA = Calcium; C R E A = Creatinine; G L A = Gamma-carboxy-glutamic acid; iPTH = Intact parathyroid hormone; PH = Phosphorus; OC = Osteocalcin; PHPT = Primary hyperparathyroidism

Osteocalcin (bone GLA protein, OC) is a 49-amino-acid bone-matrix protein which is synthesized by the osteoblasts and can be measured in the peripheral circulation by radioimmunoassay [11]. In histomorphometric studies conducted in patients with various endocrine disorders including primary hyperparathyroidism, in patients with postmenopausal osteoporosis, and in normal subjects as well serum OC levels have been found to be a specific biochemical parameter of bone formation [1, 2,

7]. The determination of serum alkaline phosphatase (AP) is frequently applied in the evaluation of patients with bone disorders; however, serum AP originates not only from bone, but also from liver, intestine, and other sources [6]. Primary hyperparathyroidism (PHPT) is a disorder which is generally associated with an increased bone turnover. The aim of our study was to compare the sensitivity of serum OC levels with that of serum AP levels in the evaluation of patients with PHPT.

Patients and Methods We studied 40 consecutive patients with PHPT (30 females, mean age 65+2 years; 10 males, mean age 62 _+4 years) who had been referred for surgical treatment of hyperparathyroidism. In all patients the diagnosis of PHPT was based on typical laboratory findings and later confirmed by histological examination of the parathyroid tissue. Surgical exploration revealed that 38 patients had a solitary adenoma, one patient had two adenomas, and one patient presented with four-gland hyperplasia. Twenty patients had signs of subperiosteal resorption and/or diffuse osteopenia on bone X-rays. Blood samples for the determination of parathy-

352

P. Pietschmann et al. : Osteocalcin in Hyperparathyroidism

Table 1. Age and the serum levels of osteocalcin (OC), intact parathyroid hormone (iPTH), alkaline phosphatase (AP), calcium (CA), phosphorus (PH) and creatinine (CREA) in the patients with primary hyperparathyroidism and normal (N) or elevated (H) serum osteocalcin levels. The values in parentheses indicate the normal range

Age (years) OC (ng/ml) iPTH (pg/ml) AP (U/l) CA (mmol/1) PH (mmol/1) C R E A (mg/dl)

N

H

63 _ 3 7.6 __0.5 71 +_12 145 + 13 2.8 +0.1 0.8 +_0.1 0.9 _+0.1

65 _+2 26.4 +_5.6 230 +_45 204 _+22 2.8 __0.1 0.9 _+0.1 1.3 +_0.2

roid hormone, OC, and routine blood chemistry were taken from all patients preoperatively at 8 : 00 a.m. in the fasting state. Routine blood chemistry including AP, calcium (CA), phosphorus (PH), and creatinine (CREA) levels were measured by an American Monitor Parallel Analyzer (Richmond, Va., USA). The serum levels of intact parathyroid hormone (iPTH), which are assumed to represent the biologically active PTH, were determined by a radioimmunoassay kit purchased from the Nichols Institute (San Juan Capistrano, Calif., USA). The serum levels of OC were measured by a radioimmunoassay manufactured by CIS International (Gif sur Yvette, France) as described in detail earlier [10]. Both radioimmunoassays had intraassay coefficients of variation less than 8% and interassay coefficients of variation less than 14%. The minimal detectable concentration of OC was 0.2 ng/ml; that of iPTH, 2 pg/ml. For the determination of normal ranges, serum OC and AP were measured in 106 healthy normal subjects (58 males, 48 females; age range 20-81 years). The normal range was defined as the range from the 5th to the 95th percentile, i.e., 4.0 ng/ml -11.5 ng/ml for OC and 63-169 U/1 for AP. The mean serum OC in the normal subjects was 7.1 _+ 0.2 ng/ml. All the data in the text and the table are given as the mean + SEM. The Kruskall-Wallis test and Kendall-Tau correlation coefficient were used for statistical analysis.

N.S. p < 0.0001 p < 0.005 p < 0.02 N.S. N.S. N.S.

(4.0-11.5) ( < 60) (63-169) (2.1-2.6) (0.8-1.5) (0.5-1.4)

the levels of OC, but not the levels of AP, were increased. Six patients (15%) presented with elevated serum AP but normal OC levels. The biochemical parameters of the patients with PHPT, subdivided into those with elevated and those with normal serum OC levels, are shown in Table 1. The serum levels of iPTH and AP were significantly higher in the PHPT patients with elevated OC levels. In both groups of patients the levels of calcium and phosphorus were similar. The serum creatinine levels tended to be higher in the PHPT patients with elevated OC levels; however, the differences were not statistically significant. Seven patients had slight elevations in serum levels of gamma-glutamyltranspeptidase. The serum level of alkaline phosphatase was elevated in only one of these patients (this patient also presented with an increased serum OC level). The serum levels of the aspartate and the alanine aminotransferase were within the normal range in all patients. In the group of all patients with PHPT a significant positive correlation could be found between the serum OC levels and the levels of iPTH (-c-0.40, p < 0.0003), the serum AP levels (z = 0.37, p < 0.0008), and the serum creatinine levels (z=0.30, p < 0.03). In contrast, no significant correlation between the serum OC levels and age (z = 0.08, N.S.), the serum calcium levels (z=0.01, N.S.), and the serum phosphorus levels (z =0.13, N.S.) could be established.

Discussion Results

The mean serum OC level in the patients with PHPT was 18.0_+3.4 ng/ml. The serum levels of OC were elevated in 22 patients (55%) and were within the normal range in the remaining 18 patients with PHPT. The serum levels of AP were elevated in 18 patients (45 %); in 10 patients (25 %)

In our study on patients with histologically confirmed PHPT, the mean serum OC level was more than twofold higher in the PHPT patients than in normal subjects. These findings are in line with data in the literature reporting increased serum OC levels in PHPT [2, 4, 11-13] and confirm a high prevalence of increased bone turnover in PHPT.

P. Pietschmann et al. : Osteocalcin in Hyperparathyroidism

In the studies cited above, the serum levels of the patients with PHPT were statistically compared with a control group. However, in evaluating a single patient in clinical praxis it is necessary to relate a parameter to a defined normal range. We are not aware of any study in the literature reporting a direct comparison of the prevalence of increased serum OC levels in PHPT with that of elevated serum AP levels, l[n the present study, in accordance with previous reports [3, 8, 13], we found a positive correlation between the serum levels of OC and AP; nevertheless, 25% of our patients with PHPT had increased serum OC levels but normal serum AP lew~ls. These data might indicate that in PHPT OC is a more sensitive parameter of bone formation than AP. Interestingly, 15% of the PHPT patients had normal OC but increased serum AP levels. It is possible that in these patients the alkaline phosphatase reflects a different biological event than OC, as has been suggested for Paget's disease [9]. If this is the case, the combined measurement of OC and AP might increase the sensitivity to alterations of bone metabolism in hyperparathyroidism. (In the present study the combined measurement of OC and AP would have detected 70% of the patients.) We cannot, however, exclude the possibility that the elevated AP levels in the patients with normal OC levels are due, at least in part, to contributions from extraosseous tissue. Perhaps the determination of the isoenzymes of AP would be of clinical interest in the cases with divergent behavior of OC and AP. In the PHPT patients with elevated serum OC levels, the levels of iPTH and AP were significantly higher than in the patients with normal serum OC levels. De la Piedra et al. found a correlation in PHPT between serum OC levels and the urinary hydroxyproline/creatinine ratio [3]. These data and the findings of our study suggest that patients with PHPT presenting with elevated serum OC levels may have a more active', form of the disease. In conclusion, our findings indicate that serum OC levels might be a clinically useful additional parameter in the evaluation of patients with PHPT. Acknowledgement. This study was supported in part by a re-

353 parameter for bone formation in postmenopausal osteoporosis. Lancet I: 1091-1093 2. Deftos LJ, Parthemore JG, Price PA (1982) Changes in plasma bone GLA protein during treatment of bone disease. Calcif Tissue Int 34:121-124 i 3. De la Piedra C, Toural V, Rapado A (1987) Osteocalcin and urinary hydroxyproline/creatinineratio in the differential diagnosis of primary hyperparathyroidism and hypercalcaemia of malignancy. Scand J Clin Lab Invest 47:587592 4. Delmas PD, Demiaux B, Malaval L, Chapuy MC, Edouard C, Meunier PJ (1986) Serum bone gamma carboxyglutamic acid-containing protein in primary hyperparathyroidism and in malignant hypercalcemia. J Clin Invest 77:985-991 5. Delmas PD, Malaval L, Arlot ME, Meunier PJ (1985) Serum bone Gla-protein compared to bone histomorphometry in endocrine diseases. Bone 6:339-342 6. Fishman WH (1974) Perspectives on alkaline phosphatase isoenzymes. Am J Med 56:617-650 7. Garcia-Carrasco MG, Gruson M, De Vernejoul MC, Denne MA, Miravet L (1988) Osteocalcin and bone morphometric parameters in adult without bone disease. Calcif Tissue Int 42:13-17 8. Minisola S, Scarnecchia .L, Scarda A, Bigi F, Tabolli S, Valorta C, Mazzuoli G (1988) Serum osteocalcin in primary hyperparathyroidism: short-term effect of surgery. Mineral Electrolyte Metab 14:201-207 9. Papapoulos SE, Frohlich M, Mudde AH, Harnick HIJ, Berg HVD, Bijvoet OLM (1987) Serum osteocalcin in Paget's disease of bone: basal concentrations and response to bisphosphonate treatment. J Clin Endocrinol Metab 65 : 89-94 10. Pietschmann P, Woloszczuk W, Panzer S, Kyrle P, Smolen J (1988) Decreased serum osteocalcin levels in phenprocoumon-treated patients. J Clin Endocrinol Metab 66:10711074 1i. Price PA, Parthemore JG, Deftos LJ (1980) New biochemical marker for bone metabolism. Measurement by radioimmunoassay of bone GLA protein in the plasma of normal subjects and patients with bone disease. J Clin Invest 66 : 878-883 12. Stepan JJ, Presl J, Broulik P, Pacovsky V (1987) Serum osteocalcin levels and bone alkaline phosphatase isoenzyme after oophorectomy and in primary hyperparathyroidism. J Clin Endocrinol Metab 64:1079-1082 13. Torres R, de la Piedra C, Rapado A (1989) Osteocalcin and bone remodelling in Paget's disease of bone, primary hyperparathyroidism, hypercalcaemia of malignancy and involutional osteoporosis. Scand J Lab Invest 49:279-285

Received: January 4, 1991 Returned for revision: February 18, 1991 Accepted: March 13, 1991

search grant from the Lorenz B6hler Stiftung, Wien.

References 1. Brown JP, Delmas PD, Malaval L, Edouard C, Chapuy MC, Meunier PJ (1984) Serum bone GLA protein: a specific

Dr. Peter Pietschmann 2. Medizinische Universit/itsklinik Garnisongasse 13 A-1090 Wien, Osterreich

Serum osteocalcin levels in primary hyperparathyroidism.

The serum levels of osteocalcin, a 49-amino-acid bone-matrix protein, have been found to be a specific biochemical parameter of bone formation. The ai...
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