Effect of calcium pidolate on biochemical and hormonal parameters in involutional osteoporosis

Maturitas, 12 (1990) 105-l 11 Elsevier Scientific Publishers Ireland Ltd. MAT 00582

Effect of calcium pidolate on biochemical and hormonal parameters in involutional osteoporosis H. Rico’, J.A. Cabranes2, E.R. Hernandez’, G . Escudero2

J. Pkrez de1 Molino’ and

‘Lkpartamento de Medicina de Ia Universidad de Alcala de Henares, 28871 Madrid and ‘Servicio de Medicina Nuclear del Hospital UniversitarioSan Carlos, 28040 Madrid (Spain) (Received 17 May 1989; revision received 9 February 1990; accepted 28 February 1990) The purpose of this study was to determine the value of calcium pidolate in the treatment of involutional osteoporosis. This compound has been reported to be better absorbed than other calcium salts, to lower the levels of parathyroid hormone (PTH) and to raise those of growth hormone (GH). We accordingly treated one group of 10 women suffering from involutional osteoporosis with the equivalent of 1 g elemental calcium and administered a placebo to a second group of 10 osteoporotic women whose mean age and body surface area were comparable. Basal sequential multiple analysis (SMA-12) was performed in all subjects to determine calcium, phosphorus, alkaline phosphatase (ALP) and total protein levels, the same blood samples being used for the evaluation of mean PTH, GH and osteocalcin (BGP). Urinary 24-h calcium excretion was determined and the calcium/creatinine (Ca/Cr) and hydroxyproline/Cr (HP/Cr) ratios were measured in 12-h fasting urine samples, the results being corrected for glomerular filtrate. The same parameters were measured again following a month of uninterrupted treatment. After 30 days, we observed no differences in either group as regards calcaemia, phosphataemia, ALP, total proteins, PTH, GH, BGP or 24-hour calciuria. The only noteworthy changes seen were significant decreases (P < 0.001) in the Ca/Cr and HP/Cr ratios in the group treated with calcium pidolate. These results show that calcium pidolate at the dose administered inhibits bone resorption but does not affect the levels of PTH, GH, BGP or ALP in the medium term. Our findings indicate that it has no influence on bone formation. (Key words: Involutional Osteocalcin)

osteoporosis,

Calcium pidolate, Para-thyroid

hormone, Growth hormone,

Introduction The efficacy of oral calcium in the treatment and prevention of osteoporosis is the subject of current and ongoing debate [l-4]. While some authors report it to be ineffective [5,6], others consider it to be of value [7,8]. The usefulness of calcium may depend, among other things, on an individual patient’s intestinal absorption [9] or gastric acidity [lo], and on the doses [I l] and/or type of calcium used (121. Correspondence to: H. Rico. 0378-5122/90/$03.50 0 1990 Elsevier Scientific Publishers Ireland Ltd. Printed and Published in Ireland

106

It was recently reported that calcium pyridolone [13] (also termed calcium pidolate) is absorbed better than other calcium salts by both normal and osteoporotic elderly individuals, which suggests that this compound could be effective in the treatment and prevention of osteoporosis. It has also been reported that, as compared with other calcium salts, calcium pidolate lowers the level of parathyroid hormone (PTH) and raises that of growth hormone (GH) [14]. These effects may make it useful for the individual cases of osteoporosis where reduced GH levels have been reported [ 15,161. To determine its possible value, we treated one group of osteoporotic postmenopausal women with calcium pidolate and another similar group with placebo and compared the result. Subjects and methods Two groups, each comprising 10 post-menopausal women, were studied. The patients in Group A had a mean chronological age of 72 + 8 years, a mean age at menopause of 52 + 5 years and a mean body surface area (BSA) of 1.55 + 0.3 m2. The women concerned had more that one atraumatic crushed vertebra and had been diagnosed as suffering from involutional osteoporosis after exclusion of possible secondary osteoporosis by the appropriate tests (biochemical, hormonal and haematological). None were using any drugs that might alter bone metabolism (hydantoins, vitamins A and D, glucocorticoids, heparin, anticonvulsives, diuretics or antidepressives). This group was treated with calcium pidolate at a dose of 7 g/day (equivalent to 1000 mg of elemental calcium) taken after the evening meal in the form of an oral solution (Ibercal, BOI Laboratories, Barcelona, Spain) for 30 days. The other group (Group B), in which the mean age was 73 f 7 years, the mean age at menopause was 50 f 6 years and the mean BSA was 1.57 f 0.3 m2, consisted of 10 osteoporotic women who met the same criteria as those in Group A. The subjects in Group B were treated with a placebo administered in the same form and quantity over the same period as the calcium pidolate. As is usual when osteoporosis is diagnosed, vitamin D deficiency was ruled out by measuring serum levels of 25(OH)D, which were found to be in the normal range u71. Prior to the start of treatment a basal sequential multiple analysis (SNA) (Technicon, Tarrytown, NY) was performed in all subjects at 0900 h, using peripheral blood samples. In 24-hour urine samples collected without having imposed prior dietary restrictions (mean intake of calcium was 560 f 80 mg/day in the two groups), total calcium was determined by atomic absorption using a Perkin-Elmer Model 5000 analyzer with an AS-50 automatic sampler (PerkinElmer, Norwalk, CT). Using methods described elsewhere the concentrations of hydroxyproline (OHP) [ 181, creatinine (Cr) [19] and calcium (see above) were determined in a 12-h overnight urine sample of the fasting subjects; before this urine collection a protein- and gelatin-free diet was followed during 3 days. The mean molecular PTH and osteocalcin (BGP) values were determined in

NS 71 f 12 80 2 15 NS

P-value B Pre-treatment Post-treatment P-value

3.5 1.9

NS 10.1 f 4.2 9.7 fi 4.8 NS

9.0 f 8.8 f

BGP ng/ml

NS 2.8 f 3.1 f NS

2.8 f 2.2 f

GH ng/ml

0.7 2.1

1.1 1.0

207 195 NS 220 201 NS f f

38 36

f 67 + 40

Ca24 mg/24 h

0.192 f 0.136 f < 0.001 0.168 f 0.160 f NS

0.016 0.024

0.024 0.016*

CaKr mg;/lOOGF

0.020 f 0.015 f < 0.001 0.018 f 0.016 * NS

0.001 0.002

0.002 0.001*

- -HP/Cr mg/lOOGF

*Differences where P < 0.001 according to the t test for pre-treatment and post-treatment paired data. PTH = parathyroid hormone, BGP = osteocalcin (bone Gla protein), GH = growth hormone, Ca = calcium, Cr = creatinine, HP = hydroxyproline, mg/ltXl GF = mg percent of glomerular filtration rate.

63 f 64 f

A Pre-treatment Post-treatment 12 18

PTH pmol/l

Group

VALUES FOR PTH, BGP, GH, 24-h URINARY CALCIUM (Ca 24) AND CA/CR AND HP/CR RATIOS IN URINE SAMPLES OBTAINED AFTER A 12-h FAST BEFORE AND AFTER TREATMENT IN A GROUP OF 10 OSTEOPOROTIC POST-MENOPAUSAL WOMEN TREATED WITH 1 g ELEMENTAL Ca AS CALCIUM PIDGLATE FOR 30 DAYS (GROUP A) AND IN A COMPARABLE GROUP OF 10 WOMEN TREATED WITH PLACEBO (GROUP B). P-VALUES WERE DETERMINED BY MEANS OF f-TEST FOR UNPAIRED DATA

TABLE I

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the blood samples taken for SMA analysis, using commercial kits (Sorin Biomedica, Saluggia, Italy, and Compagnie Oris Industrie, Cif-sur-Ivette, France), while GH was measured according to methods described elsewhere [15]. These hormonal determinations were performed in our laboratory. The interassay and intra-assay coefficients of variation were under 10%. The same analyses were performed in the same sequence 30 days after treatment was terminated. The statistical study of the differences between means and individual values was carried out using the t-test for paired and unpaired data. Results Basically, there were no significant differences between the groups as regards age, age at menopause BSA, or biochemical and hormonal parameters. Table I shows the serum values of PTH, GH and BGP, as well as the 24-h urinary calcium and the Ca/Cr and HP/Cr ratios for the two groups. In Group A, which was treated with calcium pidolate, the pretreatment and post-treatment serum values of total calcium, phosphorus and ALP did not alter significantly, the same being the case as regards 24-h calciuria. However, the Ca/Cr and HP/Cr ratios (expressed as mg percent of the glomerular filtration rate) did exhibit changes, decreasing from 0.192 f 0.024 to 0.136 & 0.016 (P < 0.001) and from 0.020 + 0.002 to 0.015 f 0.001 (P < O.OOl), respectively. According to the t-test for paired variables, the changes in both these parameters had the same level of significance. Pre-treatment and post-treatment values showed no changes in the case of PTH (63 + 12 vs. 64 f 18 pmol/l), BGP (9.0 & 3.5 vs. 8.8 + 1.9 ng/ml) or GH (2.8 + 1.1 vs. 2.2 f 1.0 ng/ml). In Group B, which received placebo, there were no significant changes in any of the parameters studied. Discussion Our results show that, at the dose used, calcium pidolate inhibits bone resorption and can thus be of value in the treatment of bone diseases attributable mainly to this cause, such as post-menopausal osteoporosis [20]. Contrary to what has been reported previously [14], the changes involved are not the consequence of a decrease in PTH or of changes in GH or BGP. The absence of any variation in calcaemia and 24-h calciuria, despite the administration of 1 g of elemental calcium, reflects the inhibitory action of calcium pidolate on bone resorption. The values in both cases are dependent on intestinal absorption, renal tubular reabsorption and bone resorption of calcium [21]. Although we did not evaluate the intestinal absorption of calcium pidolate, it may be assumed that calcaemia does not decline with the reduction in bone resorption because there is an increase in intestinal absorption, with the result that the kidney continues to handle the same amount of calcium in a 24-h period

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and produces the same daily calciuria. There are nevertheless changes in the Ca/ Cr ratio in samples collected after a 12-h fast because the calcium involved derives exclusively from bone [22]. The dose used was 7 g/day of pharmaceutical calcium pidolate, equivalent to 1 g of elemental calcium. With comparable doses of other calcium salts that are more poorly absorbed [13,23] it has been demonstrated that urinary HP excretion declines in both the short and the medium term (24, 25). According to the authors cited, this reflects a protective effect on the skeleton. The beneficial action of calcium may depend on whether the individual concerned absorbs calcium well [26] and on the dose used [ 111, as well as other factors. In the case of calcium pidolate no differences in intestinal absorption were reported by Marchandise et al. [13] in adults. On the other hand, in normal and osteoporotic senile the level of absorption of calcium pidolate in both groups was over 25% higher than that of the calcium salt with which it was compared. The mechanism via which calcium reduces bone resorption seems to be twofold. In the study by Need et al. [9], it is postulated that the reduction is due to a decrease in PTH. In another study carried out by Lowery et al. [27] in patients and normal subjects it was observed that the administration of calcium chloride had no effect on PTH but induced a rise in calcitonin. This finding would seem to suggest that the latter is the metabolic pathway through which calcium inhibits bone resorption. In fact, our own findings, as well as those of others [27] indicate that no decrease in PTH occurs, while Austin et al. [28] have demonstrated that simple calcium ingestion, which produces changes in calcaemia that are within physiological limits, induces similar calcitonin variations. However, this requires further study, since the absence of a secretory calcitonin response to a calcium stimulus has been reported in post-menopausal women [29], although it was recently observed that continued ingestion of calcium increased calcitonin secretion in patients with femoral neck fracture [30]. On the other hand, the absence of changes in PTH might be linked to the PTH fraction measured, since it is known that calcium administration reduces the levels of some forms of PTH without modifying those of others [31]. Although intestinal malabsorption of calcium in patients with osteoporosis has been reported by some investigators [32], it was not observed by others [33], as was recently confirmed by Marchandise et al. [13]. If malabsorption occurs, it may depend on the type and quantity of the calcium salt used. The administration of salts that are absorbed better, at an adequate dosage level, such as that we used in the case of calcium pidolate, with which no differences were observed between normal and osteoporotic subjects [13], may facilitate intestinal absorption and contribute to the achievement of beneficial results. The absence of variations in PTH, GH and BGP we noted after 30 days of calcium pidolate treatment may have been due to the fact that administration was long-term. The investigators who have reported changes in PTH and GH have used short-term calcium therapy [14]. In the light of our results, it is our conclusion that since, over the treatment period considered, calcium pidolate reduced HP/Cr excretion without modifying ALP or BCP, it must exert an influence on bone resorption without affecting bone formation.

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References

6 7 8 9

10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

25

26 27

Avioli LV. The calcium controversy and the recommended dietary allowance. In: Avioli LV, ed. The osteoporotic syndrome, 2nd edn. Orlando: Grune and Stratton, 1987; 57-66. Nordin BEC. Calcium deficiency and postmenopausal osteoporosis. Lancet 1985; 2: 720. Stevenson JC, Whitehead MI. Postmenopausal osteoporosis. Br Med J 1982; 285: 585-586. Lindsay R. Prevention of osteoporosis. In: Gray JAM, ed. Prevention of disease in the elderly. London: Churchill Livingstone, 1985: 95-l 13. Riis B. Thomsen K, Christiansen C. Does calcium supplementation prevent postmenopausal bone loss?. N Engl J Med 1987; 316: 173-177. Nilas L, Christiansen C, Redbro P. Calcium supplementation and postmenopausal bone loss. Br Med J 1984; 289: 1103-1106. Heaney RP. Osteoporosis. In: Bronner F, Coburn JW. eds. Disorders of mineral metabolism. New York: Academic Press, 1982: 67-l 19. Silverberg SJ, Lindsay R. Postmenopausal osteoporosis. Med Clin North Am 1987; 71: 41-57. Need AG, Horowitz M, Philcox JC, Nordin BEC. Biochemical effects of a calcium supplement in osteoporotic postmenopausal women with normal absorption and malabsorption of calcium. Mineral Electrol Metab 1987; 13: 112-l 16. Hunt JN, Johnson C. Relation between gastric secretion of acid and urine excretion of calcium after oral supplements of calcium. Dig Dis Sci 1983; 28: 417-421. Francis RM, Selby P. Osteoporosis: cause and management. Br Med J 1987; 294: 702. Rumenapf G, Schwille PO. The influence of oral alkali citrate on intestinal calcium absorption in healthy man. Clin Sci 1987; 73: 117-121. Marchandise X, Pagniez D, Ythier H, Gilquin B, Duquesnoy B, Wemeau JL. Influence of accompanying anion on intestinal radiocalcium absorption. Calcif Tissue Int 1987; 40: 8-l 1. Franchimont P, Heynen S. Effet de l’efical et du chlorure calcique sur la secretion de plusieurs hormones intervenant dans I’homeostasie de la calcification. Theor Prat Ther 1983; 28: 3-7. Rico H, Del Rio A, Vila, T, Patino R, Carrera F, Espinos D. The role of growth hormone in the pathogenesis of postmenopausal osteoporosis. Arch Intern Med 1979; 139: 1263-1265. Dequeker J, Burssens A, Bouillon R. Dynamics of growth hormone secretion in patients with osteoporosis and in patients with osteoarthrosis. Hormone Res 1982; 16: 353-356. Rico H. Hernandez ER, Bordiu E, Charro A. Niveles de 25 hidroxicolecalclferol en la cirrosis hepatica alcoh6lica compensada. Med Clin (Bare) 1983; 81: 655-657. Prockop DJ, Sjoerdsma A. Significance of hydroxyproline in man. J Clin Invest l%l; 40: 843849. Tausky HH. A microcolorimetric determination of creatinine in urine by Jaffe reaction. J Biol Chem 1954; 208: 853-856. Mundy GR, Raisz LG. Disorders of bone resorption. In: Bronner F, Coburn JW, eds. Disorders of mineral metabolism, Vol 3. New York: Academic Press, 1981: l-66. Bronner F. Calcium homeostasis. In: Bronner F, Coburn JW, eds. Disorders of mineral metabolism, Vol 2. New York: Academic Press, 1982: 45-103. Pak CYC. Pathogenesis of hypercalciuria. In: Peck WA, ed. Bone and mineral research/4. Amsterdam. Elsevier Science Publishers. 1986: 303-334. Mautalen CA, Cabrejas ML, Soto RJ. Isotopic determination of intestinal calcium absorption in normal subjects. Metab Clin Exp 1969; 18: 395-405. Horowitz M, Need AG, Philcox JC, Nordin BEC. The effect of calcium supplementation on urinary hydroxyproline in osteoporotic postmenopausal women. Am J Clin Nutr 1984; 39: 857859. Horowitz M, Need AG, Philcox JC, Nordin BEC. The effect of calcium supplements on plasma alkaline phosphatase and urinary hydroxyproline in postmenopausal women. Hormone Metab Res 1985; 17: 311-312. Walling MW. Regulation of intestinal calcium and inorganic phosphate absorption. In: Parson JA, ed. Endocrinology of calcium metabolism. New York: Raven Press, 1982: 87-102. Lowery WD, Thomas CG, Awbrey BJ, Rosenstein BD, Talmage RV. The late effect of subtotal

111

28 29 30 31

32 33

thyroidectomy and radioactive iodine therapy on calcitonin secretion and bone mineral density in women treated for Graves’ disease. Surgery 1986; 106: 1142-l 149. Austin LA. Heath H, Go VLM. Regulation of calcitonin secretion in normal man by changes of serum calcium within the physiologic range. J Clin Invest 1979; 64: 1721-1724. Deftos LJ. Calcitonin secretion. In: Bronner F, Cobum JW, eds. Disorders of mineral metabolism. Vol. 2. New York: Academic Press, 1982: 433-481. Beringer TRO, Ardill J, Taggart HNA. Effect of calcium and stanozolol on calcitonin secretion in patients with femoral neck fracture. Bone Mineral 1986; 1: 289-295. Yallow RS. Radioimmunoassay of parathyroid hormone: Past and future. In: Cecchettin M, 8egre G. eds. Calciotropic hormones and calcium metabolism. Amsterdam: Excerpta Medica, 1986: 1-9. Bullamore JR, Wilkinson R, Gallagher JC, Nordin BEC, Marshall DH. Effects of age on calcium absorption. Lancet 1970; 2: 535-537. Avioli LV, MacDonald JE, Lee SW. The influence of age on the intestinal absorption of 47Ca in women and its relation to 47Ca absorption in postmenopausal osteoporosis. J Clin Invest 1965; 44: 1960-1964.