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. 1972 Apr;51(4):945–954. doi: 10.1172/JCI106889

Changes in Serum and Urinary Calcium during Treatment with Hydrochlorothiazide: Studies on Mechanisms

Arnold S Brickman 1,2,3, Shaul G Massry 1,2,3, Jack W Coburn 1,2,3
PMCID: PMC302208  PMID: 4552338

Abstract

Studies were undertaken in man to evaluate the roles of volume depletion and of the parathyroid glands in mediating the changes in serum and urinary calcium which follow the administration of hydrochlorothiazide, 100 mg twice daily, for 4 days, 42 studies were carried out in 16 normal subjects, 9 patients with hyperparathyroidism, and 7 vitamin D-treated subjects with hypoparathyroidism. In six studies in normal subjects, daily sodium losses during thiazide administration were quantitatively replaced, and in six other studies the effect of equivalent sodium losses produced by furosemide was evaluated.

Although the magnitude of sodium losses was similar in three groups during therapy with thiazides, urinary calcium fell and urinary phosphorus increased significantly only in normal subjects and those with hyperparathyroidism; no change occurred in patients with hypoparathyroidism. With the replacement of the thiazide-induced sodium losses by NaCl in normals, urinary calcium did not change as urinary sodium increased 4- to 5-fold. Furosemide administration produced similar sodium losses while urinary calcium remained at or above control levels. After correction for changes in plasma protein concentration caused by thiazide-induced hemoconcentration, mean levels of serum calcium were significantly increased only in subjects with hyperparathyroidism and vitamin D-treated patients with hypoparathyroidism.

The results indicate that both depletion of extracellular fluid volume and the presence of the parathyroid glands are necessary for the decrease in urinary calcium in response to thiazide therapy. Both the reduction in urinary calcium and increase in urinary phosphate after the use of thiazides may be due, in part, to potentiation of the action of the parathyroid hormone on the nephron. The rise in serum calcium could be due to thiazide-induced release of calcium from bone into extracellular fluid, particularly in states where bone resorption may be augmented, i.e., vitamin D therapy or hyperparathyroidism.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adams P., Chalmers T. M., Hill L. F., Truscott B. M. Idiopathic hypercalciuria and hyperparathyroidism. Br Med J. 1970 Dec 5;4(5735):582–585. doi: 10.1136/bmj.4.5735.582. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Antoniou L. D., Eisner G. M., Slotkoff L. M., Lilienfield L. S. Relationship between sodium and calcium transport in the kidney. J Lab Clin Med. 1969 Sep;74(3):410–420. [PubMed] [Google Scholar]
  3. Brickman A. S., Coburn J. W., Koppel M. H., Peacock M., Massry S. G. The effect of hydrochlorothiazide administration on serum and urinary calcium in normal, hypoparathyroid and hyperparathyroid subjects. Studies on mechanisms. Isr J Med Sci. 1971 Mar;7(3):518–519. [PubMed] [Google Scholar]
  4. Chase L. R., Aurbach G. D. Parathyroid function and the renal excretion of 3'5'-adenylic acid. Proc Natl Acad Sci U S A. 1967 Aug;58(2):518–525. doi: 10.1073/pnas.58.2.518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chase L. R., Fedak S. A., Aurbach G. D. Activation of skeletal adenyl cyclase by parathyroid hormone in vitro. Endocrinology. 1969 Apr;84(4):761–768. doi: 10.1210/endo-84-4-761. [DOI] [PubMed] [Google Scholar]
  6. DUARTE C. G., BLAND J. H. CALCIUM, PHOSPHORUS AND URIC ACID CLEARANCES AFTER INTRAVENOUS ADMINISTRATION OF CHLOROTHIAZIDE. Metabolism. 1965 Mar;14:211–219. doi: 10.1016/0026-0495(65)90061-2. [DOI] [PubMed] [Google Scholar]
  7. DUARTE C. G., BLAND J. H. CHANGES IN METABOLISM OF CALCIUM, PHOSPHORUS AND URIC ACID AFTER ORAL ADMINISTRATION OF CHLOROTHIAZIDE. Metabolism. 1965 Aug;14:899–903. doi: 10.1016/0026-0495(65)90128-9. [DOI] [PubMed] [Google Scholar]
  8. Donath A., Nordio S., Macagno F., Gatti R. The effect of hydrochlorothiazide on calcium and strontium transport in intestine and kidney. Helv Paediatr Acta. 1970 Jul;25(3):293–300. [PubMed] [Google Scholar]
  9. Duarte C. G., Watson J. F. Calcium reabsorption in proximal tubule of the dog nephron. Am J Physiol. 1967 Jun;212(6):1355–1360. doi: 10.1152/ajplegacy.1967.212.6.1355. [DOI] [PubMed] [Google Scholar]
  10. Duarte C. G., Winnacker J. L., Becker K. L., Pace A. Thiazide-induced hypercalcemia. N Engl J Med. 1971 Apr 15;284(15):828–830. doi: 10.1056/NEJM197104152841506. [DOI] [PubMed] [Google Scholar]
  11. Eisenberg E. Effects of varying phosphate intake in primary hyperparathyroidism. J Clin Endocrinol Metab. 1968 May;28(5):651–660. doi: 10.1210/jcem-28-5-651. [DOI] [PubMed] [Google Scholar]
  12. Eknoyan G., Suki W. N., Martinez-Maldonado M. Effect of diuretics on urinary excretion of phosphate, calcium, and magnesium in thyroparathyroidectomized dogs. J Lab Clin Med. 1970 Aug;76(2):257–266. [PubMed] [Google Scholar]
  13. Epstein F. H. Calcium and the kidney. Am J Med. 1968 Nov;45(5):700–714. doi: 10.1016/0002-9343(68)90206-4. [DOI] [PubMed] [Google Scholar]
  14. Frederich A., Berger C., Gharib C. Influence d'un sulfamide diurétique, l'hydrochlorothiazide sur l'élimination urinaire du calcium. Therapie. 1965 May-Jun;20(3):695–707. [PubMed] [Google Scholar]
  15. Harrison A. R., Rose G. A. The effect of bendrofluazide on urinary and faecal calcium and phosphorus. Clin Sci. 1968 Apr;34(2):343–350. [PubMed] [Google Scholar]
  16. KLEEMAN C. R., BERNSTEIN D., ROCKNEY R., DOWLING J. T., MAXWELL M. H. Studies on the renal clearance of diffusible calcium and the role of the parathyroid glands in its regulation. Yale J Biol Med. 1961 Aug;34:1–30. [PMC free article] [PubMed] [Google Scholar]
  17. Koppel M. H., Massry S. G., Shinaberger J. H., Hartenbower D. L., Coburn J. W. Thiazide-induced rise in serum calcium and magnesium in patients on maintenance hemodialysis. Ann Intern Med. 1970 Jun;72(6):895–901. doi: 10.7326/0003-4819-72-6-895. [DOI] [PubMed] [Google Scholar]
  18. LAMBERG B. A., KUHLBACK B. Effect of chlorothiazide and hydrochlorothiazide on the excretion of calcium in urine. Scand J Clin Lab Invest. 1959;11:351–357. doi: 10.3109/00365515909060464. [DOI] [PubMed] [Google Scholar]
  19. LICHTWITZ A., PARLIER R., de SEZE, HIOCO D., MIRAVET L. [The hypocalciuric effect of diuretic sulfonamides]. Sem Med Prof Med Soc. 1961 Aug 14;37:2350–2362. [PubMed] [Google Scholar]
  20. Massry S. G., Coburn J. W., Chapman L. W., Kleeman C. R. Effect of NaCl infusion on urinary Ca++ and Mg++ during reduction in their filtered loads. Am J Physiol. 1967 Nov;213(5):1218–1224. doi: 10.1152/ajplegacy.1967.213.5.1218. [DOI] [PubMed] [Google Scholar]
  21. Massry S. G., Coburn J. W., Chapman L. W., Kleeman C. R. Role of serum Ca, parathyroid hormone, and NaCl infusion on renal Ca and Na clearances. Am J Physiol. 1968 Jun;214(6):1403–1409. doi: 10.1152/ajplegacy.1968.214.6.1403. [DOI] [PubMed] [Google Scholar]
  22. Moore P. F. The effects of diazoxide and benzothiadiazine diuretics upon phosphodiesterase. Ann N Y Acad Sci. 1968 Apr 11;150(2):256–260. doi: 10.1111/j.1749-6632.1968.tb19050.x. [DOI] [PubMed] [Google Scholar]
  23. NASSIM J. R., HIGGINS B. A. CONTROL OF IDIOPATHIC HYPERCALCIURIA. Br Med J. 1965 Mar 13;1(5436):675–681. doi: 10.1136/bmj.1.5436.675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Paloyan E., Farland M., Pickleman J. R. Hyperparathyroidism coexisting with hypertension and prolonged thiazide administration. JAMA. 1969 Nov 17;210(7):1243–1245. [PubMed] [Google Scholar]
  25. Parfitt A. M. Chlorothiazide-induced hypercalcemia in juvenile osteoporosis and hyperparathyroidism. N Engl J Med. 1969 Jul 10;281(2):55–59. doi: 10.1056/NEJM196907102810201. [DOI] [PubMed] [Google Scholar]
  26. Parfitt A. M. The acute effects of mersalyl, chlorothiazide and mannitol on the renal excretion of calcium and other ions in man. Clin Sci. 1969 Apr;36(2):267–282. [PubMed] [Google Scholar]
  27. Pickleman J. R., Straus F. H., 2nd, Forland M., Paloyan E. Thiazide-induced parathyroid stimulation. Metabolism. 1969 Oct;18(10):867–873. doi: 10.1016/0026-0495(69)90062-6. [DOI] [PubMed] [Google Scholar]
  28. Rasmussen H., Pechet M., Fast D. Effect of dibutyryl cyclic adenosine 3',5'-monophosphate, theophylline, and other nucleotides upon calcium and phosphate metabolism. J Clin Invest. 1968 Aug;47(8):1843–1850. doi: 10.1172/JCI105874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. SEITZ H., JAWORSKI Z. F. EFFECT OF HYDROCHLOROTHIAZIDE ON SERUM AND URINARY CALCIUM AND URINARY CITRATE. Can Med Assoc J. 1964 Feb 8;90:414–420. [PMC free article] [PubMed] [Google Scholar]
  30. Senft G., Munske K., Schultz G., Hoffmann M. Der Einfluss von Hydrochlorothiazid und anderen sulfonamidierten Diuretica auf die 3',5'-AMP-Phosphodiesterase-Aktivität in der Rattenniere. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1968;259(4):344–359. [PubMed] [Google Scholar]
  31. Sotorník I., Schück O., Stríbrná J. Influence of diuretics on renal calcium excretion. Experientia. 1969 Jun 15;25(6):591–592. doi: 10.1007/BF01896529. [DOI] [PubMed] [Google Scholar]
  32. WALSER M. Calcium clearance as a function of sodium clearance in the dog. Am J Physiol. 1961 May;200:1099–1104. doi: 10.1152/ajplegacy.1961.200.5.1099. [DOI] [PubMed] [Google Scholar]
  33. WIDROW S. H., LEVINSKY N. G. The effect of parathyroid extract on renal tubular calcium reabsorption in the dog. J Clin Invest. 1962 Dec;41:2151–2159. doi: 10.1172/JCI104673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Yendt E. R., Gagné R. J., Cohanim M. The effects of thiazides in idiopathic hypercalciuria. Am J Med Sci. 1966 Apr;251(4):449–460. doi: 10.1097/00000441-196604000-00009. [DOI] [PubMed] [Google Scholar]

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