Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1977 Nov;60(5):1046–1053. doi: 10.1172/JCI108855

Osteomalacia Due to 1α,25-Dihydroxycholecalciferol Deficiency

ASSOCIATION WITH A GIANT CELL TUMOR OF BONE

Marc K Drezner 1,2,3, Mark N Feinglos 1,2,3
PMCID: PMC372456  PMID: 908749

Abstract

Oncogenic osteomalacia is a syndrome in which unexplained osteomalacia remits after resection of a coexisting mesenchymal tumor. We have investigated the mechanism by which a giant cell tumor of bone caused biopsy-proved osteomalacia in a 42-yr-old woman. The biochemical abnormalities were: hypophosphatemia; decreased renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate; negative calcium and phosphorus balance; hyperaminoaciduria; and subnormal calcemic response to exogenously administered parathyroid hormone. Malabsorption, hypophosphatasia, fluorosis, and acidosis were excluded as causes of the osteomalacia. Serum 25-hydroxycholecalciferol was normal (27±1 ng/ml). However, the serum concentration of 1α,25-dihydroxycholecalciferol was low (1.6±0.1 ng/100 ml). Oral administration of physiological amounts of 1α,25-dihydroxycholecalciferol resulted in resolution of the biochemical abnormalities of the syndrome and healing of the bone pathology. We suggest that tumor-induced inhibition of 1α,25-dihydroxycholecalciferol synthesis caused the osteomalacia. The causal role of the tumor was proved by demonstrating that resection was accompanied by roentgenographic evidence of bone healing and maintenance of normal serum phosphorus; renal tubular maximum for the reabsorption of phosphate; calcium and phosphorus balance; aminoaciduria; and calcemic response to exogenous parathyroid hormone.

Full text

PDF
1046

Images in this article

1050Image
on p.1050

Selected References

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

  1. ANKER R. M. The determination of creatine and creatinine in urine; a correction factor for the determination of twenty-four-hour urinary excretion values. J Lab Clin Med. 1954 May;43(5):798–801. [PubMed] [Google Scholar]
  2. Arnaud C. D., Tsao H. S., Littledike T. Radioimmunoassay of human parathyroid hormone in serum. J Clin Invest. 1971 Jan;50(1):21–34. doi: 10.1172/JCI106476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arnstein A. R., Frame B., Frost H. M. Recent progress in osteomalacia and rickets. Ann Intern Med. 1967 Dec;67(6):1296–1330. doi: 10.7326/0003-4819-67-6-1296. [DOI] [PubMed] [Google Scholar]
  4. Bijvoet O. L. Renal phosphate excretion in man. Folia Med Neerl. 1972;15(2):84–93. [PubMed] [Google Scholar]
  5. Bouillon R., Reynaert J., Claes J. H., Lissens W., De Moor P. The effect of anticonvulsant therapy on serum levels of 25-hydroxy-vitamin D, calcium, and parathyroid hormone. J Clin Endocrinol Metab. 1975 Dec;41(06):1130–1135. doi: 10.1210/jcem-41-6-1130. [DOI] [PubMed] [Google Scholar]
  6. Brickman A. S., Coburn J. W., Massry S. G., Norman A. W. 1,25 Dihydroxy-vitamin D3 in normal man and patients with renal failure. Ann Intern Med. 1974 Feb;80(2):161–168. doi: 10.7326/0003-4819-80-2-161. [DOI] [PubMed] [Google Scholar]
  7. Brickman A. S., Coburn J. W., Norman A. W. Action of 1,25-dihydroxycholecalciferol, a potent, kidney-produced metabolite of vitamin D, in uremic man. N Engl J Med. 1972 Nov 2;287(18):891–895. doi: 10.1056/NEJM197211022871801. [DOI] [PubMed] [Google Scholar]
  8. Brumbaugh P. F., Haussler D. H., Bursac K. M., Haussler M. R. Filter assay for 1alpha, 25-dihydroxyvitamin D3. Utilization of the hormone's target tissue chromatin receptor. Biochemistry. 1974 Sep 24;13(20):4091–4097. doi: 10.1021/bi00717a005. [DOI] [PubMed] [Google Scholar]
  9. Case records of the Massachusetts General Hospital. Case 38-1965. N Engl J Med. 1965 Aug 26;273(9):494–504. doi: 10.1056/NEJM196508262730909. [DOI] [PubMed] [Google Scholar]
  10. DRYER R. L., TAMMES A. R., ROUTH J. I. The determination of phosphorus and phosphatase with N-phenyl-p-phenylenediamine. J Biol Chem. 1957 Mar;225(1):177–183. [PubMed] [Google Scholar]
  11. DeLuca H. F. Vitamin D endocrinology. Ann Intern Med. 1976 Sep;85(3):367–377. doi: 10.7326/0003-4819-85-3-367. [DOI] [PubMed] [Google Scholar]
  12. Dent C. E., Smith R. Nutritional osteomalacia. Q J Med. 1969 Apr;38(150):195–209. [PubMed] [Google Scholar]
  13. Drezner M. K., Neelon F. A., Haussler M., McPherson H. T., Lebovitz H. E. 1,25-Dihydroxycholecalciferol deficiency: the probable cause of hypocalcemia and metabolic bone disease in pseudohypoparathyroidism. J Clin Endocrinol Metab. 1976 Apr;42(4):621–628. doi: 10.1210/jcem-42-4-621. [DOI] [PubMed] [Google Scholar]
  14. Evans D. J., Azzopardi J. G. Distinctive tumours of bone and soft tissue causing acquired vitamin-D-resistant osteomalacia. Lancet. 1972 Feb 12;1(7746):353–354. doi: 10.1016/s0140-6736(72)92844-9. [DOI] [PubMed] [Google Scholar]
  15. Fischer J. A., Binswanger U., Dietrich F. M. Human parathyroid hormone. Immunological characterization of antibodies against a glandular extract and the synthetic amino-terminal fragments 1-12 and 1-34 and their use in the determination of immunoreactive hormone in human sera. J Clin Invest. 1974 Dec;54(6):1382–1394. doi: 10.1172/JCI107885. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fraser D., Kooh S. W., Kind H. P., Holick M. F., Tanaka Y., DeLuca H. F. Pathogenesis of hereditary vitamin-D-dependent rickets. An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D. N Engl J Med. 1973 Oct 18;289(16):817–822. doi: 10.1056/NEJM197310182891601. [DOI] [PubMed] [Google Scholar]
  17. Fraser D., Kooh S. W., Scriver C. R. Hyperparathyroidism as the cause of hyperaminoaciduria and phosphaturia in human vitamin D deficiency. Pediatr Res. 1967 Nov;1(6):425–435. doi: 10.1203/00006450-196711000-00001. [DOI] [PubMed] [Google Scholar]
  18. Friedel R. O., Schanberg S. M. Incorporation in vivo of intracisternally injected 33 P i into phospholipids of rat brain. J Neurochem. 1971 Nov;18(11):2191–2200. doi: 10.1111/j.1471-4159.1971.tb05077.x. [DOI] [PubMed] [Google Scholar]
  19. Hahn T. J., Hendin B. A., Scharp C. R., Haddad J. G., Jr Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med. 1972 Nov 2;287(18):900–904. doi: 10.1056/NEJM197211022871803. [DOI] [PubMed] [Google Scholar]
  20. Harris F., Hoffenberg R., Black E. Calcium kinetics in vitamin D deficiency rickets. I. Plasma kinetic studies after intravenous and oral Ca47. Metabolism. 1965 Oct;14(10):1101–1111. doi: 10.1016/0026-0495(65)90159-9. [DOI] [PubMed] [Google Scholar]
  21. Hughes M. R., Baylink D. J., Jones P. G., Haussler M. R. Radioligand receptor assay for 25-hydroxyvitamin D2/D3 and 1 alpha, 25-dihydroxyvitamin D2/D3. J Clin Invest. 1976 Jul;58(1):61–70. doi: 10.1172/JCI108459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Husdan H., Rapoport A. Estimation of calcium, magnesium, and phosphorus in diet and stool. Clin Chem. 1969 Aug;15(8):669–679. [PubMed] [Google Scholar]
  23. JOWSEY J., PHIL D., KELLY P. J., RIGGS B. L., BIANCO A. J., Jr, SCHOLZ D. A., GERSHON-COHEN J. QUANTITATIVE MICRORADIOGRAPHIC STUDIES OF NORMAL AND OSTEOPOROTIC BONE. J Bone Joint Surg Am. 1965 Jun;47:785–806. [PubMed] [Google Scholar]
  24. Jowsey J. Calcium release from the skeletons of rachitic puppies. J Clin Invest. 1972 Jan;51(1):9–15. doi: 10.1172/JCI106802. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kooh S. W., Fraser D., DeLuca H. F., Holick M. F., Belsey R. E., Clark M. B., Murray T. M. Treatment of hypoparathyroidism and pseudohypoparathyroidism with metabolites of vitamin D: evidence for impaired conversion of 25-hydroxyvitamin D to 1 alpha,25-dihydroxyvitamin D. N Engl J Med. 1975 Oct 23;293(17):840–844. doi: 10.1056/NEJM197510232931702. [DOI] [PubMed] [Google Scholar]
  26. Linkswiler H. M., Joyce C. L., Anand C. R. Calcium retention of young adult males as affected by level of protein and of calcium intake. Trans N Y Acad Sci. 1974 Apr;36(4):333–340. doi: 10.1111/j.2164-0947.1974.tb01584.x. [DOI] [PubMed] [Google Scholar]
  27. Linovitz R. J., Resnick D., Keissling P., Kondon J. J., Sehler B., Nejdl R. J., Rowe J. H., Deftos L. J. Tumor-induced osteomalacia and rickets: a surgically curable syndrome. Report of two cases. J Bone Joint Surg Am. 1976 Apr;58(3):419–423. [PubMed] [Google Scholar]
  28. Lotz M., Zisman E., Bartter F. C. Evidence for a phosphorus-depletion syndrome in man. N Engl J Med. 1968 Feb 22;278(8):409–415. doi: 10.1056/NEJM196802222780802. [DOI] [PubMed] [Google Scholar]
  29. MacGregor M. E. Paediatric aspects of hypoparathyroidism. Proc R Soc Med. 1968 Jun;61(6):583–588. [PMC free article] [PubMed] [Google Scholar]
  30. Mawer E. B., Taylor C. M., Backhouse J., Lumb G. A., Stanbury S. W. Failure of formation of 1,25-dihydroxycholecalciferol in chronic renal insufficiency. Lancet. 1973 Mar 24;1(7804):626–628. doi: 10.1016/s0140-6736(73)92197-1. [DOI] [PubMed] [Google Scholar]
  31. Morgan D. B., Paterson C. R., Woods C. G., Pulvertaft C. N., Fourman P. Osteomalacia after gastrectomy. A response to very small doses of vitamin D. Lancet. 1965 Nov 27;2(7422):1089–1091. doi: 10.1016/s0140-6736(65)90061-9. [DOI] [PubMed] [Google Scholar]
  32. Moser C. R., Fessel W. J. Rheumatic manifestations of hypophosphatemia. Arch Intern Med. 1974 Oct;134(4):674–678. [PubMed] [Google Scholar]
  33. Norman A. W., Henry H. The role of the kidney and vitamin D metabolism in health and disease. Clin Orthop Relat Res. 1974 Jan-Feb;(98):258–287. doi: 10.1097/00003086-197401000-00032. [DOI] [PubMed] [Google Scholar]
  34. Olefsky J., Kempson R., Jones H., Reaven G. "Tertiary" hyperparathyroidism and apparent "cure" of vitamin-D-resistant rickets after removal of an ossifying mesenchymal tumor of the pharynx. N Engl J Med. 1972 Apr 6;286(14):740–745. doi: 10.1056/NEJM197204062861402. [DOI] [PubMed] [Google Scholar]
  35. PRADER A., ILLIG R., UEHLINGER E., STALDER G. [Rickets following bone tumor]. Helv Paediatr Acta. 1959 Dec;14:554–565. [PubMed] [Google Scholar]
  36. Pollack J. A., Schiller A. L., Crawford J. D. Rickets and myopathy cured by removal of a nonossifying fibroma of bone. Pediatrics. 1973 Sep;52(3):364–371. [PubMed] [Google Scholar]
  37. Puschett J. B., Fernandez P. C., Boyle I. T., Gray R. W., Omdahl J. L., DeLuca H. F. The acute renal tubular effects of 1,25-dihydroxycholecalciferol. Proc Soc Exp Biol Med. 1972 Oct;141(1):379–384. doi: 10.3181/00379727-141-36781. [DOI] [PubMed] [Google Scholar]
  38. Russell R. G., Smith R., Preston C., Walton R. J., Woods C. G., Henderson R. G., Norman A. W. The effect of 1,25-dihydroxycholecalciferol on renal tubular reabsorption of phosphate, intestinal absorption of calcium and bone histology in hypophosphataemic renal tubular rickets. Clin Sci Mol Med. 1975 Mar;48(3):177–186. doi: 10.1042/cs0480177. [DOI] [PubMed] [Google Scholar]
  39. Salassa R. M., Jowsey J., Arnaud C. D. Hypophosphatemic osteomalacia associated with "nonendocrine" tumors. N Engl J Med. 1970 Jul 9;283(2):65–70. doi: 10.1056/NEJM197007092830204. [DOI] [PubMed] [Google Scholar]
  40. Tanaka Y., Deluca H. F. Role of 1,25-dihydroxyvitamin D3 in maintaining serum phosphorus and curing rickets. Proc Natl Acad Sci U S A. 1974 Apr;71(4):1040–1044. doi: 10.1073/pnas.71.4.1040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. YOSHIKAWA S., KAWABATA M., HATSUYAMA Y., HOSOKAWA O., FUJITA T. ATYPICAL VITAMIN-D RESISTANT OSTEOMALACIA. REPORT OF A CASE. J Bone Joint Surg Am. 1964 Jul;46:998–1007. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES