Correspondence

Teriparatide, Osteoporosis, Calcium, and Vitamin D

N Engl J Med 2005; 353:634-635August 11, 2005

Article

To the Editor:

Dr. Licata reports in his letter to the editor (May 5 issue)1 that the increase in serum calcium levels after treatment of osteoporosis with the parathyroid hormone derivative teriparatide correlates “inversely with 25-hydroxyvitamin D.” Therefore, vitamin D supplementation to increase the level of 25-hydroxyvitamin D might be desirable. Indeed, Dr. Licata's own data show that patients with higher levels of 25-hydroxyvitamin D have a reduced risk of hypercalcemia.

Given this finding, we are very surprised that Dr. Licata advises caution in the use of vitamin D supplementation. Dr. Licata's letter focuses on the increase in levels of 1,25-dihydroxyvitamin D that accompanied the use of teriparatide, but there is much evidence that substantial vitamin D supplementation does not affect the level of 1,25-dihydroxyvitamin D.2-4 Since 25-hydroxyvitamin D is an important determinant of serum immunoreactive parathyroid hormone in healthy adults,5 there is still much to learn about the interrelationship between vitamin D supplementation and teriparatide.

Reinhold Vieth, Ph.D.
David E.C. Cole, M.D., Ph.D.
University of Toronto, Toronto, ON M5G 1L5, Canada
rvieth@mtsinai.on.ca

5 References

1
Licata AA. Osteoporosis, teriparatide, and dosing of calcium and vitamin D. N Engl J Med 2005;352:1930-1931
Full Text | Web of Science | Medline

2
Vieth R, Kimball S, Hu A, Walfish PG. Randomized comparison of the effects of the vitamin D3 adequate intake versus 100 mcg (4000 IU) per day on biochemical responses and the wellbeing of patients. Nutr J 2004;3:8-8
CrossRef | Medline

3
Vieth R, Ladak Y, Walfish PG. Age-related changes in the 25-hydroxyvitamin D versus parathyroid hormone relationship suggest a different reason why older adults require more vitamin D. J Clin Endocrinol Metab 2003;88:185-191
CrossRef | Web of Science | Medline

4
Barger-Lux MJ, Heaney RP, Dowell S, Chen TC, Holick MF. Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos Int 1998;8:222-230
CrossRef | Web of Science | Medline

5
Pepe J, Romagnoli E, Nofroni I, et al. Vitamin D status as the major factor determining the circulating levels of parathyroid hormone: a study in normal subjects. Osteoporos Int 2005;16:805-812
CrossRef | Web of Science | Medline

To the Editor:

Licata describes three patients who had elevated levels of serum calcium six or more hours after receiving teriparatide (Forteo, Lilly). In a fracture prevention trial,1 11 percent of patients receiving 20 μg of teriparatide, as compared with 2 percent of patients treated with placebo, had at least one elevated serum calcium value in blood samples drawn four to six hours after the injection of the study drug. These elevations were not associated with adverse clinical events, and serum calcium measurements made more than 16 hours after injection of the dose were elevated in only one patient each in the teriparatide group (receiving a dose of 20 μg per day) and the placebo group. The transient rise in serum calcium after the injection of teriparatide is consistent with the known renal effects of parathyroid hormone.

The Forteo product label warns that patients with preexisting hypercalcemia should not be treated with teriparatide. The labeling for teriparatide suggests that blood samples be drawn at least 16 hours after dosing. Subsequent normalization in the serum calcium level has been observed in patients with hypercalcemia without a reduction in the dose of teriparatide or supplementation with calcium and vitamin D.2 However, a reduction in calcium supplementation may be considered.3

John H. Krege, M.D.
David W. Donley, Ph.D.
Robert Marcus, M.D.
Eli Lilly, Indianapolis, IN 46285
kregejh@lilly.com

3 References

1
Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-1441
Full Text | Web of Science | Medline

2
Ettinger B, San Martin J, Crans G, Pavo I. Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res 2004;19:745-751
CrossRef | Web of Science | Medline

3
Hodsman AB, Bauer DC, Dempster D, et al. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev (in press).

Author/Editor Response

My own observational data confirmed the lack of hypercalcemia that Dr. Krege and colleagues observed in the controlled trial of teriparatide. They are probably responding to the introductory statement that some patients developed persistent hypercalcemia — in other words, an increase in the level of serum calcium that is independent of the timing of blood sampling after drug administration. The patients in whom this problem developed would appear to have overused calcium supplements. The question is how hypercalcemia could have developed when physiologic systems are in place to limit the absorption of calcium as intake rises. The explanation may lie in the increase in 1,25-dihydroxyvitamin D that is observed in some patients. The message for practitioners is to advise patients to limit their intake of elemental calcium to that prescribed.

The observations of Drs. Vieth and Cole are points well taken. Today there is great concern about vitamin D deficiency. Experts are intimating that higher doses of the vitamin should be considered in our guidelines. The suggestion that patients receiving teriparatide should limit their supplementation of vitamin D seems counterintuitive, as they suggest. Normal physiologic mechanisms limit the increase in levels of 1,25-dihydroxyvitamin D despite substantial supplementation with vitamin D. However, this normal regulation may not be the case with teriparatide. In some patients, levels of 1,25-dihydroxyvitamin D increase despite regulatory signals that should have prevented it (i.e., increased levels of serum calcium and decreased levels of intact parathyroid hormone).

This finding may reflect a lack of normal regulation reminiscent of sarcoidosis, in which normal physiologic control of 1,25-dihydroxyvitamin D is absent and vitamin D intake has a direct effect on the production of 1,25-dihydroxyvitamin D and on serum calcium levels.1,2 Obviously, teriparatide (a drug) and sarcoidosis (a disease) are quite different. But the similarities as noted should give us pause. We do not yet fully understand the interrelationship of this type of drug and vitamin D. Present clinical experience arises from the use of anticatabolic drugs, which are distinctly different from this type of drug. This concern could be a false alarm, but until we have more data, it seems prudent for clinicians to be more vigilant and to elicit information about which nonprescribed supplements and vitamins patients are taking.

Angelo A. Licata, M.D., Ph.D.
Cleveland Clinic Foundation, Cleveland, OH 44195

2 References

1
Hendrix JZ. The remission of hypercalcemia and hypercalciuria in systemic sarcoidosis by vitamin D depletion. Clin Res 1963;11:2200-2205

2
Bell NH, Gill JR Jr, Bartter FC. On the abnormal calcium absorption in sarcoidosis: evidence for increased sensitivity to vitamin D. Am J Med 1964;36:500-513
CrossRef | Web of Science | Medline

Citing Articles (4)

Citing Articles

1
Caterina Borgna-Pignatti, Maria Rita Gamberini. (2011) Complications of thalassemia major and their treatment. Expert Review of Hematology 4:3, 353-366
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2
Francisco Javier Castellote Varona, María Buttazzo. (2010) Hipercalcema inducida por fármacos en el anciano. Revista Española de Geriatría y Gerontología 45:5, 308-309
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3
R. A. Wermers, C. P. Recknor, F. Cosman, L. Xie, E. V. Glass, J. H. Krege. (2008) Effects of teriparatide on serum calcium in postmenopausal women with osteoporosis previously treated with raloxifene or alendronate. Osteoporosis International 19:7, 1055-1065
CrossRef
4
P. D. Miller, E. N. Schwartz, P. Chen, D. A. Misurski, J. H. Krege. (2007) Teriparatide in postmenopausal women with osteoporosis and mild or moderate renal impairment. Osteoporosis International 18:1, 59-68
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