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Reply to MF McCarty

Department of Geriatric Medicine University Medical Center Utrecht PO Box 85500 3508 GA Utrecht Netherlands E-mail: h.c.j.p.janssen{at}azu.nl

Dear Sir:

We appreciate McCarty’s letter in response to our review on vitamin D deficiency, muscle function, and falls in elderly people. As we stated in our article, the serum 1,25-dihydroxyvitamin D₃ [1,25(OH)D₃] concentration is under tight metabolic control by feedback mechanisms, which will keep it within reference limits (40–140 pmol/L in our laboratory) in case of a moderate shortage in 25-hydroxyvitamin D₃ [25(OH)D₃]; this statement is in agreement with McCarty. However, substrate dependency and seasonal variations in 1,25(OH)D₃ have been described in elderly people (1, 2).

Although experimental studies, both in vitro and in vivo, have provided abundant evidence of the mechanisms by which 1,25(OH)D₃ directly affects muscle function through a vitamin D receptor (3), the available clinical studies indicate a relation between 25(OH)D₃ and muscle function. In our report, we provided 2 possible explanations for this discrepancy; in McCarty’s letter, another is given. Although we value his suggestion that mild secondary hyperparathyroidism associated with poor vitamin D status mediates the effect of vitamin D deficiency on muscle function, a few remarks on this subject are in order.

Indeed, muscle weakness has been found in some but not all patients with primary hyperparathyroidism (4, 5). After surgery, muscle strength in patients with primary hyperparathyroidism has been found to improve (6, 7), although this improvement did not correlate with serum calcium or parathyroid hormone (PTH) concentrations.

Furthermore, maximum voluntary knee-extension strength was measured in 55 vitamin D–deficient Arab women who underwent high-dose vitamin D and calcium treatment (8). In correlation analysis, it was found that maximum voluntary knee-extension strength was positively correlated with 25(OH)D₃ concentrations and inversely correlated with PTH concentrations, but it was not significantly related to 1,25(OH)D₃ concentrations (respectively: r = 0.34, P < 0.001; r = -0.33, P < 0.001; r = -0.14, NS). When multivariate regression analysis between maximum voluntary knee-extension strength and 25(OH)D₃, 1,25(OH)D₃, and PTH concentrations was done, only 25(OH)D₃ remained significantly (P = 0.02) related to maximum voluntary knee-extension strength.

This finding contrasts with that in the study of Stein et al (9), in which PTH remained independently associated with falling in multiple logistic regression analysis and 25(OH)D₃ did not. McCarty states that this finding is consistent with the view that secondary hyperparathyroidism mediates the muscle weakness associated with vitamin D deficiency. However, an alternative explanation was provided by Birge (10), who stated in an editorial, "It [PTH] may be a better biological marker than 25(OH)D₃ for vitamin D deficiency at the tissue level. Serum levels of 25(OH)D₃ do not reflect the tissue response to the sterol. This becomes particularly relevant when we consider the variable and increasing resistance to vitamin D with hormonal status and advancing age. In addition, multiple alleles in the vitamin D receptor protein gene also determine tissue responsivity."

In conclusion, the books are clearly not closed on the mechanisms responsible for vitamin D deficiency and muscle weakness. Substantial evidence points to a direct relation between vitamin D metabolites and muscle function, but we cannot exclude a possible negative synergistic influence of increased PTH and low serum vitamin D metabolites on muscle strength. We agree with McCarty that more research is needed on this matter.

REFERENCES

1. Lips P, Wiersinga A, van Ginkel FC, et al. The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects. J Clin Endocrinol Metab 1988;67:644–50.[Abstract]
2. Bouillon RA, Auwerx JH, Lissens WD, Pelemans WK. Vitamin D status in the elderly; seasonal substrate deficiency causes 1,25-dihydroxycholecalciferol deficiency. Am J Clin Nutr 1987;45:755–63.[Abstract/Free Full Text]
3. Boland R, de Boland AR, Marinissen MJ, Santillan G, Vazquez G, Zanello S. Avian muscle cells as targets for the secosteroid hormone 1,25-dihydroxy-vitamin D₃. Mol Cell Endocrinol 1995;114:1–8.[Medline]
4. Smith R, Stern G. Muscular weakness in osteomalacia and hyperparathyroidism. J Neurol Sci 1969;8:511–20.[Medline]
5. Jansson S, Grimby G, Hagne I, Hedman I, Tisell L-E. Muscle structure and function before and after surgery for primary hyperparathyroidism. Eur J Surg 1991;157:13–6.[Medline]
6. Kristofferson A, Boström A, Söderberg T. Muscle strength is improved after parathyroidectomy in patients with primary hyperparathyroidism. Br J Surg 1992;79:165–8.[Medline]
7. Chou F-F, Sheen-Chen S-M, Leong C-P. Neuromuscular recovery after parathyroidectomy in primary hyperparathyroidism. Surgery 1995;117:18–25.[Medline]
8. Glerup H, Mikkelsen K, Poulsen L, et al. Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int 2000;66:419–24.[Medline]
9. Stein MS, Wark JD, Scherer SC, et al. Falls relate to vitamin D and parathyroid hormone in an Australian nursing home and hostel. J Am Geriatr Soc 1999;47:1195–201.[Medline]
10. Birge SJ. Can falls and hip fractures be prevented in frail older adults? J Am Geriatr Soc 1999;47:1265–6 (editorial).[Medline]

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