JOURNAL OF BONE A N D MINERAL RESEARCH Volume 5, Number 7, 1990 Mary Ann Liebert, Inc., Publishers
Letter to the Editor To the Editor: In the article on altered vitamin D metabolism in Mexican-Americans in the January issue,(') Reasner et al. made a surprising conclusion that should not be left unchallenged. They stated that depletion of vitamin D and 25-hydroxyvitamin D, (25-OHDJ in the Mexican-Americans resulted in compensatory increases in serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D, [ 1,25(OH),D,].'') There is no scientific rationale for this explanation, and it contradicts much of what we know from basic research. The secretion of PTH is promoted by low calcium and by low 1,25-(OH)zD3. There is no evidence that other vitamin D metabolites play any role in regulating PTH secretion. Since the Mexican-Americans had the same serum calcium concentrations but higher 1,25(OH),D, concentrations than the whites, there is no obvious reason that PTH levels were higher in the MexicanAmericans. Low 25-OHD3 levels do not increase 1,25-(OH),D,. Instead, all available evidence shows that when low 25-OHD, levels coincide with high 1,25-(OH)2D,, then it is the high concentrations of circulating 1,25-(OH)*D, that are the cause of the low 25-OHD3 concentrations. Clements et al. have shown that the high concentrations of 1 ,25-(OH),D, associated with dietary calcium restriction result in more rapid metabolism and excretion of 25-OHD3 into the bile.'') They also demonstrated a similar phenomenon in hyperparathyroid patients.I3] Halloran et al. showed that 1,25-(OH)2D3infusion increased the metabolic clearance of 25-OHD3.'*' We attributed the low levels of 25-OHD3 in rats severely depleted in calcium to the consumption of 25OHD, by their extremely active l-hydroxylase.'s) In rats in which vitamin D metabolite levels were followed during the progression of vitamin D depletion, the 1,25-(OH),D, concentration never increased, it remained normal for a prolonged period and declined once vitamin D depletion became severe.l6) Reasner et al. evidently based their conclusion on a previous study of vitamin D-deficient obese subjects that was also published in this journal.(7)In that study by Bell et al., the measured concentrations of 1,25-(OH),D, were lower after the subjects were treated daily with 25OHD,.'7) However, those 1 ,25-(OH),D, measurements probably reflected a minimum daily level present at 24 h after each dose of 25-OHD3. In subjects given large daily doses of 25-OHD3 the circulating concentration of 25OHD, rises and falls continuously. The synthesis of 1,25(OH),D, should rise and fall along with the daily fluctuations in 25-OHD3 concentrations because I-hydroxylase activity in vivo is determined by mass action in rats(*)and in humans. ( 9 ) If samples had been taken from the obese sub-
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jects at earlier times following the 25-OHD, dose, then the 1,25-(OH),D3 concentrations would likely have been higher. That serum vitamin D concentrations were especially low in the Mexican-Americans supports the conclusion that these individuals acquired relatively less vitamin D. However, it is hard to imagine that this finding is related to the reduced incidence of osteoporotic fractures in Mexican-Americans. Since serum calcium, phosphate, magnesium, gla protein, and all the urinary parameters were not different from those of the whites, there is n o logical connection to account for the higher PTH and 1,25(OH),D, levels in the Mexican-Americans. Instead of vitamin D status, some other basic difference must cause the ethnic dissimilarities in PTH and 1,25-(OH),D, levels. Reinhold Vieth, Ph.D. Department of Clinical Biochemistry and the Bone and Mineral Group University of Toronto and the Research Institute of the Queen Elizabeth Hospital 550 University Ave. Toronto, Ontario, M5G 2A2, Canada
REFERENCES 1. Reasner CA, Dunn JF, Fetchik DA, Lie1 Y , Hollis BW, Epstein S, Shary J, Mundy GR, Bell NH 1990 Alteration of vitamin D metabolism in Mexican-Americans. J Bone Min Res 5:13-17. 2. Clements MR, Johnson L, Fraser DR 1987 A new mechanism for induced vitamin D deficiency in calcium deprivation. Nature 325:62-65. 3. Clements MR, Davies M, Fraser DR, Lumb GA, Mawer EB, A d a m PH 1987 Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism. Clin Sci 73:659-664. 4. Halloran BP, Bikle DD, Levins MJ, Castro ME, Globus RK, Holton 1986 Chronic 1,25-dihydroxyvitamin D, administration in the rat reduces the serum concentration of 25-hydroxyvitamin D by increasing metabolic clearance rate. J Clin Invest 78:622-628. 5. Vieth R, Fraser D, Kooh SW 1987 Low dietary calcium reduces 25-hydroxycholecalciferolin plasma of rats. J Nutr 117: 9 14-9 1 8. 6. Mallon JP, Boris A, Bryce GF 1981 Decrease in serum levels of 1,25-dihydroxycholecalciferolin rats and chicks fed a vitamin D-deficient diet. J Nutr 111:665-667. 7. Bell NH, Epstein, Shary J, Greene V, Oexmann MJ, Shaw V 1988 Evidence for a probable role for 25-hydroxyvitamin D in the regulation of human calcium metabolism. J Bone Min Res 3:489-495. 8. Vieth R, McCarten K, Norwich KH 1990 Role of 25-hydroxyvitamin D3 dose in determining rat 1,25-dihydroxyvitamin D, production. Am J Physiol 258:E780-E789. 9. Mawer EB, Hann JT, Berry JL, Davies M 1985 Vitamin D metabolism in patients intoxicated with ergocalciferol. Clin Sci 68:135-141.
Letter to the Editor To the Editor: In the article on altered vitamin D metabolism in Mexican-Americans in the January issue,(') Reasner et al. made a surprising conclusion that should not be left unchallenged. They stated that depletion of vitamin D and 25-hydroxyvitamin D, (25-OHDJ in the Mexican-Americans resulted in compensatory increases in serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D, [ 1,25(OH),D,].'') There is no scientific rationale for this explanation, and it contradicts much of what we know from basic research. The secretion of PTH is promoted by low calcium and by low 1,25-(OH)zD3. There is no evidence that other vitamin D metabolites play any role in regulating PTH secretion. Since the Mexican-Americans had the same serum calcium concentrations but higher 1,25(OH),D, concentrations than the whites, there is no obvious reason that PTH levels were higher in the MexicanAmericans. Low 25-OHD3 levels do not increase 1,25-(OH),D,. Instead, all available evidence shows that when low 25-OHD, levels coincide with high 1,25-(OH)2D,, then it is the high concentrations of circulating 1,25-(OH)*D, that are the cause of the low 25-OHD3 concentrations. Clements et al. have shown that the high concentrations of 1 ,25-(OH),D, associated with dietary calcium restriction result in more rapid metabolism and excretion of 25-OHD3 into the bile.'') They also demonstrated a similar phenomenon in hyperparathyroid patients.I3] Halloran et al. showed that 1,25-(OH)2D3infusion increased the metabolic clearance of 25-OHD3.'*' We attributed the low levels of 25-OHD3 in rats severely depleted in calcium to the consumption of 25OHD, by their extremely active l-hydroxylase.'s) In rats in which vitamin D metabolite levels were followed during the progression of vitamin D depletion, the 1,25-(OH),D, concentration never increased, it remained normal for a prolonged period and declined once vitamin D depletion became severe.l6) Reasner et al. evidently based their conclusion on a previous study of vitamin D-deficient obese subjects that was also published in this journal.(7)In that study by Bell et al., the measured concentrations of 1,25-(OH),D, were lower after the subjects were treated daily with 25OHD,.'7) However, those 1 ,25-(OH),D, measurements probably reflected a minimum daily level present at 24 h after each dose of 25-OHD3. In subjects given large daily doses of 25-OHD3 the circulating concentration of 25OHD, rises and falls continuously. The synthesis of 1,25(OH),D, should rise and fall along with the daily fluctuations in 25-OHD3 concentrations because I-hydroxylase activity in vivo is determined by mass action in rats(*)and in humans. ( 9 ) If samples had been taken from the obese sub-
791
jects at earlier times following the 25-OHD, dose, then the 1,25-(OH),D3 concentrations would likely have been higher. That serum vitamin D concentrations were especially low in the Mexican-Americans supports the conclusion that these individuals acquired relatively less vitamin D. However, it is hard to imagine that this finding is related to the reduced incidence of osteoporotic fractures in Mexican-Americans. Since serum calcium, phosphate, magnesium, gla protein, and all the urinary parameters were not different from those of the whites, there is n o logical connection to account for the higher PTH and 1,25(OH),D, levels in the Mexican-Americans. Instead of vitamin D status, some other basic difference must cause the ethnic dissimilarities in PTH and 1,25-(OH),D, levels. Reinhold Vieth, Ph.D. Department of Clinical Biochemistry and the Bone and Mineral Group University of Toronto and the Research Institute of the Queen Elizabeth Hospital 550 University Ave. Toronto, Ontario, M5G 2A2, Canada
REFERENCES 1. Reasner CA, Dunn JF, Fetchik DA, Lie1 Y , Hollis BW, Epstein S, Shary J, Mundy GR, Bell NH 1990 Alteration of vitamin D metabolism in Mexican-Americans. J Bone Min Res 5:13-17. 2. Clements MR, Johnson L, Fraser DR 1987 A new mechanism for induced vitamin D deficiency in calcium deprivation. Nature 325:62-65. 3. Clements MR, Davies M, Fraser DR, Lumb GA, Mawer EB, A d a m PH 1987 Metabolic inactivation of vitamin D is enhanced in primary hyperparathyroidism. Clin Sci 73:659-664. 4. Halloran BP, Bikle DD, Levins MJ, Castro ME, Globus RK, Holton 1986 Chronic 1,25-dihydroxyvitamin D, administration in the rat reduces the serum concentration of 25-hydroxyvitamin D by increasing metabolic clearance rate. J Clin Invest 78:622-628. 5. Vieth R, Fraser D, Kooh SW 1987 Low dietary calcium reduces 25-hydroxycholecalciferolin plasma of rats. J Nutr 117: 9 14-9 1 8. 6. Mallon JP, Boris A, Bryce GF 1981 Decrease in serum levels of 1,25-dihydroxycholecalciferolin rats and chicks fed a vitamin D-deficient diet. J Nutr 111:665-667. 7. Bell NH, Epstein, Shary J, Greene V, Oexmann MJ, Shaw V 1988 Evidence for a probable role for 25-hydroxyvitamin D in the regulation of human calcium metabolism. J Bone Min Res 3:489-495. 8. Vieth R, McCarten K, Norwich KH 1990 Role of 25-hydroxyvitamin D3 dose in determining rat 1,25-dihydroxyvitamin D, production. Am J Physiol 258:E780-E789. 9. Mawer EB, Hann JT, Berry JL, Davies M 1985 Vitamin D metabolism in patients intoxicated with ergocalciferol. Clin Sci 68:135-141.
