0021-972X/91/7203-0628$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
Vol. 72, No. 3 Printed in U.S.A.
Subclinical Vitamin D Deficiency in Postmenopausal Women with Low Vertebral Bone Mass* DENNIS T. VILLAREAL, ROBERTO CIVITELLI, ARKADI CHINES, AND LOUIS V. AVIOLI Division of Endocrinology and Bone Metabolism, Jewish Hospital of St. Louis at Washington University Medical Center, St. Louis, Missouri 63110
only in the low 25OHD group did VBD correlate directly with 25OHD (r = 0.41; P < 0.01), and inversely with iPTH (r = -0.47; P < 0.01). Multivariate analyses revealed that iPTH was the major determinant of the observed decrease in VBD. Seasonal variations of serum 25OHD were noted only in the control population; in this group the 25OHD levels also correlated with sunlight exposure (r = 0.48; P < 0.01), as assessed by an outdoor score. Thus, vitamin D deficiency develops when both the endogenous and exogenous sources are insufficient and contributes to a reduced bone mass in elderly women. (J Clin Endocrinol Metab 72: 628-634, 1991)
ABSTRACT. To define the potential role of subclinical vitamin D deficiency in postmenopausal bone loss, we analyzed the levels of circulating 25-hydroxyvitamin D (25OHD) in 539 midwestern Caucasian women screened for osteoporosis. Low 25OHD (
20-
0
o o o
o
o
•
30-
(/I
o a> as
o0
40 :
o
O^x
em '•
e
••
m
• m
m
o
•
OB
to
•
Ǥ
10-
•
(B
0-
1
1
h-
1
_
.
10
15
Outdoor score
100 90 80 oo
70
o
o o
o
60 FIG. 5. Relationship between serum 25OHD levels and dietary vitamin D intake in subjects with low serum 25OHD (•) and normal controls (O). Illustrated is the regression line for the low 25OHD group.
X CM
50 \ o
o
e 00
o oo
o
o
o
o
O
O
o o o«
0
o
O
o O
O
90
o O
O
E I 40
0 0
O
O
o 0
•4—I-
100
200
300
400
500
Dietary vitamin D intake (lU/day) picture is more compatible with secondary hyperparathyroidism, developing as a consequence of subclinical vitamin D deficiency, as previously reported (1, 24, 25). On the other hand, the absence of correlation between iPTH and 25OHD is not surprising, since at physiologi-
cal concentrations, 25OHD is not directly involved in the feedback control of PTH. Although it is generally agreed that a reduction in 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] occurs as the initial event in vitamin D deficiency, leading to calcium
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 March 2015. at 02:55 For personal use only. No other uses without permission. . All rights reserved.
VITAMIN D AND BONE MASS 100 8 0 •• (n-12)^ v.-^
o G" 60--
n
(n-11)
40-
(n-14)
(n-12)
V)
20(n-11)
(n-1»)
1
—1 spring
winter
(n-10)
(n-,3)
1
summer
fall
FIG. 6. Serum levels of 25OHD in the different seasons in individuals with low serum 25OHD (•) and control subjects (O). *, P < 0.001 compared to winter, spring, and fall (by Tukey's multiple range test).
malabsorption, what sustains the intestinal absorptive defect of the mineral in cases where the secondary hyperparathyroidism is able to normalize serum 1,25(OH)2D3 levels is not clear (27). Our study, lacking the 1,25-(OH)2D3 measurements, is not conclusive on this issue. At this juncture, it is worth mentioning that in contrast to young vitamin D-depleted individuals, some elderly subjects are unable to respond adequately to secondary hyperparathyroidism with an increase in 1,25(OH)2D3, presumably due to a deficiency of la-hydroxylase (28). Alternatively, it has been suggested that 25OHD might have a physiological effect by itself, inasmuch as in adults with histologically proven osteomalacia, biochemical and histological indices of vitamin D depletion appear to correlate better either with the sum of 1,25-(OH)2D3 and 25OHD or with 25OHD alone than with 1,25-(OH)2D3 alone (27, 29, 30). This might be one of the mechanisms by which in our patients 25OHD provided a significant, albeit minor, source of VBD variance in the multivariate analysis. On the contrary, PTH most likely affects bone tissue directly. Our data are consistent with the findings of Fonseca et al. (31), who demonstrated that appendicular bone mass, as assessed by single photon densitometry of the forearm, was significantly reduced in patients with nutritional vitamin D deficiency and related to the degree of secondary hyperparathyroidism. However, vitamin D depletion may have been more severe in their patients, since all had bone tenderness and/or proximal myopathy. On the other hand, using similar photon densitometric techniques, neither Tsai et al. (32) nor Sowers et al. (33) could detect any relationship between serum 25OHD levels and bone mineral density; however, their studies were conducted in large unselected female populations, and most of the subjects had a normal vitamin D status. In our study we also found no relationship between bone mineral density (as assessed by QCT) and circulating 25OHD in the group with normal vitamin D status;
633
however, such a correlation was detected in the patients with vitamin D deficiency, supporting the hypothesis that subclinical hypovitaminosis D contributes to a reduction in vertebral bone mass in postmenopausal women. Our study also suggests that vitamin D deficiency may be more frequent than previously recognized. It has been assumed that the fortification of dairy products with vitamin D and the relatively southerly latitude of the U.S. would prevent the development of vitamin D deficiency in the U.S. population, except in certain elderly, debilitated, and institutionalized patients (19, 34). However, even though all of our subjects were ambulatory and generally regarded as healthy individuals, some of them had limited sunlight exposure, and all but three subjects also had a dietary vitamin D intake substantially lower than the recommended dietary allowance. Furthermore, significant seasonal variations in serum 25OHD, with a peak in the summer, were observed in the controls, but not in the low 25OHD group. These observations are important, since, as the present study demonstrates, when dietary vitamin D intake is low, sunlight becomes the critical factor for maintaining an efficient vitamin D homeostasis. In fact, there was a significant positive correlation between sunlight exposure and serum 25OHD in both the entire study population and the individuals with normal serum 25OHD values. Since women with either low or normal 25OHD levels had similar dietary vitamin D intakes, our results indicate that in white postmenopausal females, vitamin D deficiency is primarily accounted for by diminished sunlight exposure. On the other hand, in agreement with previous reports (1517), the positive correlation between 25OHD and dietary vitamin D intake noted in individuals with low 25OHD suggests that in this subset of women, circulating 25OHD levels are primarily dependent on dietary sources. However, the vitamin D intake is apparently inadequate to compensate for the lack of sunshine exposure. The notion that sunshine exposure is the main determinant of a normal vitamin D status in white postmenopausal women living in the midwestern U.S. is consistent with the observation of Haddad and Hahn (35) that 25OHD3, which reflects primarily endogenous D3 production by the skin, is the dominant circulating moiety of 25OHD in Caucasian adults living in St. Louis. In conclusion, our data suggest that subclinical vitamin D deficiency is not an uncommon finding in midwestern white postmenopausal females and is associated with a low VBD. Since vitamin D deficiency can contribute to bone loss, probably through secondary hyperparathyroidism, it is important to consider vitamin D status when evaluating an osteoporotic condition in postmenopausal women, wherein a low serum 25OHD level constitutes an indication for vitamin D supplementation. In addi-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 March 2015. at 02:55 For personal use only. No other uses without permission. . All rights reserved.
VILLAREAL ET AL.
634
tion, elderly women confined to a limited indoor life should be encouraged to increase outdoor activities and sunlight exposure in order to reduce the potential of developing subclinical vitamin D deficiency.
Acknowledgments The authors wish to thank Mrs. Young Me-Soon for performing the 25OHD assay, Christy Delabar, R.D., and Jill Stoll, R.D., for the dietary analysis, and Mr. James Havranek for editorial assistance.
References 1. Parfitt AM, Chir B, Gallagher JC, et al. Vitamin D and bone health in the elderly. Am J Clin Nutr. 1982;36:1014-31. 2. Chalmers J, Conacher WDH, Gardner DL, Scott PJ. Osteomalacia—a common disease in elderly women. J Bone Joint Surg. 1967;49B:403-23. 3. Aaron JE, Gallagher JC, Anderson J, Stasiak L. Frequency of
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
osteomalacia and osteoporosis in fractures of the proximal femur. Lancet. 1974;l:229-33. Aaron JE, Gallagher JC, Nordin BEC. Seasonal variation of histological osteomalacia in femoral neck fractures. Lancet. 1974;2:846. Alhava EM. Diseases contributing to fragility of bone in patients with hip fractures. Ann Clin Res. 1974;6:246-52. Eid AM. Osteomalacia as a contributing factor in fracture of the femoral neck in the elderly in Qatar. Clin Orthop. 1978;132:12935. Solomon L. Fracture of the femoral neck in the elderly: bone ageing or disease? S Afr J Surg. 1973;ll:269-79. Brown IRF, Bakowska A, Millard PH. Vitamin D status of patients with femoral neck fractures. Age Ageing. 1976;5:127-31. Baker MR, McDonnell H, Peacock M, Nordin BEC. Plasma 25 hydroxyvitamin D concentrations in patients with fracture of the femoral neck. Br Med J. 1979;l:589-90. Weisman Y, Salama K, Harell A, Edelstein S. Serum 24,25-dihydroxyvitamin D and 25 hydroxyvitamin D concentrations in femoral neck fracture. Br Med J. 1978;2:1196-7. Wootton R, Brereton PJ, Clark MB, et al. Fractured neck of femur in the elderly: an attempt to identify patients at risk. Clin Sci. 1979;57:93-101. Webb, AR, Holick MF. The role of sunlight in the cutaneous production of vitamin D3. Annu Rev Nutr. 1988;8:375-99. Hodkinson HM, Stanton BR, Round P, Morgan C. Sunlight, vitamin D, and osteomalacia in elderly. Lancet. 1973:l;9lO-2. Corless D, Beer M, Boucher BJ, Gupta SP. Vitamin D status in long-stay geriatric patients. Lancet. 1975:l;1404-6. Nayal AS, MacKinnon VJ, Hamilton JG, Rose P, Kong, M. 25Hydroxyvitamin D, diet and sunlight exposure in patients admitted to a geriatric unit. Gerontology. 1978;24:117-22. Lamberg-Allardt C. Vitamin D intake, sunlight exposure and 25hydroxyvitamin D levels in the elderly during one year. Ann Nutr Metab. 1984;28:144-50. Lyss PMD, Ginkel FC, Jangen MJM, et al. Determinants of vitamin D status in patients with hip fracture and in elderly control
JCE & M • 1991 Vol 72 • No 3
subjects. Am J Clin Nutr. 1987;46:1005-10. 18. 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;45:75563. 19. Riggs BL, Melton III LJ. Involutional osteoporosis. N Engl J Med. 1986;314:1676-86. 20. Haddad JG, Chyu KJ. Competitive protein-binding radioassay for 25 hydroxycholecalciferol. J Clin Endocrinol Metab. 1971;33:9925. 21. Martin KJ, Hruska K, Freitag J, Bellorin-Font E, Klahr S, Slatopolsky E. Clinical utility of radioimmunoassays for parathyroid hormone. Mineral Electrolyte Metab. 1980;3:283-90. 22. Pacifici R, Susman N, Carr PL, Birge SJ, Avioli LV. Single and dual energy tomographic analysis of spinal trabecular bone: a comparative study in normal and osteoporotic women. J Clin Endocrinol Metab. 1987;64:209-14. 23. Seeman E, Wahner HW, Offord KP, Kumar R, Johnson WJ, Riggs BL. Differential effects of endocrine dysfunction on the axial and appendicular skeleton. J Clin Invest. 1982;69:1302-9. 24. Frame B, Parfitt AM. Osteomalacia: current concepts. Ann Intern Med. 1978;89:966-82. 25. Stanbury SW, Vitamin D and hyperparathyroidism. J R Coll Physicians Lond. 1981;15:205-16. 26. Marcus R, Madvig P, Young G. Age related changes in parathyroid hormone and parathyroid hormone action in normal humans. J Clin Endocrinol Metab. 1984;58:223-30. 27. Parfitt AM: Osteomalacia and related disorders. In: Avioli LV, Krane S, eds. Metabolic bone disease and clinically related disorders, 2nd ed. Philadelphia: Saunders; 1990;329-95. 28. Dandona P, Menon RK, Shenoy R, Houlder S, Thomas M, Mallinson WJW. Low 1,25-dihydroxyvitamin D, secondary hyperparathyroidism, and normal osteocalcin in elderly subjects. J Clin Endocrinol Metab. 1986;63:459-62. 29. Rao DS, Villanueva A, Mattews M, et al. Histologic evolution of vitamin D depletion in patients with intestinal malabsorption or dietary deficiency. In: Frame B, Potts Jr JT, eds. Clinical disorders of bone and mineral metabolism. Amsterdam: Excerpta Medica; 1983;224-6. 30. Nordin BEC, Heyburn PJ, Peacock M, et al. Osteoporosis and osteomalacia. Clin Endocrinol Metab. 1980;9:177-205. 31. Fonseca V, Agnew JE, Nay D, Dandona P. Bone density and cortical thickness in nutritional vitamin D deficiency: effect of secondary hyperparathyroidism. Ann Clin Biochem. 1988;25:2714. 32. Tsai KS, Wahner KP, Afford LJ, Melton III LJ, Kumar R, Riggs BL. Effect of aging on vitamin D stores and bone density in women. Calcif Tissue Int. 1987;40:241-3. 33. Sowers MR, Wallace RB, Hollis BW, Lemke JH. Parameters related to 25-OH-D levels in a population-based study of women. Am J Clin Nutr. 1986;43:621-8. 34. Webb AR, Pilbeam C, Hanafin N, Holick M. An evaluation of the relative contributions of exposure to sunlight and of diet to the circulating concentrations of 25 hydroxyvitamin D in an elderly nursing home population in Boston. Am J Clin Nutr. 1990;51:107581. 35. Haddad JG, Hahn TJ. Natural and synthetic sources of circulating 25-hydroxyvitamin D in man. Nature. 1973;244:515-6.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 March 2015. at 02:55 For personal use only. No other uses without permission. . All rights reserved.
Vol. 72, No. 3 Printed in U.S.A.
Subclinical Vitamin D Deficiency in Postmenopausal Women with Low Vertebral Bone Mass* DENNIS T. VILLAREAL, ROBERTO CIVITELLI, ARKADI CHINES, AND LOUIS V. AVIOLI Division of Endocrinology and Bone Metabolism, Jewish Hospital of St. Louis at Washington University Medical Center, St. Louis, Missouri 63110
only in the low 25OHD group did VBD correlate directly with 25OHD (r = 0.41; P < 0.01), and inversely with iPTH (r = -0.47; P < 0.01). Multivariate analyses revealed that iPTH was the major determinant of the observed decrease in VBD. Seasonal variations of serum 25OHD were noted only in the control population; in this group the 25OHD levels also correlated with sunlight exposure (r = 0.48; P < 0.01), as assessed by an outdoor score. Thus, vitamin D deficiency develops when both the endogenous and exogenous sources are insufficient and contributes to a reduced bone mass in elderly women. (J Clin Endocrinol Metab 72: 628-634, 1991)
ABSTRACT. To define the potential role of subclinical vitamin D deficiency in postmenopausal bone loss, we analyzed the levels of circulating 25-hydroxyvitamin D (25OHD) in 539 midwestern Caucasian women screened for osteoporosis. Low 25OHD (
20-
0
o o o
o
o
•
30-
(/I
o a> as
o0
40 :
o
O^x
em '•
e
••
m
• m
m
o
•
OB
to
•
Ǥ
10-
•
(B
0-
1
1
h-
1
_
.
10
15
Outdoor score
100 90 80 oo
70
o
o o
o
60 FIG. 5. Relationship between serum 25OHD levels and dietary vitamin D intake in subjects with low serum 25OHD (•) and normal controls (O). Illustrated is the regression line for the low 25OHD group.
X CM
50 \ o
o
e 00
o oo
o
o
o
o
O
O
o o o«
0
o
O
o O
O
90
o O
O
E I 40
0 0
O
O
o 0
•4—I-
100
200
300
400
500
Dietary vitamin D intake (lU/day) picture is more compatible with secondary hyperparathyroidism, developing as a consequence of subclinical vitamin D deficiency, as previously reported (1, 24, 25). On the other hand, the absence of correlation between iPTH and 25OHD is not surprising, since at physiologi-
cal concentrations, 25OHD is not directly involved in the feedback control of PTH. Although it is generally agreed that a reduction in 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] occurs as the initial event in vitamin D deficiency, leading to calcium
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 March 2015. at 02:55 For personal use only. No other uses without permission. . All rights reserved.
VITAMIN D AND BONE MASS 100 8 0 •• (n-12)^ v.-^
o G" 60--
n
(n-11)
40-
(n-14)
(n-12)
V)
20(n-11)
(n-1»)
1
—1 spring
winter
(n-10)
(n-,3)
1
summer
fall
FIG. 6. Serum levels of 25OHD in the different seasons in individuals with low serum 25OHD (•) and control subjects (O). *, P < 0.001 compared to winter, spring, and fall (by Tukey's multiple range test).
malabsorption, what sustains the intestinal absorptive defect of the mineral in cases where the secondary hyperparathyroidism is able to normalize serum 1,25(OH)2D3 levels is not clear (27). Our study, lacking the 1,25-(OH)2D3 measurements, is not conclusive on this issue. At this juncture, it is worth mentioning that in contrast to young vitamin D-depleted individuals, some elderly subjects are unable to respond adequately to secondary hyperparathyroidism with an increase in 1,25(OH)2D3, presumably due to a deficiency of la-hydroxylase (28). Alternatively, it has been suggested that 25OHD might have a physiological effect by itself, inasmuch as in adults with histologically proven osteomalacia, biochemical and histological indices of vitamin D depletion appear to correlate better either with the sum of 1,25-(OH)2D3 and 25OHD or with 25OHD alone than with 1,25-(OH)2D3 alone (27, 29, 30). This might be one of the mechanisms by which in our patients 25OHD provided a significant, albeit minor, source of VBD variance in the multivariate analysis. On the contrary, PTH most likely affects bone tissue directly. Our data are consistent with the findings of Fonseca et al. (31), who demonstrated that appendicular bone mass, as assessed by single photon densitometry of the forearm, was significantly reduced in patients with nutritional vitamin D deficiency and related to the degree of secondary hyperparathyroidism. However, vitamin D depletion may have been more severe in their patients, since all had bone tenderness and/or proximal myopathy. On the other hand, using similar photon densitometric techniques, neither Tsai et al. (32) nor Sowers et al. (33) could detect any relationship between serum 25OHD levels and bone mineral density; however, their studies were conducted in large unselected female populations, and most of the subjects had a normal vitamin D status. In our study we also found no relationship between bone mineral density (as assessed by QCT) and circulating 25OHD in the group with normal vitamin D status;
633
however, such a correlation was detected in the patients with vitamin D deficiency, supporting the hypothesis that subclinical hypovitaminosis D contributes to a reduction in vertebral bone mass in postmenopausal women. Our study also suggests that vitamin D deficiency may be more frequent than previously recognized. It has been assumed that the fortification of dairy products with vitamin D and the relatively southerly latitude of the U.S. would prevent the development of vitamin D deficiency in the U.S. population, except in certain elderly, debilitated, and institutionalized patients (19, 34). However, even though all of our subjects were ambulatory and generally regarded as healthy individuals, some of them had limited sunlight exposure, and all but three subjects also had a dietary vitamin D intake substantially lower than the recommended dietary allowance. Furthermore, significant seasonal variations in serum 25OHD, with a peak in the summer, were observed in the controls, but not in the low 25OHD group. These observations are important, since, as the present study demonstrates, when dietary vitamin D intake is low, sunlight becomes the critical factor for maintaining an efficient vitamin D homeostasis. In fact, there was a significant positive correlation between sunlight exposure and serum 25OHD in both the entire study population and the individuals with normal serum 25OHD values. Since women with either low or normal 25OHD levels had similar dietary vitamin D intakes, our results indicate that in white postmenopausal females, vitamin D deficiency is primarily accounted for by diminished sunlight exposure. On the other hand, in agreement with previous reports (1517), the positive correlation between 25OHD and dietary vitamin D intake noted in individuals with low 25OHD suggests that in this subset of women, circulating 25OHD levels are primarily dependent on dietary sources. However, the vitamin D intake is apparently inadequate to compensate for the lack of sunshine exposure. The notion that sunshine exposure is the main determinant of a normal vitamin D status in white postmenopausal women living in the midwestern U.S. is consistent with the observation of Haddad and Hahn (35) that 25OHD3, which reflects primarily endogenous D3 production by the skin, is the dominant circulating moiety of 25OHD in Caucasian adults living in St. Louis. In conclusion, our data suggest that subclinical vitamin D deficiency is not an uncommon finding in midwestern white postmenopausal females and is associated with a low VBD. Since vitamin D deficiency can contribute to bone loss, probably through secondary hyperparathyroidism, it is important to consider vitamin D status when evaluating an osteoporotic condition in postmenopausal women, wherein a low serum 25OHD level constitutes an indication for vitamin D supplementation. In addi-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 30 March 2015. at 02:55 For personal use only. No other uses without permission. . All rights reserved.
VILLAREAL ET AL.
634
tion, elderly women confined to a limited indoor life should be encouraged to increase outdoor activities and sunlight exposure in order to reduce the potential of developing subclinical vitamin D deficiency.
Acknowledgments The authors wish to thank Mrs. Young Me-Soon for performing the 25OHD assay, Christy Delabar, R.D., and Jill Stoll, R.D., for the dietary analysis, and Mr. James Havranek for editorial assistance.
References 1. Parfitt AM, Chir B, Gallagher JC, et al. Vitamin D and bone health in the elderly. Am J Clin Nutr. 1982;36:1014-31. 2. Chalmers J, Conacher WDH, Gardner DL, Scott PJ. Osteomalacia—a common disease in elderly women. J Bone Joint Surg. 1967;49B:403-23. 3. Aaron JE, Gallagher JC, Anderson J, Stasiak L. Frequency of
4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
osteomalacia and osteoporosis in fractures of the proximal femur. Lancet. 1974;l:229-33. Aaron JE, Gallagher JC, Nordin BEC. Seasonal variation of histological osteomalacia in femoral neck fractures. Lancet. 1974;2:846. Alhava EM. Diseases contributing to fragility of bone in patients with hip fractures. Ann Clin Res. 1974;6:246-52. Eid AM. Osteomalacia as a contributing factor in fracture of the femoral neck in the elderly in Qatar. Clin Orthop. 1978;132:12935. Solomon L. Fracture of the femoral neck in the elderly: bone ageing or disease? S Afr J Surg. 1973;ll:269-79. Brown IRF, Bakowska A, Millard PH. Vitamin D status of patients with femoral neck fractures. Age Ageing. 1976;5:127-31. Baker MR, McDonnell H, Peacock M, Nordin BEC. Plasma 25 hydroxyvitamin D concentrations in patients with fracture of the femoral neck. Br Med J. 1979;l:589-90. Weisman Y, Salama K, Harell A, Edelstein S. Serum 24,25-dihydroxyvitamin D and 25 hydroxyvitamin D concentrations in femoral neck fracture. Br Med J. 1978;2:1196-7. Wootton R, Brereton PJ, Clark MB, et al. Fractured neck of femur in the elderly: an attempt to identify patients at risk. Clin Sci. 1979;57:93-101. Webb, AR, Holick MF. The role of sunlight in the cutaneous production of vitamin D3. Annu Rev Nutr. 1988;8:375-99. Hodkinson HM, Stanton BR, Round P, Morgan C. Sunlight, vitamin D, and osteomalacia in elderly. Lancet. 1973:l;9lO-2. Corless D, Beer M, Boucher BJ, Gupta SP. Vitamin D status in long-stay geriatric patients. Lancet. 1975:l;1404-6. Nayal AS, MacKinnon VJ, Hamilton JG, Rose P, Kong, M. 25Hydroxyvitamin D, diet and sunlight exposure in patients admitted to a geriatric unit. Gerontology. 1978;24:117-22. Lamberg-Allardt C. Vitamin D intake, sunlight exposure and 25hydroxyvitamin D levels in the elderly during one year. Ann Nutr Metab. 1984;28:144-50. Lyss PMD, Ginkel FC, Jangen MJM, et al. Determinants of vitamin D status in patients with hip fracture and in elderly control
JCE & M • 1991 Vol 72 • No 3
subjects. Am J Clin Nutr. 1987;46:1005-10. 18. 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;45:75563. 19. Riggs BL, Melton III LJ. Involutional osteoporosis. N Engl J Med. 1986;314:1676-86. 20. Haddad JG, Chyu KJ. Competitive protein-binding radioassay for 25 hydroxycholecalciferol. J Clin Endocrinol Metab. 1971;33:9925. 21. Martin KJ, Hruska K, Freitag J, Bellorin-Font E, Klahr S, Slatopolsky E. Clinical utility of radioimmunoassays for parathyroid hormone. Mineral Electrolyte Metab. 1980;3:283-90. 22. Pacifici R, Susman N, Carr PL, Birge SJ, Avioli LV. Single and dual energy tomographic analysis of spinal trabecular bone: a comparative study in normal and osteoporotic women. J Clin Endocrinol Metab. 1987;64:209-14. 23. Seeman E, Wahner HW, Offord KP, Kumar R, Johnson WJ, Riggs BL. Differential effects of endocrine dysfunction on the axial and appendicular skeleton. J Clin Invest. 1982;69:1302-9. 24. Frame B, Parfitt AM. Osteomalacia: current concepts. Ann Intern Med. 1978;89:966-82. 25. Stanbury SW, Vitamin D and hyperparathyroidism. J R Coll Physicians Lond. 1981;15:205-16. 26. Marcus R, Madvig P, Young G. Age related changes in parathyroid hormone and parathyroid hormone action in normal humans. J Clin Endocrinol Metab. 1984;58:223-30. 27. Parfitt AM: Osteomalacia and related disorders. In: Avioli LV, Krane S, eds. Metabolic bone disease and clinically related disorders, 2nd ed. Philadelphia: Saunders; 1990;329-95. 28. Dandona P, Menon RK, Shenoy R, Houlder S, Thomas M, Mallinson WJW. Low 1,25-dihydroxyvitamin D, secondary hyperparathyroidism, and normal osteocalcin in elderly subjects. J Clin Endocrinol Metab. 1986;63:459-62. 29. Rao DS, Villanueva A, Mattews M, et al. Histologic evolution of vitamin D depletion in patients with intestinal malabsorption or dietary deficiency. In: Frame B, Potts Jr JT, eds. Clinical disorders of bone and mineral metabolism. Amsterdam: Excerpta Medica; 1983;224-6. 30. Nordin BEC, Heyburn PJ, Peacock M, et al. Osteoporosis and osteomalacia. Clin Endocrinol Metab. 1980;9:177-205. 31. Fonseca V, Agnew JE, Nay D, Dandona P. Bone density and cortical thickness in nutritional vitamin D deficiency: effect of secondary hyperparathyroidism. Ann Clin Biochem. 1988;25:2714. 32. Tsai KS, Wahner KP, Afford LJ, Melton III LJ, Kumar R, Riggs BL. Effect of aging on vitamin D stores and bone density in women. Calcif Tissue Int. 1987;40:241-3. 33. Sowers MR, Wallace RB, Hollis BW, Lemke JH. Parameters related to 25-OH-D levels in a population-based study of women. Am J Clin Nutr. 1986;43:621-8. 34. Webb AR, Pilbeam C, Hanafin N, Holick M. An evaluation of the relative contributions of exposure to sunlight and of diet to the circulating concentrations of 25 hydroxyvitamin D in an elderly nursing home population in Boston. Am J Clin Nutr. 1990;51:107581. 35. Haddad JG, Hahn TJ. Natural and synthetic sources of circulating 25-hydroxyvitamin D in man. Nature. 1973;244:515-6.
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