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Relationship of Intestinal Calcium Absorption to 1,25-Dihydroxyvitamin D [1,25(OH)₂D] Levels in Young Versus Elderly Women: Evidence for Age-Related Intestinal Resistance to 1,25(OH)₂D Action¹

Endocrine Research Unit (S.P., B.L.R., S.K.), Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905; Section of Metabolic Analysis and Mass Spectrometry (A.L.Y., N.E.V.), National Institute of Child Health and Human Development, Bethesda, Maryland 20892; and Section of Biostatistics (W.M.F.), Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Sundeep Khosla, M.D., Endocrine Research Unit, Mayo Clinic, 200 First Street SW, 5-194 Joseph, Rochester, Minnesota 55905. Email: khosla.sundeep@mayo.edu.

Intestinal calcium absorption decreases with aging, but it is unclear whether this is attributable to an age-related intestinal resistance to 1,25-dihydroxyvitamin D [1,25(OH)₂D] action. Thus, we assessed the in vivo dose response of active intestinal calcium absorption to a broad range of circulating 1,25(OH)₂D levels in elderly [age (mean ± SD), 72.5 ± 3.0 yr] vs. young women (age, 28.7 ± 5.3 yr; n = 20 per group), who were stratified into 5 subgroups: group 1 was given a high calcium intake of 75 mmol/day, suppressing 1,25(OH)₂D levels; group 2 was given a normal calcium diet of 15–30 mmol/day, representing basal 1,25(OH)₂D levels; group 3 was given a low-calcium diet of 5 mmol/day to stimulate endogenous 1,25(OH)₂D production; group 4 was given the low-calcium diet plus 1 µg/day 1,25(OH)₂D; and group 5 was given a low-calcium diet plus 2 µg/day 1,25(OH)₂D. After 7 days of diet and/or 1,25(OH)₂D treatment, fasting fractional calcium absorption (FCA) was assessed by a double-tracer method using stable calcium isotopes. Serum 1,25(OH)₂D and vitamin D-binding protein levels were measured concurrently, and the free 1,25(OH)₂D index [molar ratio of 1,25(OH)₂D to DBP] was calculated.

FCA was significantly correlated with the free 1,25(OH)₂D index in the young (R = 0.63, P = 0.003) but not in the elderly women (R = 0.27, P = 0.25). Moreover, the slope of the relationship between FCA and free 1,25(OH)₂D index (representing intestinal sensitivity to 1,25(OH)₂D) was significantly greater in the young (compared with the elderly) women [mean ± SEM, 0.15 ± 0.04 (young) vs. 0.03 ± 0.02, elderly, P = 0.03]. Thus, using an experimental design that allowed us to assess FCA over a wide range of 1,25(OH)₂D levels, we demonstrate that elderly women have a resistance to 1,25(OH)₂D action that may contribute to their negative calcium balance, secondary hyperparathyroidism, and bone loss.

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