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University of Connecticut, School of Allied Health, U-101, 358 Mansfield Road, Storrs, CT 06269-2101, E-mail: jane.kerstetter{at}uconn.edu
Johns Hopkins School of Hygiene and Public Health, Center for Human Nutrition, Johns Hopkins University, Baltimore, MD 21205-2179
Yale School of Medicine, 333 Cedar Street, PO Box 208020, Fitkin 1, New Haven, CT 06520-8020
Dear Sir:
We read with interest Heaney's recent study that showed no effect of dietary protein on calcium absorption (1). In his observational study of women consuming their habitual diets, dietary protein intake did not influence intestinal calcium absorption estimated by using dual calcium isotopic techniques. By contrast, we found in 3 prospective intervention studies, in which the diet was tightly controlled, that a reduction in dietary protein led to secondary hyperparathyroidism and a decline in calcium absorption (2–4).
We found that secondary hyperparathyroidism was observed within 4 d of initiation of a low-protein diet and persisted for 2 wk (3). Our findings were remarkably consistent and robust. In studies involving 45 adults, nearly all of the subjects experienced the same changes: abrupt and large increases in all measures of the parathyroid hormone (PTH)-1--hydroxylase axis (2, 5). Thus, for example, in our original study, in which 16 young women consumed 0.7 g protein/kg, we observed the following changes in the PTH-1--hydroxylase axis (3). Serum PTH increased 2.7-fold, from 14.1 ± 0.4 (day 0) to 37.7 ± 1.9 nmol/L (day 4; upper limit of normal for PTH: 20 nmol/L). Similarly, serum 1,25-dihydroxyvitamin D increased 1.3-fold from 102.3 ± 4.2 (day 0) to 132.1 ± 4.3 pmol/L (day 4; upper limit of normal: 144 pmol/L) and nephrogenous cyclic AMP excretion increased 1.6-fold from 15.4 ± 0.7 (day 0) to 24.2 ± 1.1 nmol/L glomerular filtrate (day 4; upper limit of normal: 25.0 nmol/L glomerular filtrate). Twenty-four–hour urinary calcium excretion fell from 3.35 ± 0.42 to 2.70 ± 0.35 mmol/d. These acute perturbations in the PTH-1--hydroxylase axis were due, at least in part, to a decline in intestinal calcium absorption. This was evident from the finding that, when protein intakes were reduced from 2.1 to 0.7 g•kg-1•d-1 in premenopausal women, calcium absorption fell from 26 ± 3% to19 ± 2% as determined by using dual stable calcium isotopes (2).
It is important to emphasize the rigor of the experimental design used in all of our studies. Each subject served as her own control for every diet, ie, each subject was studied at each protein intake. Every subject regulated her calcium intake for 2 wk before the actual experiment began. These lead-in diets were designed to ensure that all subjects were starting the study at approximately the same intakes of calcium, protein, and sodium to minimize variation in baseline data. Indeed, baseline measures of the PTH-1--hydroxylase axis were consistently normal (2–4). In the aggregate, our data strongly support the conclusion that an abrupt decrease in dietary protein leads to a reduction in calcium absorption and consequent secondary hyperparathyroidism.
We believe that the difference between Heaney's findings and ours may be related, in part, to differences in study design and data analysis. The between-individual variability in intestinal calcium absorption was high even under rigidly controlled experimental conditions. For example, in our experimental interventions, important nutrients were tightly controlled. Dietary protein intakes ranged from 0.69 to 0.72 g/kg, dietary calcium intakes ranged from 795 to 810 mg/kg, and dietary fiber, phosphorus, caffeine, and sodium intakes were also controlled (2). Despite the constancy of the diet, intestinal calcium absorption varied widely between healthy premenopausal women studied under identical study conditions, from 11% to 26%. Having each subject serve as her own control allowed us to detect protein-induced changes in calcium absorption.
In an attempt to control for the variation in calcium absorption due to different habitual calcium intakes, a corrected calcium absorption was calculated for each subject in Heaney's study. The normalization of the absorption data, based on dietary calcium, may have inadvertently obscured the effect of protein. About 75% of dietary calcium is derived from dairy foods, which are also an important source of protein. By controlling for the effect of dietary calcium on intestinal calcium absorption, Heaney may also have controlled for much of the effect of protein.
The critical question, as Heaney and Wood (6) point out in the accompanying editorial, is whether acute changes in mineral metabolism induced by a low-protein diet have long-term implications for bone heath. The answer is not yet known. If low dietary protein intakes indeed lower calcium absorption, a compensatory rise in serum PTH (secondary hyperparathyroidism) would be the physiologic response. We documented this acute change. The long-term effects of protein on bone turnover are not fully understood and studies are ongoing in our laboratory to investigate this.
A low-protein diet could be deleterious to the skeleton, particularly if it is accompanied by a small chronic reduction in calcium absorption. In this context, it is of interest that 2 recent large epidemiologic studies found that when other dietary factors were controlled for, individuals who consumed low-protein diets had lower bone mineral densities (7, 8). One recent prospective study also found that low protein intakes were associated with an increased risk of hip fracture (9). Although difficult to undertake, long-term, carefully controlled intervention studies are necessary to quantitate the chronic effect of low-protein diets on the skeleton.
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