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© 2003 The American Society for Nutritional Sciences J. Nutr. 133:855S-861S, March 2003

Supplement: New Perspectives on Dietary Protein and Bone Health

Low Protein Intake: The Impact on Calcium and Bone Homeostasis in Humans1,2

Jane E. Kerstetter3, Kimberly O. O’Brien* and Karl L. Insogna{dagger}

School of Allied Health, University of Connecticut, Storrs, CT 06269-2101, * Johns Hopkins Bloomberg School of Public Health, Center for Human Nutrition, Baltimore, MD 21218 and {dagger} Yale University School of Internal Medicine, New Haven, CT 06520-8020

3To whom correspondence should be addressed. E-mail: Jane.Kerstetter{at}uconn.edu


   ABSTRACT
TOP
 ABSTRACT
Dietary protein and calcium...
 The traditional view
 The acute impact of...
 The chronic impact of...
 Summary and conclusions
 LITERATURE CITED
 
Increasing dietary protein results in an increase in urinary calcium. Despite over 80 y of research, the source of the additional urinary calcium remains unclear. Because most calcium balance studies found little effect of dietary protein on intestinal calcium absorption, it was assumed that the skeleton was the source of the calcium. The hypothesis was that the high endogenous acid load generated by a protein-rich diet would increase bone resorption and skeletal fracture. However, there are no definitive nutrition intervention studies that show a detrimental effect of a high protein diet on the skeleton and the hypothesis remains unproven. Recent studies from our laboratory demonstrate that dietary protein affects intestinal calcium absorption. We conducted a series of short-term nutrition intervention trials in healthy adults where dietary protein was adjusted to either low, medium or high. The highest protein diet resulted in hypercalciuria with no change in serum parathyroid hormone. Surprisingly, within 4 d, the low protein diet induced secondary hyperparathyroidism that persisted for 2 wk. The secondary hyperparathyroidism induced by the low protein diet was attributed to a reduction in intestinal calcium absorption (as assessed by dual stable calcium isotopes). The long-term consequences of these low protein–induced changes in calcium metabolism are not known, but they could be detrimental to skeletal health. Several recent epidemiological studies demonstrate reduced bone density and increased rates of bone loss in individuals habitually consuming low protein diets. Therefore, studies are needed to determine whether low protein intakes directly affect rates of bone resorption, bone formation or both.

KEY WORDS: • dietary protein • urinary calcium • calcium absorption • parathyroid hormone • bone

Almost 10 million Americans have been diagnosed with osteoporosis and 34 million have osteopenia (1 ). The health problems that accompany low bone mass are reaching near epidemic proportions in the United States and worldwide. There is little doubt that dietary calcium and vitamin D are critical nutrients for both accruing and maintaining skeletal mass. Compared to calcium and vitamin D, much less is known about how other nutrients, such as dietary protein, affect bone. A long-standing hypothesis was that a high protein diet was detrimental to bone because it generated a high endogenous acid load that would require buffering from bone, thereby increasing resorption (2 ). However, recent nutrition intervention trials and epidemiological data suggest that high protein diet–induced hypercalciuria is attributable, for the most part, to increased intestinal calcium absorption, leaving uncertain the effect that a high protein diet has on the skeleton. In contrast, low protein diets decrease intestinal calcium absorption (see below) and in the majority of recent epidemiological studies, are associated with reduced bone mass. This review summarizes our current understanding of the effects of a protein-restricted diet on calcium and bone homeostasis.


   Dietary protein and calcium in the United States
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 ABSTRACT
 Dietary protein and calcium...
The traditional view
 The acute impact of...
 The chronic impact of...
 Summary and conclusions
 LITERATURE CITED
 
The mean protein intake for adult men and women in the United States and the percentage of individuals consuming each level of protein are summarized in Table 1 (3 ). For purposes of this review, we identified low, medium, high and very high protein diets compared to the recommended daily allowance (RDA) as defined in Table 1 . The most current RDA for protein remains at 0.8 g protein/kg in the adult (4 ). Between 15 and 38% of adult men and 27 and 41% of adult women have dietary protein intakes below the RDA.


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  		TABLE 1 Percentage of individuals with diets within the given ranges of protein intake in the United States1

 
As summarized in Table 2 , the majority of adult men and women in the United States consume <100% of the 1989 RDA for calcium (800 mg for men and women over the age of 25 y) (3 ). Calcium intakes from nutritional supplements are not included in the CSFII data (suggesting the data in Table 2 overestimated calcium deficiency). In 1999 the RDA for calcium was increased to 1000–1200 mg, depending on age (suggesting data in Table 2 will now underestimate calcium deficiency). For purposes of this review, we identified very low, low, medium and high calcium diets compared to the 1989 RDA. Therefore, when considering the impact of dietary protein on calcium metabolism, it should be kept in mind that most Americans consume a diet rich in protein but poor in calcium.


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  		TABLE 2 Percentage of individuals with diets within the given ranges of Ca intake in the United States1

 

   The traditional view
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 ABSTRACT
 Dietary protein and calcium...
 The traditional view
The acute impact of...
 The chronic impact of...
 Summary and conclusions
 LITERATURE CITED
 
Studies conducted over the past 80 y document that a high protein diet increases urinary Ca excretion in humans. We have reviewed data from 26 clinical intervention trials in adult humans where the diet was controlled, dietary protein was manipulated (150 g protein and less) and urinary calcium was measured (Fig. 1 ) (5 –30 ). Despite varied experimental designs, most studies reported a positive relationship between protein intake and urinary calcium and the overall association is strong (P < 0.001, r = 0.1). The linear regression equation from Figure 1 is

where urine Ca is expressed as mmol/d and dietary protein is g/d, slope = 3.208E-02 and y-intercept is 1.501. These data clearly establish that dietary protein is an important regulator of urinary calcium excretion, at least as important as dietary calcium (11 ,31 ).



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  		FIGURE 1 Relationship between dietary protein and urinary calcium excretion in 26 studies (5 –30 ). Each point represents the mean from one of those studies.

 
However, the source of the urinary Ca excreted during high protein conditions is unclear. As noted above, one possibility is that the additional Ca excreted in the urine results from increased bone resorption. If the increase in resorption was not accompanied by a matched increase in bone formation, the uncoupling would eventually result in increased bone loss and risk of fracture. If this "bone hypothesis" is correct, several perturbations in Ca homeostasis would occur as described below.
  1. First, dietary protein (especially from animal sources rich in the sulfur amino acids) should increase endogenous acid production. The available data clearly support the "acid ash"–generating capacity of dietary protein [cited in Barzel and Massey (2 )]. The richer the protein source is in sulfur amino acids, the more fixed acid it generates. In fact, the potential renal acid load (PRAL) of a diet can be estimated from the composition of the diet using established formulas (32 ,33 ).
  2. In response to the acid load induced by a high animal protein diet, bone may be called upon to act as a reservoir of alkali, and as a consequence, bone Ca is also mobilized. There is adequate experimental evidence that an acid environment increases osteoclast-mediated bone resorption, whereas resorption is suppressed at a neutral or alkali pH (20 ,34 –38 ).
  3. The long-term consequence of this reliance on bone to buffer the endogenous acid would be increased rates of skeletal loss and a decrease in bone mineral density (BMD). However, the epidemiological data bearing on this point support a different conclusion. There are at least 10 epidemiological studies in which BMD is the primary outcome showing that a high protein diet is associated with a high BMD (not a low BMD, as might be predicted) (39 –48 ). There is only one study showing a negative association (49 ) and four showing no association (50 –53 ). The nutrition intervention studies in which markers of bone turnover were measured under various protein conditions are few and inconsistent (23 ,54 ).
  4. The hypothesis would also predict that a long-term, high protein diet would increase fractures. Surprisingly, given the BMD data, the epidemiological evidence, by and large, demonstrate an increased fracture rate in populations consuming high protein diets (55 –58 ) with only one divergent study (59 ). The discrepancy between the BMD and the fracture epidemiological data is not understood, at this point.

The above "bone hypothesis" was further supported by the observation that dietary protein reportedly does not affect intestinal Ca absorption. Most human balance studies report no difference in Ca absorption when dietary protein is altered (7 –12 ,15 ,18 ,60 ), although there are a few exceptions (6 ,16 ,61 ).

However, studies conducted over the past 8 y in our laboratory call the traditional high protein bone hypothesis to question. We have found that a high protein diet induces hypercalciuria primarily because it increases intestinal Ca absorption. Second, a low protein diet acutely reduces intestinal Ca absorption, resulting in an abrupt rise in serum parathyroid hormone. Finally, emerging epidemiological data from our group and others suggest that the long-term consequences of these changes in intestinal handling of Ca may adversely affect skeletal homeostasis. In this review, we summarize the most recent nutrition intervention trials and the epidemiological studies that suggest a need to revisit our traditional thinking about how dietary protein affects bone.


   The acute impact of low protein diets
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 ABSTRACT
 Dietary protein and calcium...
 The traditional view
 The acute impact of...
The chronic impact of...
 Summary and conclusions
 LITERATURE CITED
 
In three studies conducted over the past several years (22 ,25 ,27 ), we examined the impact of moderately low protein diets on mineral and skeletal metabolism in healthy adults. These data describe a hitherto underappreciated perturbation in calcium homeostasis induced by an acute modest reduction in dietary protein intake.

In 1997 we reported the short-term effect of three levels of dietary protein [low (0.7 g/kg), medium (1.0 g/kg) and high (2.1 g/kg)] on calcium metabolism in 16 healthy women (age 26.7 ± 1.3 y) (22 ). The study consisted of three interventions, each of which included 2 wk of a well-balanced adjustment diet (moderate calcium, sodium and protein) followed by an experimental period of 4 d (or 14 d in 7 subjects). During the experimental period, all diets contained 40 mmol calcium and 100 mEq sodium. Alcohol was not permitted and caffeinated beverages were limited to one a day. All foods on the experimental diet were weighed to within 0.1 g in the General Clinical Research Center kitchen and subjects consumed all of the experimental diet. All diets were consumed in random order by all subjects, thus permitting the use of a repeated-measures ANOVA for the statistical analyses.

As expected, the rise in urinary calcium excretion mirrored the rise in dietary protein intake at 4 d. Mean 24-h urinary calcium excretion during the three diets was 2.7 ± 0.3 (low protein), 3.2 ± 0.3 (medium protein) and 4.9 ± 0.5 (high protein) mmol/d. The most surprising finding in the first study was that by d 4 of the low protein diet, striking elevations in serum parathyroid hormone (PTH) and circulating concentrations of 1,25(OH)2vitamin D (calcitriol) developed in all subjects (Fig. 2 ). In fact, concentrations of these calcitropic hormones, in most cases, exceeded the upper limits of normal. Serum PTH was increased 1.5- to 2.4-fold by d 4 and 1.6- to 2.7-fold by d 14 over values seen in subjects consuming a moderate (1.0 g/kg) protein intake. The rise in PTH was accompanied by significant increases in both serum calcitriol and nephrogenous cyclic AMP excretion (NcAMP, a sensitive and specific indicator of PTH bioactivity). Thus, healthy young women abruptly developed secondary hyperparathyroidism within 4 d of a moderately low protein diet, which was otherwise balanced and sufficient in all other nutrients. The secondary hyperparathyroidism persisted after 2 wk of a low protein diet and, in preliminary studies, after 4 wk of the same diet (J. Kerstetter, unpublished observation). We found that a low protein diet induced secondary hyperparathyroidism in men and postmenopausal women as well (62 ). Secondary hyperparathyroidism is defined as the appropriate rise in circulating concentrations of PTH in response to a hypocalcemic challenge.



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  		FIGURE 2 Mean ± SEM of calcitropic hormones in young women (n = 16) who consumed low (triangles down), medium (open circles) or high (triangles up) protein diets. The upper limits of normal are designated by the dashed lines. Significantly different from the medium protein diet on the same day, *P < 0.05, **P < 0.005, ***P < 0.0001. [Reprinted with permission by the American Journal of Clinical Nutrition © Am J Clin Nutr. American Society for Clinical Nutrition (22 ).]

 
The finding that low protein diets induce secondary hyperparathyroidism was unanticipated. However, subsequently Giannini et al. (63 ) reported observations similar to our own. He studied 18 patients (10 men and 8 women aged 45.6 ± 12.3 y) with idiopathic hypercalciuria and renal calculi as they consumed a diet containing 0.8 g protein/kg and 24 mmol calcium. Urinary calcium excretion fell and serum PTH rose within 15 d of restricting protein intake (63 ).

What induces the elevation in serum PTH when protein intake is limited? Because dietary calcium was kept constant and moderate (20–24 mmol) in both our study (22 ) and that of Giannini et al. (63 ), dietary calcium insufficiency is not the explanation. This leaves open the possibilities that intestinal and/or skeletal handling of calcium are altered by a low protein diet.

Most calcium balance studies in humans (7 –12 ,15 ,18 ,60 ) could find no effect of dietary protein on intestinal calcium absorption, although there were three reports to the contrary (6 ,16 ,61 ). Calcium balance studies may not be sufficiently sensitive to detect an effect. Further, given the earliest research of Sherman and McCance (64 ,65 ), in which dietary protein impacted calcium absorption, we decided to revisit the question and employ dual stable calcium isotopes to directly measure intestinal calcium absorption at different levels of dietary protein.

The second study utilized the same experimental protocol described in our first study except that we measured intestinal calcium absorption at d 4 using dual stable calcium isotopes. Seven women completed the study while consuming high (2.1 g protein/kg) and low protein (0.7 g protein/kg) diets and the results were published (25 ). Since then, using precisely the same protocol, we have studied 13 additional healthy women (10 young and 3 postmenopausal). The results of the combined studies of the 20 women are summarized in Figure 3 .



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  		FIGURE 3 Individual changes in 24-h urine calcium and intestinal calcium absorption in response to 4 d of a low (0.7 g protein/kg) and high (2.1 g protein/kg) protein diet in 20 healthy women. Means are shown by horizontal short black lines. Gray circles represent the 3 postmenopausal women, and the open circles represent the 17 young women. [Adapted with permission by the American Journal of Clinical Nutrition © Am J Clin Nutr. American Society for Clinical Nutrition (25 ).]

 
The data are noteworthy for two reasons. First, despite a homogeneous population and well-controlled dietary conditions, the interindividual variability in both urinary calcium and intestinal calcium absorption is large. The variability confirms earlier work by Heaney et al. (66 –68 ). To control for the large interindividual variability, we used a paired study design in which each subject serves as her own control. Every subject ingested both the low and high protein diets in random order and changes within a single subject were measured. Calcium absorption during the low protein diet averaged 18 ± 1%, significantly lower than during the high protein diet 26 ± 2%, (P = 0.00003, paired t test). These data provide direct evidence that impaired intestinal calcium absorption explains in part the secondary hyperparathyroidism and hypocalciuria observed when dietary protein is restricted (25 ). In fact, the change in intestinal calcium absorption from low to high protein (~8%) explains ~80% of the change in urinary calcium excretion between the low and high protein diets (3.4 ± 0.3 to 5.4 ± 0.4 mmol/d, P = 0.000001). Dietary calcium was constant at 20 mmol.

Two recent isotopic studies were published that concluded that dietary protein did not affect intestinal calcium absorption (69 ,70 ). The reason for the discrepant results probably lies in the study design. In the Heaney and Dawson-Hughes report (69 ,70 ), calcium absorption was measured while subjects consumed their usual diets, and despite respectable sample sizes, there was no association between calcium absorption and protein intake. The large and natural interindividual variability in calcium absorption (evident from Fig. 3 where subject’s diets were tightly controlled) in combination with other uncontrolled dietary factors likely precluded finding an association between protein and calcium absorption.

In our first study, a protein intake of 0.7 g/kg led to impaired intestinal calcium absorption and secondary hyperparathyroidism, whereas subjects consuming 1.0 g/kg demonstrated little change in calcium homeostasis. Because the range of dietary protein between 0.7 and 1.0 g/kg encompasses the current RDA for this nutrient (0.8 g/kg) (4 ), we next undertook a dose-response study to examine the effect of graded levels of dietary protein (0.7, 0.8, 0.9 and 1.0 g protein/kg) on calcium homeostasis (27 ). Following our standard 4-d experimental model, all four diets were administered randomly to eight healthy young women and the principal findings are summarized in Figure 4 .



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  		FIGURE 4 Individual responses in calcitropic hormones in eight healthy women as they consumed four levels of dietary protein for 4 d. [Reprinted with permission by the American Journal of Clinical Nutrition © Am J Clin Nutr. American Society for Clinical Nutrition (22 ).]

 
Baseline urinary calcium and calcitropic hormones were within normal limits and similar before all interventions (not shown). Serum PTH rose by d 4 in all subjects consuming the 0.7 and 0.8 g protein/kg diets, whereas during the 0.9 and 1.0 g protein/kg diets, concentrations of calcitropic hormones remained normal. A parallel response was seen in calcitriol and NcAMP. Given that impaired intestinal calcium absorption was observed at the 0.7 g/kg level of protein intake (25 ), it is likely that calcium absorption was also reduced on the 0.8 g/kg diet, although absorption was not directly measured.

These dose-dependent data are important for two reasons (27 ). First, they demonstrate that the response to a progressive reduction in dietary protein intake is not a graded phenomenon, but rather a threshold effect, with the abrupt appearance of disordered mineral homeostasis observed at levels of protein intake below 0.9 g/kg. Second, they suggest that in healthy young women consuming a well-balanced, calcium-sufficient diet (20 mmol), the current RDA for protein (0.8 g/kg) results, in at least the short-term, in altered calcium homeostasis.

It is important to recall that the current dietary reference intake (DRI) for calcium for adult women is 25 mmol (71 ), a level higher than the 20 mmol used in our experiments. However, the average calcium intake for U.S. adult women is in the 15–18 mmol range (3 ), slightly less than the 20 mmol used in the experiments. It would be important to know whether the current higher DRI for calcium would ameliorate the secondary hyperparathyroidism induced by the low protein diet. Likewise, we do not know whether the secondary hyperparathyroidism is exacerbated when calcium intake is lower than 20 mmol, which would be the case for almost 80% of adult women in the United States (3 ).


   The chronic impact of low protein diets
TOP
 ABSTRACT
 Dietary protein and calcium...
 The traditional view
 The acute impact of...
 The chronic impact of...
Summary and conclusions
 LITERATURE CITED
 
Do the acute changes in calcium metabolism induced by a low protein diet have a long-term impact on bone health? The answer, at present, is not known. There are no well-controlled published intervention studies conducted over a sufficient length of time. To begin to address the question, we have begun studying calcium homeostasis in women as they consume low protein diets for extended periods, up to 7 wk. In an interim analysis we found that the reduction in urine calcium and the secondary hyperparathyroidism observed at 2 wk (Fig. 2) is still seen at 4 wk (J. Kerstetter, unpublished observation). Beyond the 4th wk, there is a partial resolution of the secondary hyperparathyroidism, despite persistent hypocalciuria. This likely represents a new steady state of calcium homeostasis. In the new steady state, subtle elevations in serum PTH and calcitriol persist, although absolute values remain within normal limits. The adjustments that underlie this new steady state are currently being investigated, but could include increased bone resorption, increased calcium absorption or both. Such subtle changes in calcium metabolism are difficult to detect without rigorously controlled experimental conditions. Although difficult to undertake, it is important that long-term, carefully controlled intervention studies be designed to test the hypothesis that low protein diets have an impact on bone health.

Epidemiological studies, taken as a whole, do not satisfactorily answer the question of how chronically low protein diets impact the skeleton. When BMD is the primary outcome, most (39 –48 ), but not all (49 –53 ), epidemiological studies show a positive relationship between protein intake and BMD. Stated another way, most of the epidemiological evidence shows that when other known dietary factors are controlled, those individuals who consume low protein diets have lower BMD. Using the National Health and Nutrition Examination Survey (NHANES) III database, we found that in 1882 non-Hispanic white women 50 y old and older, after adjusting for age and body weight, a low protein intake was associated with a significantly lower hip bone mineral density (Fig. 5 ) (47 ). Consistent with these data, Hannan and colleagues (46 ) studied 615 participants in the Framingham Osteoporosis Study over a 4-y period and found that lower levels of protein intake were associated with significantly higher rates of bone loss at the hip and spine. These findings confirm the earlier work of Freudenheim et al. (39 ), who reported that a low protein intake was associated with greater loss in bone density from the wrist in 35- to 65-y-old women. Most recently, Promislow et al. (48 ) found a positive association between total dietary protein intake and BMD in elderly men and women participating in the Rancho Bernardino study. Therefore, there is substantial agreement in those studies in which BMD is the primary outcome. Munger et al. (59 ), reporting data from the Iowa Women’s Health Study, found an increased risk of hip fracture in 55- to 69-y-old women consuming the lowest amounts of protein. Our observation that low protein intakes reduce intestinal calcium absorption provides a potential pathophysiologic explanation for these epidemiological findings.



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  		FIGURE 5 Relationship between dietary protein intake and total femur bone mineral density (BMD) (means ± SEM in g/cm2) in non-Hispanic white women > 50 y old from NHANES III. Number of individuals for each of the levels of protein intake are 0–43 g, n = 480; 44–58 g, n = 471; 59–75 g, n = 446; > 75 g, n = 425. [Reprinted with permission by Calcium Tissue International (47 ).]

 
Paradoxically [with the exception of the Munger et al. study (59 )], when fracture is the principal outcome, low protein intakes are associated with lower rates of fracture in most epidemiological studies (55 –58 ,72 ). The explanation for this apparent paradox between the epidemiological studies where fracture or BMD is the primary outcome, is at present, not known.

Adequate dietary protein may also help in fracture healing and in preventing bone loss after fracture. Bonjour and colleagues (73 ) studied the effects of 6 mo of protein supplementation, after osteoporotic hip fracture, in a group of elderly subjects. These patients had self-selected protein intakes that were very low (~40 g). The administration of additional protein (+20 g) was associated with significant attenuation of proximal femur bone loss in the fractured hip such that, at 1 y, bone loss rates were 50% lower in the protein-supplemented individuals. The correction of poor protein nutrition also improved serum prealbumin and insulin-like growth factor 1 (IGF-1) concentrations and decreased the length of rehabilitation (73 ).


   Summary and conclusions
TOP
 ABSTRACT
 Dietary protein and calcium...
 The traditional view
 The acute impact of...
 The chronic impact of...
 Summary and conclusions
LITERATURE CITED
 
There is agreement that diets moderate in protein (in the approximate range of 1.0 to 1.5 g protein/kg) are associated with normal calcium metabolism and presumably do not alter skeletal homeostasis. Approximately 30–50% of adults in the United States consume dietary protein that could be considered moderate. At low protein intakes, intestinal calcium absorption is reduced, resulting in increases in serum PTH and calcitriol that persist for at least 2–4 wk. The long-term implications of these findings are unknown; however, recent epidemiological data suggest increased rates of bone loss in individuals consuming such diets. Individuals consuming high protein intakes, particularly from omnivorous sources, develop hypercalciuria that is attributable for the most part to an increase in intestinal calcium absorption. Whether high protein diets result in an increase in bone resorption and higher fracture rates remains uncertain.

Bone is complex tissue that changes slowly. As such, it is difficult to design and conduct well-controlled nutrition studies in humans to quantify the effect of one nutrient on bone. However, given the increasing prevalence of osteoporosis and the clear impact of dietary protein on calcium metabolism, it is imperative that we gain a better understanding of the complex interplay between dietary protein and skeletal health. Toward that end, longer-term physiologic studies and, eventually, dietary intervention studies will be required to provide better-informed dietary protein guidelines for optimal skeletal health.


   FOOTNOTES
 
1 Presented as part of a working group program "New Perspectives on Dietary Protein and Bone Health" given at the 24th Annual Meeting of the American Society for Bone and Mineral Research, San Antonio, TX, September 20, 2002. This program was sponsored by the American Society for Bone and Mineral Research and was supported by a grant from the National Dairy Council®. Guest editors for this program were Lisa A. Spence, National Dairy Council, Rosemont, IL and Connie M. Weaver, Purdue University, West Lafayette, IN. Back

2 This work was supported by grants from the U.S. Department of Agriculture (00-35200-9579, 97-35200-4420, 94-37200-0668), the National Institutes of Health (DK52128-03, NIH MO1-RR00125, NIH 5P30AR46032-04), the Catherine Weldon Donaghue Women’s Health Investigator Program at Yale University and the University of Connecticut. Back


   LITERATURE CITED
TOP
 ABSTRACT
 Dietary protein and calcium...
 The traditional view
 The acute impact of...
 The chronic impact of...
 Summary and conclusions
 LITERATURE CITED
 

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