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Role of Dietary Sodium in Osteoporosis

Creighton University, Omaha, Nebraska

Address reprint requests to: Robert P. Heaney, M.D., John A. Creighton University Professor, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178. E-mail: rheaney{at}creighton.edu

	ABSTRACT

TOP ABSTRACT Background Sodium-Calcium Interactions Sodium and Bone Potassium and Anion Effects REFERENCES

 
Sodium, in the form of sodium chloride, elevates urinary calcium excretion and, at prevailing calcium intakes, evokes compensatory responses that may lead to increased bone remodeling and bone loss. The calciuria is partly due to salt-induced volume expansion, with an increase in GFR, and partly to competition between sodium and calcium ions in the renal tubule. Potassium intakes in the range of current recommendations actually reduce or prevent sodium chloride-induced calciuria.

At calcium intakes at or above currently recommended levels, there appear to be no deleterious effects of prevailing salt intakes on bone or the calcium economy, mainly because adaptive increases in calcium absorption offset the increased urinary loss. Such compensation is likely to be incomplete at low calcium intakes. Limited evidence suggests equivalent bone-sparing effects of either salt restriction or augmented calcium intakes. Given the relative difficulty of the former, and the ancillary benefits of the latter, it would seem that the optimal strategy to protect the skeleton is to ensure adequate calcium and potassium intakes.

Key words: sodium, salt, calcium, calciuria, osteoporosis, calcium requirement

	Background

TOP ABSTRACT Background Sodium-Calcium Interactions Sodium and Bone Potassium and Anion Effects REFERENCES

 
The adult human body contains from 90 to 130 g sodium [1]. Roughly half of that is in bone, and the bulk of the remainder is in extracellular fluid (ECF), where it plays a crucial role in determining the osmolality of the milieu interior. About half of bone sodium is exchangeable with ECF sodium; by contrast, less than 1% of bone calcium exchanges with ECF calcium ions. This large difference in exchangeability indicates that bone sodium is located quite superficially, i.e., on the surfaces of crystals that are themselves located on microanatomic bone surfaces. Bone sodium is not known to play a critical role in bone material properties or in calcium homeostasis. Its presence in bone is generally attributed to the fact that it is the principal cation of the ECF that bathes the bone-forming site during its mineralization. As such, some of the ECF sodium is simply trapped as ECF water is displaced by growing calcium phosphate crystals. Probably because of its superficial location, some bone sodium is mobilized in systemic acidosis, approximately in parallel with the mobilization of bone carbonate (which is also superficially located). While some investigators suggest that bone sodium plays a role in total body sodium homeostasis, the majority view is that bone is at most a passive participant in ECF sodium homeostasis. It is important to recall that "exchangeability" means a bi-directional movement of ions—one ion into bone for each one out. Thus "exchangeability" is not the same as, and does not connote, "availability".

The nutritional requirement for sodium has been set most recently at 1500 mg (65 mmol)/d [2]. This is almost certainly higher than actual need, as indigenous peoples of the Amazon basin, for example, ingest less than one-tenth that amount [3]. At the same time, the estimated requirement is substantially less than the quantities usually ingested in developed nations. The nations of Europe and North America have median sodium intakes that range from about 2300 mg (100 mmol)/d on the low side to about 4300 (187 mmol) on the higher end [3]. East and Southeast Asian societies have median sodium intakes as high as 5300–6000 mg (230–260 mmol)/d. Ingested sodium serves several functions in addition to its essential nutrient role (i.e., replacing excretory and cutaneous losses that would otherwise threaten intravascular volume). Sodium added to foods enhances desirable flavors, masks unpleasant flavors, improves texture, inhibits bacterial action, and controls yeast fermentation. Often high salt foods do not taste "salty", as the added salt is serving other functions. A good example is found in the dry cereal, Cheerios^TM, which does not taste salty, but contains more than twice as much salt per serving as do potato chips, which do have a distinctly salty taste.

	Sodium-Calcium Interactions

TOP ABSTRACT Background Sodium-Calcium Interactions Sodium and Bone Potassium and Anion Effects REFERENCES

 
While within the skeleton sodium and calcium interactions are probably of minor importance, a more significant, and certainly better studied interaction of sodium and calcium occurs at the level of diet, and in the subsequent processing of the absorbed dietary minerals. As long ago as 1937 Aub et al. observed that sodium chloride increased urine calcium [4], and in 1961 Walser showed that sodium and calcium competed for the same reabsorption mechanism in the proximal renal tubule [5]. This means that an increase in the filtered load of either sodium or calcium leads to increased excretion of both ions, thereby establishing the mechanistic basis by which a sodium load produces calciuria. However, McCarron et al. [5a] showed that high salt intakes resulted in volume expansion and an increase in filtered calcium load, and attributed the sodium-induced calciuria to that mechanism.

A possible role for sodium intake in the pathogenesis of osteoporosis was first emphasized by Goulding who, in a series of animal and human experiments, showed that sodium intake could affect bone mass in animals, and that the effect required a functioning parathyroid apparatus [6–10].

The effects of sodium on the calcium economy are nicely summarized in several review papers [11–13]. My purpose here is to bring these reviews up to date by focusing principally on more recent reports. Numerous studies have found statistically significant positive and quite consistent correlations between 24-h urine sodium excretion and 24-h urine calcium [4,7–9,14–23]. Taken together, the available studies indicate that urine calcium rises by from 0.5 to 1.5 mmol (20–60 mg) for every 100 mmol (2300 mg) sodium ingested. Most reviewers have used the mid point of that range (i.e., 1.0 mmol/100 mmol) to characterize the effect. In most studies the calciuric effect of increased sodium intake has been found in most or all subjects. However, Ginty et al. [23a] reported a substantial subset of their subjects who exhibited absolutely no calciuria in response to sodium loading. By contrast, Evans et al. [23b] reported a calciuric response in every one of their subjects. The reasons for these reported differences in individual response are unclear, but could possibly reflect differences in volume expansion in response to sodium loading [5a].

Given the fact that contemporary North American sodium intakes generally fall between 100 and 200 mmol/d (i.e., 2300–4600 mg/d), it follows that approximately 1.0 to 2.0 mmol (40–80 mg) of the 24-h total urine calcium excretion is being pulled out of the body by sodium. Ho et al. [22] concluded that sodium intake was the principal determinant of urine calcium in Hong Kong Chinese, and Matkovic et al. [23] came to a similar conclusion for pubertal girls in the U.S. Itoh and Suyama [14], in a study of nearly 900 Japanese adults in whom sodium intakes tend to be much higher than in Europe or North America, found a positive correlation between sodium intake and urine calcium in both sexes, and across all age groups, even after adjusting for weight and for dietary intakes of protein, phosphorus, and calcium.

Thus, on prevailing diets, sodium intake accounts for much of the obligatory urinary loss of calcium from the body, and it would be for this reason that sodium intake might play a role in the pathogenesis of osteoporosis. Clearly, if absorbed calcium is less than the amount needed to offset this loss (in addition to what is needed to cover bone building and cutaneous and digestive juice losses), then bone mass must suffer. Moreover, the remodeling activity needed to release calcium from bone would also be elevated. Both low mass and high remodeling are now recognized as risk factors for osteoporotic fractures [24].

It would be expected that increased urinary calcium loss following a sodium load would produce a fall in extracellular fluid calcium ion concentration. Such a fall would, in turn, produce a rise in parathyroid hormone secretion, with a consequent increase in synthesis of 1,25(OH)₂D₃, and ultimately in both calcium absorption efficiency and bone remodeling activity. The predicted changes have been found in some, but not all studies [17,25]. Breslau et al. demonstrated that a change in urine calcium evoked the predicted directional change in serum PTH in serum 1,25(OH)₂D₃ concentration, and in calcium absorption efficiency as well, at least in premenopausal women [17,19]. But they failed to observe changes in absorption in a small study involving postmenopausal women. These findings suggested, at least qualitatively, that premenopausal women could handle the challenge of contemporary sodium intakes with less skeletal impact than postmenopausal women and, by implication, that sodium intakes may be contributing to postmenopausal osteoporosis.

At least two groups of investigators have found that calcium absorption efficiency rises with induced calciuria, as from a sodium load [17,25], and falls with urine calcium, as from the calcium-sparing effect of thiazides [26]. These changes indicate that there is an at least directional adjustment for variations in excretory loss, i.e., intestinal absorption rises when urine loss increases, and falls when urinary loss is reduced. Breslau et al. [17] reported that the change in absorption, while occurring in normal subjects, did not occur in two patients with surgical hypoparathyroidism, consistent with Goulding’s findings in rats [6]. By contrast, Meyer et al. [25] did find an increase in calcium absorption efficiency in two patients with hypoparathyroidism following a sodium load, suggesting, at least in these individuals, that the response was mediated by some mechanism other than increased PTH secretion. While the discrepancy between these studies cannot be resolved with available data, it does appear reasonably certain that, other effects aside, a sodium load leads to increased PTH secretion with all of its usual consequences (increased 1,25(OH)₂D₃ synthesis, increased calcium absorption, increased bone resorption, and improved renal tubular reabsorption of calcium). But additional mechanisms may be operative as well.

What is critically important, but not precisely known, is whether the absorptive compensation is quantitatively adequate to offset the high obligatory loss. Ultimately this depends upon how high the dietary calcium intake may be. At typical calcium intakes (e.g., about 600 mg (15 mmol)/d), women at mid-life have a gross absorption efficiency of about 27% [27], and endogenous fecal calcium (EFC) loss of about 110 mg (2.75 mmol)/d. Computing actual mass transfers, one notes that 27% of 600 mg is a gross absorption of 162 mg (4 mmol). Against the offset of EFC loss, that gain translates to net absorption of 52 mg (for a net absorption efficiency of about 9%). A rise in sodium intake of 100 mmol/d will increase obligatory calcium loss by about 1 mmol (40 mg)/d. To extract that much additional calcium from the diet would require a gross absorption efficiency of 34%, or about a 25% increase in absorption fraction above the mean for that intake. That may just barely be possible at this calcium intake.

Closer to the extremes of calcium intake, the results are less ambiguous. At an intake of about 300 mg (7.5 mmol) Ca/d (about the 25^th percentile for mid-life women), absorption fraction averages about 37% [27], for a gross absorption of 111 mg (2.8 mmol). To offset an additional 40 mg (1 mmol) urinary loss would require an increase in absorption efficiency to about 50%—very likely beyond the capacity of most middle-aged women. By contrast, at an intake of 1200 mg/d (as currently recommended after age 50), absorption efficiency averages about 20%, for a gross absorption of 240 mg (6 mmol) and a net absorption of about 120 mg (3 mmol). To offset an additional 40 mg (1 mmol), urinary loss would require an increased absorption efficiency to only 23%—clearly feasible.

These quantitative considerations help to make sense of the several reports indicating that the effects of sodium on various bone status indicators are dependent upon calcium intake [28,29]. In brief, if calcium intake is in the range currently recommended, sodium intakes in the range prevailing in most of the developed nations has little or no net effect on calcium balance, since increased urinary calcium losses evoke adaptive responses that result in improved dietary calcium extraction. That protection fails when diet calcium is low.

	Sodium and Bone

TOP ABSTRACT Background Sodium-Calcium Interactions Sodium and Bone Potassium and Anion Effects REFERENCES

 
Several groups of investigators have shown that bone remodeling, as measured by various remodeling biomarkers, varies inversely with sodium intake [7,9,20,30–32] and that sodium restriction reduces excretion of resorption biomarkers. This finding is consistent with and follows upon the effect of sodium loads on increasing PTH secretion and is predictable inasmuch as the elevation in PTH evoked by excess calcium losses would inevitably increase bone remodeling. Evans et al. [31a], in a small study, found the increase in resorption following one week of high sodium intake to be confined to postmenopausal women, but the confidence limits for the rise in pre- and postmenopausal women overlapped, and it is not clear that the two groups differed significantly from one another. Nevertheless, the larger rises in calciuria in the postmenopausal women are consistent with other studies [e.g., 17,191 indicating more effective compensation pre-menopause. Often the observed increase in remodeling has been taken to indicate that sodium increases bone loss, although this does not necessarily follow, and there are few reports of a direct connection between sodium intake and subnormal bone status in humans at typical sodium intakes.

The very wide range in national salt intakes demonstrated in Intersalt [3], most of them in considerable excess of probable nutritional need, affords an opportunity to test salt’s role in the pathogenesis of osteoporosis. But little or no association emerges from such analyses. Finland and the United Kingdom, with relatively high rates of osteoporosis, have lower salt intakes than Hungary, Spain, or Malta, for example, with generally lower rates of osteoporosis. Japan, with one of the highest salt intakes of a developed nation, has substantially fewer hip fractures than European Caucasian populations. However, all such ecologic studies are fraught with difficulty. Good estimates of true osteoporosis prevalence are not available for many of the populations studied by Intersalt, and, more importantly, these populations differ widely in genetic susceptibility to osteoporosis, vitamin D status, and calcium intake, among other critical variables. Nevertheless, the data available from Intersalt certainly do not point to a strong pathogenetic role for salt.

However, there is at least one case report of probably salt-associated osteoporosis [33]. A 50-year-old postmenopausal woman with adequate hormone replacement therapy had high turnover osteoporosis with vertebral compression fractures and a urine calcium in excess of 7.5 mmol/d (300 mg). She was observed in the hospital to be using table salt from a paper bag, in quantities so large as to make the food on her plate white, and she reported having done so for the previous 20 years. Therapeutic reduction in salt intake reduced her urinary calcium loss to below 2.5 mmol (100 mg)/d. Presumably, if salt is a factor in the pathogenesis of osteoporosis, it is acting by its calciuric effect, at least in individuals at typical calcium intakes, where absorptive adaptation would be insufficient to compensate for excess losses of the magnitude observed in this patient.

Whether clinically significant bone loss actually occurs at more typical salt intakes has been the subject of very few studies. Greendale et al. found no association between sodium intake from diet records and bone status 15 years later [34]. Sodium intakes in their subjects averaged about 150 mmol (3450 mg)/d in men and 112 mmol (2576 mg)/d in women. However, estimates of sodium intake from diet records correlate poorly with actual sodium intake, and thus this negative finding cannot absolve sodium intake in this connection. Accurate estimates of sodium intake require measurement of 24-h urine sodium, preferably over a several day interval. This need probably explains the scarcity of epidemiological studies testing the association of sodium intake and bone mass.

Dawson-Hughes et al. [15], in a 4-year prospective study, found the expected correlation between sodium intake (as measured by urinary sodium) and urinary calcium excretion in healthy elderly men and women, but no correlation of sodium intake with bone mineral density at any site, in either sex. Sodium intakes in their study averaged 156 mmol (3600 mg)/d in men, and 118 mmol (2700 mg)/d in women, i.e., fairly typical for North America. In this study the authors reported that the correlation between urine sodium and urine calcium was strongest at high calcium intakes, while Nordin [11,12] reported the opposite. There is no evident explanation for this discordance. In any event, this failure by Dawson-Hughes, et al. to find skeletal differences is suggestive of compensation for the sodium-induced calciuria, as described above.

The principal human study linking high salt intake to bone loss was by Devine et al. [35], who showed that change in bone mineral density at the total hip and at an ultradistal ankle site over a two year period was inversely related to sodium intake estimated from urine sodium content. But they found no such effect at the spine, femoral neck, intertrochanteric region, or radius. From multiple regression models these investigators calculated that halving the sodium intake of their subjects (from –2000 to –1000 mg/d) would have been predicted to obliterate the hip bone loss. But in the same model, doubling of calcium intake (i.e., raising it into the currently recommended range) would have produced approximately the same beneficial effect, without requiring a reduction in salt intake.

	Potassium and Anion Effects

TOP ABSTRACT Background Sodium-Calcium Interactions Sodium and Bone Potassium and Anion Effects REFERENCES

 
For the most part, when the papers cited in this review speak of "sodium," what is meant is "sodium chloride," i.e. table salt, the form in which about 90% of contemporary sodium intakes are ingested. The accompanying anion is usually ignored. This is probably a mistake. Berkelhammer et al. [36] showed clearly, in patients receiving total parenteral nutrition (TPN), that substituting acetate for chloride in TPN solutions reduced urine calcium losses dramatically. In oral feeding studies, Lutz [37] showed that substituting sodium bicarbonate for sodium chloride promptly reduced urine calcium. Similarly, sodium bicarbonate loads do not induce an increase in urine calcium, unlike sodium chloride [37,38]. Fig. 1 illustrates, schematically, the differing effects on urine calcium of various sodium and potassium salts.

View larger version (15K): [in this window] [in a new window]   Fig. 1. Effects of various sodium and potassium salts on urine calcium. (Copyright Robert P. Heaney, 2003. Used with permission.)

View larger version (26K): [in this window] [in a new window]   Fig. 2. Effect of a high salt load, with and without supplemental potassium citrate, on 24-hr urine calcium excretion in postmenopausal women. The low salt regimen provided 87 mmol (5 g) salt/d and the high salt, 225 mmol (13.2 g)/d. The potassium supplement provided 90 mmol (29.2 g) potassium citrate/d. N = 26 for each of the treatment groups. The rise in urine calcium on the high salt regimen was highly statistically significant (P < 0.005). Plotted from the data of Sellmeyer et al. [39]. (Copyright Robert P. Heaney, 2003. Used with permission.)

	Discussion

 
Summarizing the data available up to the year 2000, much as has been done for more recent work in this brief review, Burger et al. [42] concluded that a sodium-osteoporosis link was still conjectural. Four years later, reviewing the additional evidence accumulated in the interval, Prentice [43] came to essentially the same conclusion, summarizing as follows: "Current healthy-eating advice to decrease sodium intake...is unlikely to be detrimental to bone health..." Hardly a ringing indictment of sodium as a cause of osteoporosis.

Based on the multiple regression model of Devine et al. [35], one might tentatively conclude that contemporary sodium intakes elevate the calcium requirement—at least for bone status. However, the two reclamatory strategies suggested by the Devine model are not equivalent. Higher calcium intakes (i.e., in the range of currently recommended values) confer numerous non-skeletal health benefits [44], while the advantages of low sodium intakes, although widely touted, are at best problematic [45]. Furthermore, from the standpoint of feasibility, higher calcium intakes are much easier to achieve and sustain than are reductions in sodium intake of the magnitude required to offset sodium’s effect on obligatory urinary calcium excretion [46].

Finally, one must note that, even if sodium’s effect on bone mass is normally compensated for by adaptive increases in calcium absorption (or by high calcium intakes), any accompanying increase in bone remodeling may constitute a risk factor for fracture [24]. The reduction in remodeling activity produced by high calcium intakes provides protection against that mechanism of fragility. In any event, choosing one or the other of the options offered by the Devine model would certainly seem to be more prudent than doing neither.

Received January 9, 2006.

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TOP ABSTRACT Background Sodium-Calcium Interactions Sodium and Bone Potassium and Anion Effects REFERENCES

 

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