REVIEW URRENT C OPINION

Sodium homeostasis and bone Mark J. Hannon and Joseph G. Verbalis

Purpose of review Sodium balance is primarily regulated through the renin–angiotensin–aldosterone system. Extracellular fluid (ECF) sodium concentrations ([Naþ]) reflect the overall body sodium content, but are also influenced by the osmoregulatory system, which is regulated by the posterior pituitary hormone arginine vasopressin (AVP). Consequently, changes in total body sodium content are not always accurately reflected by the ECF [Naþ]. This review summarizes the growing evidence base suggesting that skeletal bone, which is rich in sodium, may play a key role in overall body sodium homeostasis. Recent findings Hyponatremia, even when relatively mild, leads to increased morbidity and mortality in diverse clinical scenarios. In particular, hyponatremia has been shown to increase gait instability, falls, and fracture risk. It now appears likely that at least part of the fracture risk is because of the adverse effects of hyponatremia on bone density and quality. The mechanisms through which this occurs are not yet completely understood, but prominently involve increased bone osteoclast formation and activity. An additional direct effect of AVP on bone remodeling has also been recently suggested. Summary Recent evidence expands upon the previously accepted concepts of body sodium homeostasis and suggests that sodium balance can be augmented by inputs from skeletal bone, which acts as a sodium-rich reservoir that can be deployed during times of sodium deficiency. However, this evolutionarily adaptive mechanism to maintain sodium homeostasis during times of environmental sodium deprivation also has adverse consequences by negatively impacting bone quality and increasing fracture risk. Keywords bone, falls, fracture risk, osteoporosis, sodium balance, vasopressin

INTRODUCTION Sodium is the major extracellular cation and, therefore, is the most important contributor to plasma osmolality, which in healthy humans is tightly regulated and varies by only 1–2% during physiological conditions in which there is free access to water. This precise regulation of plasma osmolality is maintained by the homeostatic process of osmoregulation [1]; increases in plasma osmolality are detected by specialized osmoreceptor cells in the anterior hypothalamus, causing increased synthesis and secretion of the pituitary hormone arginine vasopressin (AVP), which leads to renal water reabsorption. There is a linear relationship between plasma osmolality and plasma AVP concentrations throughout the physiological range of plasma tonicity [2], and this homeostatic process occurs continuously to maintain plasma osmolality within a relatively narrow reference range. The classic sodium balance studies of Harrison, Kaltreider, Forbes, and others showed that losses of total body sodium demonstrated by external www.co-nephrolhypertens.com

balance studies are not always reflected by changes in the sodium concentration ([Naþ]) of serum or the extracellular fluid (ECF) [3–6]. It has also been known for many years that bone mineral is extremely rich in sodium [3,7], up to 40% of which is exchangeable with circulating sodium within a relatively short time period [4,8]. Bone mineral undergoes constant turnover throughout life [9] and is the only tissue in which the sodium concentration is actually higher than in the ECF [3]. This leads to the possibility of bone acting as an internal sodium ‘reservoir’. The sodium content of bone increases with age, whereas the proportion available Division of Endocrinology and Metabolism, Georgetown University Medical Center, Washington, District of Columbia, USA Correspondence to Mark J. Hannon, MD, Georgetown University Medical Center, 233 Building D, 4000 Reservoir Road NW, Washington, DC 20007, USA. Tel: +1 202 687 4923; e-mail: [email protected] co.uk Curr Opin Nephrol Hypertens 2014, 23:370–376 DOI:10.1097/01.mnh.0000447022.51722.f4 Volume 23  Number 4  July 2014

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Sodium homeostasis and bone Hannon and Verbalis

KEY POINTS  Hyponatremia is the most common electrolyte disorder encountered in clinical practice, and even mild hyponatremia is associated with cognitive deficits, increased mortality, and increased risk of falls and fractures.  Bone mineral is rich in sodium content, which may act as an internal sodium ‘reservoir’ that can be mobilized during states of sodium deficiency.  What is an evolutionarily protective mechanism to maintain sodium homeostasis during sodium deficiency becomes maladaptive during dilutional hyponatremias such as SIADH, because the sodium released from bone is excreted by the kidneys in the absence of aldosterone-mediated renal sodium conservation in this condition.  This theory is supported by recent basic and clinical evidence showing a clear association between hyponatremia and increased bone resorption, leading to osteoporosis and increased fracture risk.  The mechanism through which hyponatremia increases bone resorption is not fully understood but appears to be primarily related to osteoclast sensing of serum and ECF [Naþ] rather than plasma AVP levels, with subsequent stimulation of osteoclast proliferation and resorptive activity.

for rapid mobilization declines. Subsequent radioisotope studies of acute acidosis and sodium depletion in rats showed that bone sodium content was acutely depleted by these procedures [10,11], supporting the theory that bone acts as a sodium storage reservoir that could be mobilized to maintain the sodium content of the ECF at levels adequate to maintain blood volume, blood pressure, and tissue perfusion during times of sodium deficiency, similar to the release of bone calcium to maintain calcium homeostasis during calcium deprivation. However, little work was done in subsequent years to further evaluate this possibility. This changed over the last decade, as more advanced data from both rat studies and large population databases have re-advanced the concept of bone as a storage reservoir for sodium, with chronic alterations in serum sodium balance conversely having adverse effects on bone quality and fracture risk. This review will summarize the classic 20th century studies which first demonstrated the high sodium content of bone, and then will describe the more recent human and experimental data that has revealed strong associations between hyponatremia, bone density and quality, and fracture risk.

HYPONATREMIA AND FRACTURE RISK Hyponatremia is the most common electrolyte imbalance encountered in clinical practice [12] and is especially common in the elderly [13]. Hyponatremia may progress to a chronic disorder, which is found in up to 11% of ambulatory outpatients [14]. Hyponatremia from multiple causes and in heterogeneous clinical settings is associated with increased morbidity and mortality [15,16,17 ,18, 19,20 ]. Although some of the adverse outcomes associated with hyponatremia can be accounted for by the serious medical illness causing the hyponatremia [19], data show that hyponatremia itself is associated with adverse outcomes independently of the underlying condition [21]. It is also becoming increasingly apparent that patients with even mild hyponatremia, which was historically thought to be relatively asymptomatic, also have excess mortality compared with patients with normal plasma [Naþ] [15,16,22,23]. Furthermore, even mild hyponatremia has been linked to a significantly increased risk of gait instability, falls, and fractures in the elderly [24–29]. The adaptive process of the brain to chronic hyponatremia initially involves cellular loss of electrolytes (potassium, sodium, and chloride) to the ECF, followed by subsequent loss of organic osmolytes, largely amino acids [30], including glutamate which is the most prevalent excitatory neurotransmitter in the brain. Loss of intracellular glutamate could contribute to some of the gait instability and falls found in patients with chronic hyponatremia [31], by virtue of delaying the synaptic neurotransmission of action potentials in motor neurons important for the maintenance of postural muscle tone. Furthermore, a rat model of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in aged rats showed that chronic hyponatremia exacerbated multiple manifestations of senescence including hypogonadism, decreased body fat, skeletal muscle sarcopenia, and cardiomyopathy [32 ]. Although falls alone are an obvious risk factor for fractures in the elderly, the earlier data already outlined relating to the importance of sodium in the crystalline structure of bone for sodium homeostasis suggested that hyponatremia might also contribute to bone loss, thereby further increasing the fracture risk. &

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HYPONATREMIA-INDUCED OSTEOPOROSIS Increasing interest in hyponatremia as a potential new independent risk factor for fractures led to the publication of a study in 2010 that examined the effects of chronic hyponatremia on bone density in

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Mineral metabolism

both an animal model and a large human population database [33]. The investigators utilized an established rat model of SIADH to produce chronic severe hyponatremia with a mean serum [Naþ] of 110 mmol/l, which was maintained for 3 months. Analysis of excised rat femora using dual-energy X-ray absorptiometry (DXA) revealed a 30% reduction in bone mineral density (BMD) in the hyponatremic rats. Subsequent analysis using microcomputed tomography measurements showed marked reductions in both trabecular and cortical bone. The second part of this study examined the effect of chronic hyponatremia on humans using the National Health and Nutrition Examination Survey (NHANES) III database, which includes serum [Naþ] and hip BMD data from an ethnically diverse ambulatory U.S. population. NHANES individuals who were hyponatremic had an increased risk of osteoporosis of the total hip (odds ratio 2.85) and the femoral neck (2.87), after adjustment for multiple known osteoporosis risk factors, despite the fact that the overall level of hyponatremia was quite mild (mean ¼ 133.0  0.2 mmol/l). A subsequent study examining the effects of sustained hyponatremia over 18 weeks on aged rats found a progressive reduction of BMD and sodium content of the tibia and lumbar vertebrae [32 ]. Although the above clinical and biochemical findings make teleological sense given the high concentration of sodium known to be stored in skeletal bone, the above data are mostly associative in nature, with limited insight into the precise mechanism of sodium mobilization from bone. Nor are the data consistent, as Hoorn et al. [29] found that mild hyponatremia in the elderly was associated with an increased risk of vertebral and nonvertebral fractures but not with BMD reductions. However, the increased fracture risk was also independent of the number of recent falls, suggesting that although BMD was unchanged, there may have been a subtle reduction in bone quality as a result of chronic hyponatremia [29]. Recent research has focused on this issue by exploring potential causative links between chronic hyponatremia and low BMD because of reabsorption of stored bone sodium. &

POTENTIAL MECHANISMS OF HYPONATREMIA-INDUCED OSTEOPOROSIS More recent studies have examined the potential mechanisms through which hyponatremia could affect BMD and bone quality. In the study of Verbalis et al. [33], bone histomorphology was highly abnormal, with a reduction in both 372

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trabecular and cortical bone contents and an increase in the number of osteoclasts per bone area. In contrast, mineralizing surface per bone surface, as analyzed by dynamic histomorphometry, and osteoblast surface per bone surface, as analyzed by static histomorphometry, were not significantly different between the control and hyponatremic groups. Similarly, analyses of serum and urinary markers of renal and liver function did not reveal any significant differences. Although hyponatremic animals had a more pronounced reduction in 1,25(OH)2D3 concentrations, there was no significant increase in parathyroid hormone levels, nor did the bone histomorphometry suggest causative vitamin D deficiency. Furthermore, treatment with vitamin D only slightly reduced the degree of bone loss in hyponatremic rats, although it did decrease further bone loss in a subsequent study of aged hyponatremic rats [32 ]. Male hyponatremic animals also had a mild degree of primary hypogonadism. Bone formation markers were also reduced, even after vitamin D treatment, suggesting an uncoupling of formation from resorption in hyponatremic animals. These data, in aggregate, strongly support osteoclastmediated bone resorption as the primary causal factor involved in hyponatremia-induced bone loss. More detailed in-vitro studies of osteoclast number and function in the presence of low extracellular [Naþ] showed that hyponatremia increased both number and resorptive activity of murine RAW 264.7 preosteoclastic cells cultured in vitro, and primary rat bone marrow monocyte (BMM) cultures taken from rats maintained hyponatremic using a well described in-vivo model [34]. Importantly, the effect of hyponatremia was specific to sodium rather than related to overall osmolality, as normalization of the osmolality of the low sodium culture media using mannitol did not prevent the increased proliferation and resorptive activity of the osteoclasts in cell culture [34] (Fig. 1). This is in contrast to the activity of brain osmoreceptors, which clearly react to the changes in extracellular osmolality rather than individual solute concentrations [35]. Gradual chronic reduction in [Naþ] in the cell culture medium led to an increase in oxidative stress and free radical accumulation, dose-dependent decreases in intracellular calcium, and decreases in cellular uptake of ascorbic acid. Similarly, a reduction in ascorbic acid in the culture medium led to increased osteoclast activity. Ascorbic acid exerts its effects on the osteoclast through increased intracellular free oxygen radical accumulation, and proportional changes in protein expression and phosphorylation. This suggested that ascorbic acid may play a role in the sodium signaling &

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Sodium homeostasis and bone Hannon and Verbalis

6000

**

TRAP+ MNC/mm2

5000 4000

**

3000 2000 1000 0 [Na+]=136

[Na+]=112

[Na+]=112 Osm corrected

FIGURE 1. RAW 264.7 cells were grown in medium with normal [Naþ] (136 mmol/l), in medium with both low [Naþ] (112 mmol/l) and uncorrected low osmolality (237 mOsm/kg), and in medium with low [Naþ] (112 mmol/l) and corrected osmolality (290 mOsm/kg). The number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (i.e., the number of mature osteoclasts) was significantly higher in both hyponatremic groups, regardless of the medium osmolality (P < 0.001 when compared with cells cultured in eunatremic media). MNC, multinucleated cells. Reproduced with permission [34].

RELATION OF HYPONATREMIA-INDUCED OSTEOPOROSIS TO ARGININE VASOPRESSIN LEVELS The majority of cases of chronic hyponatremia in humans are due to SIADH [14], and most patients with chronic hyponatremia have osmotically inappropriately elevated AVP levels, even if the cause of the hyponatremia is not SIADH. For example, patients with diuretic-induced hypovolemic hyponatremia [41], congestive cardiac failure [42], and cirrhosis [43] all have nonsuppressed AVP levels. This has led some to hypothesize that the relative excess of AVP, rather than the hyponatremia itself, may be the cause of reduced BMD and bone quality in hyponatremic patients [44 ]. Previous studies have identified receptors on skeletal bone for other pituitary hormones, such as thyroid stimulating hormone (TSH) [45], follicle stimulating hormone [46], adrenocorticotrophic hormone [47], and oxytocin [48]. Deletion of the oxytocin receptor Oxtr causes severe osteoporosis in mice, primarily because of reduced osteoblast function [48]. Reduced TSH receptor signaling, as seen in primary hyperthyroidism, may contribute to the bone loss seen in this condition. Both AVP receptors, AVPR1a and AVPR2, can be found on osteoclasts and osteoblasts, and exert their effects through activation of the intracellular Erk signaling cascade [44 ]. Analysis of AVP receptor function by Tamma et al. [44 ] using both wildtype and AVPR1a-/- mice and an AVPR1a inhibitor revealed increased osteoblast number and function, and reduced osteoclast function and bone resorption in mice with knocked-out or pharmacologically blocked AVPR1a. Specifically, there was a significant increase in bone volume, trabecular thickness, and number, and a decrease in trabecular spacing following knockout or inhibition of AVPR1a. Inhibition of AVPR2 in AVPR1a-/- knockout mice led to similar increases in osteoblastogenesis. Conversely, injection of AVP into wildtype mice led to significant upregulation of osteoclast differentiation genes, including Cfms, Rank, and Trap. However, the data from this study were not entirely consistent. The expression of Runx2, which indicates increased osteoblast differentiation, has been shown to be increased in both AVPR1a-/- mice [44 ] and Oxtr-/- mice [48], even though AVP receptor knockout leads to increased bone formation and oxytocin receptor knockout leads to profound osteoporosis. Also, hyponatremic patients may not have an absolute AVP elevation above that of eunatremic patients; rather, the problem is that the AVP is inappropriately elevated for the patient’s osmolality and sodium level [49,50,51 ]. Furthermore, a significant relation has been shown between patients’ serum [Naþ] and BMD at the femoral neck &

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mechanism within osteoclasts, leading to increased osteoclast activity in the presence of hyponatremia.

POTENTIAL MEDIATORS OF OSTEOCLAST SODIUM SENSING Studies to date do not fully explain the actual mechanism by which osteoclasts first sense and then respond to ECF hyponatremia. A sodium-activated sodium channel, which acts as a sensor of ECF sodium, has recently been described on the thick ascending limb of the loop of Henle in rats [36]. This sensor was previously identified in specialized central nervous system neurons, sensory neurons in the peripheral nervous system, specialized ependymal and glial cells in the central nervous system, nonmyelinating Schwann cells, and epithelial cells, including the alveolar type II cells in the lung [37]. Alternatively, a recent study identified a previously unknown mechanism controlling vertebrate regeneration by modulating in-vivo sodium transport, endogenously mediated by the voltage-gated sodium channel, NaV1.2. Direct inhibition of this channel using tricaine, a well described voltage-gated channel blocker [38,39], reduced vertebrate regeneration, suggesting that reduced ECF [Naþ] might lead to reduced sodium influx, impaired bone healing, and eventual reduction in bone density and quality [40].

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Mineral metabolism

SOLID + DDAVP

0.24

LIQUID + DDAVP 0.22

BMD g/cm2

0.20

LIQUID + DDAVP

0.24 0.22

*

0.20 0.18 0.16

*

0.14 0.12 0.10

FIGURE 3. The number of osteoclasts per bone area, defined as the number of TRAP-positive multinucleated cells, was five times higher (P < 0.001) in hyponatremic rats (mean serum [Naþ] ¼ 110  2 mmol/l) receiving a liquid diet and DDAVP, when compared with eunatremic rats (mean serum [Naþ] ¼ 141  1 mmol/l) receiving a solid diet and DDAVP, despite the presence of equivalently excess AVP in both groups. AVP, arginine vasopressin; DDAVP, 1desamino-8-D-arginine; MNC, multinucleated cells; TRAP, tartrate-resistant acid phosphatase. Reproduced with permission [33].

medium was formulated identically between the groups of cultured cells except for the sodium concentration, so all cells experienced the same extracellular AVP levels [34]. Consequently, although elevated AVP levels may contribute yet another component to bone loss in some patients with SIADH, they are clearly not the primary cause of hyponatremia-induced bone loss and osteoporosis.

0.18 0.16

*

0.14 0.12 0.10

FIGURE 2. Bone mineral density was significantly reduced in hyponatremic rats (mean serum [Naþ] ¼ 110  2 mmol/l) receiving a liquid diet and DDAVP, when compared with eunatremic rats (mean serum [Naþ] ¼ 141  1 mmol/l) receiving a solid diet and DDAVP, despite the presence of equivalently excess AVP in both groups. AVP, arginine vasopressin; BMD, bone mineral density; DDAVP, 1desamino-8-D-arginine. Reproduced with permission [33]. 374

SOLID + DDAVP

TRAP+ MNC/mm2

[33], which has not been shown for AVP. In fact, AVP levels are highly variable in hyponatremia, and, as already mentioned, they often do not even exceed that of eunatremic patients. The methodological difficulties involved in measuring AVP in clinical practice means that it is difficult to relate plasma AVP concentrations to variables such as serum [Naþ] or BMD. Copeptin, which is the C-terminal glycoprotein of the AVP prohormone, has recently been established as an easy to measure and stable surrogate for endogenous AVP secretion [52–54], which may enable future studies to examine the relationship between AVP and BMD. It should also be noted that multiple previous results indicate that the phenomenon of hyponatremia-induced osteoporosis is independent of AVP levels both in vivo and in vitro. In the model of SIADH used by Verbalis and Drutarosky [55], chronic hyponatremia is induced by a combination of continuous infusion of the AVPR2 agonist desmopressin (DDAVP) in combination with a liquid diet to produce water loading and retention. One of the controls included in the study was a group of rats infused with the same dose of DDAVP but fed an isocaloric solid diet. In the absence of water loading, this group did not become hyponatremic, their BMD was not significantly reduced compared with the hyponatremic group (Fig. 2), and the number of osteoclasts present in excised bones was also not increased (Fig. 3) despite identical DDAVP infusions [33]. Furthermore, in the in-vitro studies, the culture

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RELATION OF SODIUM DEFICIENCY TO THE SYNDROME OF INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION AND HYPONATREMIA-INDUCED OSTEOPOROSIS The data accumulated to date support the hypothesis that osteoclast-mediated bone resorption during hyponatremic conditions occurs to preserve sodium homeostasis. Key to this hypothesis is that low body sodium content is sensed by osteoclasts via a low ECF [Naþ]. The sodium resorbed from bone is retained by the kidney because of activation of the renin–angiotensin–aldosterone system (RAAS) and the subsequent actions of aldosterone in the kidney. Thus, mobilization of internal sodium stores would help to stabilize ECF volume and blood pressure, Volume 23  Number 4  July 2014

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Sodium homeostasis and bone Hannon and Verbalis Table 1. Bone ash analyses in bones from aged rats L1–L2 vertebrae

Wet weight (g)

Tibia

Normo [Naþ]

Hypo [Naþ]

Normo [Naþ]

Hypo [Naþ]

1.998  0.161

1.664  0.051

1.173  0.027

1.168  0.037

Dry weight (g)

0.818  0.099

0.746  0.027

0.767  0.019

0.728  0.019

Ash weight (mg/bone)

307.8  27.8

270.0  16.2

401.1  10.9

375.4  9.0

Calcium mass (mg)

121.8  7.4

113.4  10.1

169.6  6.9

156.0  3.3

Sodium mass (mg)

22.2  0.6



19.1  1.5

19.1  0.5

15.5  0.2

Hypo [Naþ], hyponatremic aged rats; Normo [Naþ], normonatremic aged rats. Adapted with permission [32 ].  P < 0.05 compared to normonatremic group values.  P < 0.01 compared to normonatremic group values. &

and, in that sense, would be evolutionarily protective under conditions of environmental sodium deficiency. In contrast, SIADH is not a state of sodium deficiency, but rather one of dilutional hyponatremia due to water retention. Consequently, the low serum [Naþ] in SIADH is primarily because of excess water, not sodium deficiency. However, if serum [Naþ] is the signal by which osteoclasts sense ECF and total body sodium, then this would represent a pathological ‘misinterpretation’ of the low serum [Naþ] as signifying deficient total body sodium. Furthermore, any sodium resorbed from bone during SIADH is not retained, but is instead excreted by the kidneys as the RAAS is downregulated in SIADH. Consequently, there is no brake to the stimulated bone resorption, as the serum [Naþ] remains low no matter how much bone is resorbed. This would lead to continued osteoclast-mediated bone resorption as long as the hyponatremia persists. Direct evidence of this was demonstrated by measuring bone sodium content after 3 months of sustained hyponatremia in rats; bone sodium mass decreased by 14%, even greater than the 7% decrease in bone calcium mass [32 ] (Table 1). &

FUTURE DIRECTIONS It is increasingly clear that hyponatremia is an independent risk factor for falls and fractures. Given that bone is rich in sodium which is readily exchangeable with plasma, it makes sense that the risk of fractures associated with hyponatremia may not just be related to falls, but also to innate changes in bone density and quality. The molecular and cellular mechanisms by which this happens are currently unknown. Further research must identify the potential receptors and pathways through which hyponatremia leads to abnormal osteoclast function. Similarly, more robust studies of cellular AVP action are needed to verify whether AVP itself impacts on bone remodeling, independently of the serum [Naþ], and how these different pathological stimuli might interact to increase bone fragility.

CONCLUSION It has long been recognized that bone mineral content is rich in sodium, some of which is readily exchangeable with serum [Naþ]. However, it has only become clear relatively recently that hyponatremia is an independent predictive risk factor for falls and fractures. This is partly because of the fact that even mild hyponatremia negatively impacts on cognition and gait stability, and also because hyponatremia itself leads to reduced BMD. The mechanism(s) through which hyponatremia impacts on bone are as yet unknown, but clearly involve stimulation of osteoclast formation and activity. AVP itself may impact directly on bone to exacerbate the hyponatremia-induced bone loss. It therefore appears increasingly likely that sodium homeostasis is intrinsically related to bone physiology, but further research will be needed to more accurately delineate the complex interplay between these two systems. Acknowledgements The studies in this review were supported by the National Institutes of Health (grants R01-AG029477 and UL1TR000101 to J.G.V.) and an unrestricted educational grant from the Irish Endocrine Society (to M.J.H.). Conflicts of interest Disclosures: M.J.H.: nothing to declare; J.G.V. serves as a consultant to Cornerstone Pharmaceuticals, Ferring Pharmaceuticals and Otsuka Pharmaceuticals, and has received research grants from Otsuka Pharmaceuticals.

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Volume 23  Number 4  July 2014

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Sodium homeostasis and bone.

Sodium balance is primarily regulated through the renin-angiotensin-aldosterone system. Extracellular fluid (ECF) sodium concentrations ([Na]) reflect...
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