REVIEW

CURRENT
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 balance studies are not always reflected by changes

Sodium is the major extracellular cation and, there-
fore, is the most important contributor to plasma
osmolality, which in healthy humans is tightly
regulated and varies by only 1–2% during physio-
logical conditions in which there is free access to
water. This precise regulation of plasma osmolality
is maintained by the homeostatic process of osmor-
egulation [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 re-
absorption. There is a linear relationship between
plasma osmolality and plasma AVP concentrations
throughout the physiological range of plasma ton-
icity [2], and this homeostatic process occurs con-
tinuously 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
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 concen-
tration 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: markjhannon2002@yahoo.
co.uk
Curr Opin Nephrol Hypertens 2014, 23:370–376
DOI:10.1097/01.mnh.0000447022.51722.f4

www.co-nephrolhypertens.com Volume 23
Number 4
July 2014

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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 radio-
isotope 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 main-
tain 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 alter-
ations 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.
1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Sodium homeostasis and bone Hannon and Verbalis
HYPONATREMIA AND FRACTURE RISK
Hyponatremia is the most common electrolyte
imbalance encountered in clinical practice [12]
and is especially common in the elderly [13]. Hypo-
natremia 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 hypo-
natremia [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 insta-
bility, falls, and fractures in the elderly [24–29]. The
adaptive process of the brain to chronic hyponatre-
mia initially involves cellular loss of electrolytes
(potassium, sodium, and chloride) to the ECF, fol-
lowed 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 con-
tribute to some of the gait instability and falls found
in patients with chronic hyponatremia [31], by vir-
tue of delaying the synaptic neurotransmission of
action potentials in motor neurons important for
the maintenance of postural muscle tone. Further-
more, 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 crystal-
line structure of bone for sodium homeostasis
suggested that hyponatremia might also contribute
to bone loss, thereby further increasing the fracture
risk.
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
www.co-nephrolhypertens.com 371
 Mineral metabolism
both an animal model and a large human popu-
lation 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 indi-
viduals 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 subse-
quent study examining the effects of sustained hypo-
natremia 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 explor-
ing potential causative links between chronic hypo-
natremia 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 www.co-nephrolhypertens.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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 signifi-
cant 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 osteoclast-
mediated bone resorption as the primary causal fac-
tor involved in hyponatremia-induced bone loss.
More detailed in-vitro studies of osteoclast num-
ber 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 normal-
ization 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 concen-
trations [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
Volume 23
Number 4
July 2014

6000
5000 **
TRAP+ MNC/mm2
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].
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 mech-
anism 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, non-
myelinating 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 regen-
eration 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].
1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Sodium homeostasis and bone Hannon and Verbalis
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 hypo-
natremia [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 hypo-
&
natremic patients [44 ]. Previous studies have ident-
ified 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 hyperthyroid-
ism, 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 follow-
ing knockout or inhibition of AVPR1a. Inhibition of
AVPR2 in AVPR1a-/- knockout mice led to similar
increases in osteoblastogenesis. Conversely, injec-
tion 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 recep-
&
tor 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 euna-
tremic patients; rather, the problem is that the AVP
is inappropriately elevated for the patient’s osmo-
&
lality and sodium level [49,50,51 ]. Furthermore, a
significant relation has been shown between
patients’ serum [Naþ] and BMD at the femoral neck
www.co-nephrolhypertens.com 373
 Mineral metabolism
[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 glyco-
protein of the AVP prohormone, has recently been
established as an easy to measure and stable surro-
gate for endogenous AVP secretion [52–54], which
may enable future studies to examine the relation-
ship between AVP and BMD.
It should also be noted that multiple previous
results indicate that the phenomenon of hypo-
natremia-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 des-
mopressin (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
SOLID + DDAVP
0.24
LIQUID + DDAVP
0.22
0.20
BMD g/cm2
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, 1-
desamino-8-D-arginine. Reproduced with permission [33].
374 www.co-nephrolhypertens.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
SOLID + DDAVP
0.24 LIQUID + DDAVP
0.22
*
0.20
TRAP+ MNC/mm2
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, 1-
desamino-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 con-
centration, so all cells experienced the same extra-
cellular 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.
RELATION OF SODIUM DEFICIENCY TO
THE SYNDROME OF INAPPROPRIATE
ANTIDIURETIC HORMONE SECRETION
AND HYPONATREMIA-INDUCED
OSTEOPOROSIS
The data accumulated to date support the hypo-
thesis 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

Table 1. Bone ash analyses in bones from aged rats
L1–L2 vertebrae
Normo [Naþ]
Wet weight (g) 1.998  0.161 1.664  0.051
Dry weight (g) 0.818  0.099 0.746  0.027
Ash weight (mg/bone) 307.8  27.8 270.0  16.2
Calcium mass (mg) 121.8  7.4 113.4  10.1
Sodium mass (mg) 22.2  0.6
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 protec-
tive 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 patho-
logical ‘misinterpretation’ of the low serum [Naþ]
as signifying deficient total body sodium. Further-
more, 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 inde-
pendent 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 poten-
tial receptors and pathways through which hypo-
natremia 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.
1062-4821 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Sodium homeostasis and bone Hannon and Verbalis
Tibia
Hypo [Naþ] Normo [Naþ] Hypo [Naþ]
1.173  0.027 1.168  0.037
0.767  0.019 0.728  0.019
401.1  10.9 375.4  9.0
169.6  6.9 156.0  3.3

19.1  1.5 19.1  0.5 15.5  0.2
&
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 hypo-
natremia 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 hypo-
natremia impacts on bone are as yet unknown,
but clearly involve stimulation of osteoclast for-
mation 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 UL1-
TR000101 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.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Robertson GL, Aycinena P, Zerbe RL. Neurogenic disorders of osmoregula-
tion. Am J Med 1982; 72:339–353.
2. Baylis PH, Thompson CJ. Osmoregulation of vasopressin secretion and thirst
in health and disease. Clin Endocrinol (Oxf) 1988; 29:549–576.
www.co-nephrolhypertens.com 375
 Mineral metabolism
3. Harrison HE, Darrow DC, Yannet H. The total electrolyte content of animals
and its probable relation to the distribution of body water. J Biol Chem 1936;
113:515–529.
4. Kaltreider NL, Meneely GR, Allen JR, Bale WF. Determination of the volume of
the extracellular fluid of the body with radioactive sodium. J Exp Med 1941;
74:569–590.
5. Forbes GB, Perley A. Estimation of total body sodium by isotopic dilution. I.
Studies on young adults. J Clin Invest 1951; 30:558–565.
6. Bergstrom WH, Wallace WM. Bone as a sodium and potassium reservoir.
J Clin Invest 1954; 33:867–873.
7. Gabriel S. Chemische Untersuchungen uber die Mineralstoffe der Knochen
und Zahne. Ztschr f Physiol Chem 1894; 18:257.
8. Stern TN, Cole VV, Bass AC, Overman RR. Dynamic aspects of sodium
metabolism in experimental adrenal insufficiency using radioactive sodium.
Am J Physiol 1951; 164:437–449.
9. Shohl AT. Mineral metabolism. New York: Reinhold Publishing; 1939.
10. Bergstrom WH. The participation of bone in total body sodium metabolism in
the rat. J Clin Invest 1955; 34 (Part 1):997–1004.
11. Nichols G Jr, Nichols N. Electrolyte equilibria in erythrocytes during diabetic
acidosis. J Clin Invest 1953; 32:113–120.
12. Baran D, Hutchinson TA. The outcome of hyponatremia in a general hospital
population. Clin Nephrol 1984; 22:72–76.
13. Flear CT, Gill GV, Burn J. Hyponatraemia: mechanisms and management.
Lancet 1981; 2:26–31.
14. Hannon MJ, Thompson CJ. The syndrome of inappropriate antidiuretic hor-
mone: prevalence, causes and consequences. Eur J Endocrinol 2010; 162
(Suppl. 1):S5–S12.
15. Stelfox HT, Ahmed SB, Khandwala F, et al. The epidemiology of intensive care
unit-acquired hyponatraemia and hypernatraemia in medical-surgical intensive
care units. Crit Care 2008; 12:R162.
16. Zilberberg MD, Exuzides A, Spalding J, et al. Hyponatremia and hospital
outcomes among patients with pneumonia: a retrospective cohort study.
BMC Pulm Med 2008; 8:16.
17. Gankam-Kengne F, Ayers C, Khera A, et al. Mild hyponatremia is associated
& with an increased risk of death in an ambulatory setting. Kidney Int 2013;
83:700–706.
This study showed that hyponatremia is an independent risk factor for mortality in a
young, ambulatory, ethnically diverse U.S. population even after adjustment for
multiple risk factors.
18. Gill G, Huda B, Boyd A, et al. Characteristics and mortality of severe hypona-
traemia – a hospital-based study. Clin Endocrinol (Oxf) 2006; 65:246–249.
19. Clayton JA, Le Jeune IR, Hall IP. Severe hyponatraemia in medical in-patients:
aetiology, assessment and outcome. QJM 2006; 99:505–511.
20. Corona G, Giuliani C, Parenti G, et al. Moderate hyponatremia is associated
& with increased risk of mortality: evidence from a meta-analysis. PLoS One
2013; 8:e80451.
This large meta-analysis, encompassing 81 studies and 850 222 patients, showed
that hyponatremia of multiple causes was associated with increased mortality in
various heterogeneous patient groups, and hyponatremia-related risk of overall
mortality was inversely correlated with plasma [Naþ].
21. Hoorn EJ, Lindemans J, Zietse R. Development of severe hyponatraemia in
hospitalized patients: treatment-related risk factors and inadequate manage-
ment. Nephrol Dial Transplant 2006; 21:70–76.
22. Sajadieh A, Binici Z, Mouridsen MR, et al. Mild hyponatremia carries a poor
prognosis in community subjects. Am J Med 2009; 122:679–686.
23. Waikar SS, Mount DB, Curhan GC. Mortality after hospitalization with mild,
moderate, and severe hyponatremia. Am J Med 2009; 122:857–865.
24. Renneboog B, Musch W, Vandemergel X, et al. Mild chronic hyponatremia is
associated with falls, unsteadiness, and attention deficits. Am J Med 2006;
119:71.e1–71.e8.
25. Gankam Kengne F, Andres C, Sattar L, et al. Mild hyponatremia and risk of
fracture in the ambulatory elderly. QJM 2008; 101:583–588.
26. Sandhu HS, Gilles E, DeVita MV, et al. Hyponatremia associated with large-
bone fracture in elderly patients. Int Urol Nephrol 2009; 41:733–737.
27. Kinsella S, Moran S, Sullivan MO, et al. Hyponatremia independent of
osteoporosis is associated with fracture occurrence. Clin J Am Soc Nephrol
2010; 5:275–280.
28. Tolouian R, Alhamad T, Farazmand M, Mulla ZD. The correlation of hip fracture
and hyponatremia in the elderly. J Nephrol 2012; 25:789–793.
29. Hoorn EJ, Rivadeneira F, van Meurs JB, et al. Mild hyponatremia as a risk factor
for fractures: the Rotterdam Study. J Bone Miner Res 2011; 26:1822–1828.
30. Lien YH, Shapiro JI, Chan L. Study of brain electrolytes and organic osmolytes
during correction of chronic hyponatremia. Implications for the pathogenesis
of central pontine myelinolysis. J Clin Invest 1991; 88:303–309.
31. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway
for neurologic disorders. N Engl J Med 1994; 330:613–622.
376 www.co-nephrolhypertens.com
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
32. Barsony J, Manigrasso MB, Xu Q, et al. Chronic hyponatremia exacerbates
& multiple manifestations of senescence in male rats. Age (Dordr) 2013;
35:271–288.
This study showed that, in aged rats with chronic hyponatremia because of
SIADH, the presence of hyponatremia increased bone resorption and decreased
bone ash sodium content, and also led to hypogonadism, reduced body fat,
sarcopenia, and cardiomyopathy. This is the first study to show causality in an
animal model of the effects of hyponatremia previously seen in various human
association studies.
33. Verbalis JG, Barsony J, Sugimura Y, et al. Hyponatremia-induced osteoporo-
sis. J Bone Miner Res 2010; 25:554–563.
34. Barsony J, Sugimura Y, Verbalis JG. Osteoclast response to low extracellular
sodium and the mechanism of hyponatremia-induced bone loss. J Biol Chem
2011; 286:10864–10875.
35. Zerbe RL, Robertson GL. Osmoregulation of thirst and vasopressin secretion
in human subjects: effect of various solutes. Am J Physiol 1983; 244:E607–
E614.
36. Lara LS, Satou R, Bourgeois CR, et al. The sodium-activated sodium channel
is expressed in the rat kidney thick ascending limb and collecting duct cells
and is upregulated during high salt intake. Am J Physiol Renal Physiol 2012;
303:F105–F109.
37. Watanabe E, Hiyama TY, Kodama R, Noda M. NaX sodium channel is
expressed in nonmyelinating Schwann cells and alveolar type II cells in mice.
Neurosci Lett 2002; 330:109–113.
38. Frazier DT, Narahashi T. Tricaine (MS-222): effects on ionic conductances of
squid axon membranes. Eur J Pharmacol 1975; 33:313–317.
39. Hedrick MS, Winmill RE. Excitatory and inhibitory effects of tricaine (MS-222)
on fictive breathing in isolated bullfrog brain stem. Am J Physiol Regul Integr
Comp Physiol 2003; 284:R405–R412.
40. Tseng AS, Beane WS, Lemire JM, et al. Induction of vertebrate regeneration
by a transient sodium current. J Neurosci 2010; 30:13192–13200.
41. Johnson JA, Zehr JE, Moore WW. Effects of separate and concurrent osmotic
and volume stimuli on plasma ADH in sheep. Am J Physiol 1970; 218:1273–
1280.
42. Schrier RW, Fassett RG. Pathogenesis of sodium and water retention in
cardiac failure. Ren Fail 1998; 20:773–781.
43. Cardenas A, Arroyo V. Mechanisms of water and sodium retention in cirrhosis
and the pathogenesis of ascites. Best Pract Res Clin Endocrinol Metab 2003;
17:607–622.
44. Tamma R, Sun L, Cuscito C, et al. Regulation of bone remodeling by
& vasopressin explains the bone loss in hyponatremia. Proc Natl Acad Sci
USA 2013; 110:18644–18649.
This study showed that AVP receptors are expressed in both osteoclasts and
osteoblasts. Exposure of osteoblast precursors to AVP receptor antagonism or
deletion led to increased osteoblastogenesis, whereas AVP directly stimulated
osteoclastogenesis, establishing a direct role for AVP in the causation of hypona-
tremia-induced osteoporosis.
45. Abe E, Marians RC, Yu W, et al. TSH is a negative regulator of skeletal
remodeling. Cell 2003; 115:151–162.
46. Sun L, Peng Y, Sharrow AC, et al. FSH directly regulates bone mass. Cell
2006; 125:247–260.
47. Zaidi M, Sun L, Robinson LJ, et al. ACTH protects against glucocorticoid-
induced osteonecrosis of bone. Proc Natl Acad Sci USA 2010; 107:8782–
8787.
48. Tamma R, Colaianni G, Zhu LL, et al. Oxytocin is an anabolic bone hormone.
Proc Natl Acad Sci USA 2009; 106:7149–7154.
49. Verbalis JG. Hyponatraemia. Balliere’s Clin Endocrinol Metab 1989; 3:499–
530.
50. Smith DM, McKenna K, Thompson CJ. Hyponatraemia. Clin Endocrinol (Oxf)
2000; 52:667–678.
51. Verbalis JG, Goldsmith SR, Greenberg A, et al. Diagnosis, evaluation, and
& treatment of hyponatremia: expert panel recommendations. Am J Med 2013;
126 (10 Suppl. 1):S1–S42.
This guideline uses the most recent published data and the consensus opinions of
various international experts in the field to give updated recommendations for the
optimal management of hyponatremia of multiple causes.
52. Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measure-
ment of copeptin, a stable peptide derived from the precursor of vasopressin.
Clin Chem 2006; 52:112–119.
53. Morgenthaler NG, Struck J, Jochberger S, Dunser MW. Copeptin: clinical use
of a new biomarker. Trends Endocrinol Metab 2008; 19:43–49.
54. Balanescu S, Kopp P, Gaskill MB, et al. Correlation of plasma copeptin and
vasopressin concentrations in hypo-, iso-, and hyperosmolar states. J Clin
Endocrinol Metab 2011; 96:1046–1052.
55. Verbalis JG, Drutarosky MD. Adaptation to chronic hypoosmolality in rats.
Kidney Int 1988; 34:351–360.
Volume 23
Number 4
July 2014