Osteoclast Response to Low Extracellular Sodium and the Mechanism of Hyponatremia-induced Bone Loss

Bársony, Julia; Sugimura, Yoshihisa; Verbalis, Joseph G.

doi:10.1074/jbc.m110.155002

Cited by 159 publications

(168 citation statements)

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“…More important, adults with mild hyponatremia (mean serum sodium concentration, 133 mEq/L) displayed a significantly increased risk for osteoporosis at the hip (odds ratio, 2.85; 95% CI, 1.03-7.86) and femoral neck (odds ratio, 2.87; 95% CI, 1.41-5.81). These observations may be related to stimulation of osteoclastic activity and enhanced bone resorption in the setting of a low serum sodium concentration (17). Commensurate with the above discussion, our patient had disturbed gait and had sustained a fall and fracture.…”

Section: Question 1 How Common Is Chronic Hyponatremia In the Elderly?supporting

confidence: 74%

An Elderly Patient with Chronic Hyponatremia

Berl

2013

Clinical Journal of the American Society of Nephrology

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SummaryHyponatremia is the most common electrolyte disorder. With the aging of the population and the greater propensity of the elderly to develop hyponatremia, this electrolyte disorder is of increasing importance to the practicing nephrologist. In this Attending Rounds, an illustrative patient with hyponatremia is presented. The reasons for the increased incidence and prevalence of hyponatremia in the elderly are discussed, with emphasis on the effects of aging on urinary dilution, the frequently multifactorial nature of hyponatremia in this population, and the absence of a definite cause for inappropriate and persistent vasopressin release in many such patients. The rationale for treating the hyponatremia, even when apparently asymptomatic, is discussed, with attention to cognitive function, gait, and bone structure disturbances that increase the risk for fractures. The various available treatment approaches, including water restriction, demeclocycline, loop diuretics with NaCl supplementation, urea, and vasopressin antagonists are summarized, with emphasis on the efficacy and limitations of each of these therapies.Clin J Am Soc Nephrol 8: 469-475, 2013469-475, . doi: 10.2215 Case Description L.G. is a 73-year-old woman referred for management of chronic hyponatremia. She was known to have had hyponatremia for several years, with serum sodium levels in the range of 121-127 mEq/L. She has had four pulmonary bacterial infections during the last 7 years and was found to have radiologic evidence of bronchiectasis. She has also had several episodes of transient cerebral ischemia leading to numbness and weakness. In the last year she has had increased gait instability and sustained a fall that resulted in a pelvic fracture. She had no history of cardiac or liver disease. She has long-standing rheumatoid arthritis. Medications included omeprazole, 20 mg daily; conjugated estrogens (Premarin), 0.3 mg daily; folic acid, 0.4 mg three times daily; aspirin, 81 mg daily; and monthly vitamin B 12 injections. On physical examination she appeared to be a fragile elderly woman in no acute distress. BP was 148/78 mmHg, pulse rate was 98 beats/min, and she weighed 65 kg. She appeared to be euvolemic by examination. There were deformities of the proximal interphalangeal joints. Her neurologic examination revealed that she was fully oriented, with no focal findings, but she had an obvious gait disturbance that necessitated a walker for ambulation. Laboratory results were as follows: serum sodium, 124 mEq/L; chloride, 95 mEq/L; potassium, 4.1 mEq/L; bicarbonate, 22 mEq/L; creatinine, 0.7 mg/dl; glucose, 66 mg/dl; and uric acid, 3.8 mg/dl. Urinary sodium concentration was 75 mEq/L with a urine osmolality of 382 mOsm/kg. Result of a cosyntropin stimulation test was normal, with a baseline cortisol level of 9.2 mg/dl and a stimulated level of 18.7 mg/dl. Thyroid-stimulating hormone was normal at 3.29 mIU/L. Magnetic resonance imaging of the brain and pituitary revealed no significant abnormalities. DiscussionGiven the absence of liv...

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Section: Question 1 How Common Is Chronic Hyponatremia In the Elderly?supporting

confidence: 74%

An Elderly Patient with Chronic Hyponatremia

Berl

2013

Clinical Journal of the American Society of Nephrology

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“…AVP could indeed be a primary determinant for the osteoporosis that is known to accompany chronic hyponatremic states (22)(23)(24)(25)(26)(27)(28), although high aldosterone levels, for example in SIADH, may contribute also (21). The latter is possible because hyperaldosteronism also has been shown to cause bone loss in rodents (29,30).…”

Section: Discussionmentioning

confidence: 99%

Functions of vasopressin and oxytocin in bone mass regulation

Sun

Tamma

Yuen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Prior studies show that oxytocin (Oxt) and vasopressin (Avp) have opposing actions on the skeleton exerted through high-affinity G protein-coupled receptors. We explored whether Avp and Oxtr can share their receptors in the regulation of bone formation by osteoblasts. We show that the Avp receptor 1α (Avpr1α) and the Oxt receptor (Oxtr) have opposing effects on bone mass: Oxtr −/− mice have osteopenia, and Avpr1α −/− mice display a high bone mass phenotype. More notably, this high bone mass phenotype is reversed by the deletion of Oxtr in Oxtr −/− :Avpr1α −/− doublemutant mice. However, although Oxtr is not indispensable for Avp action in inhibiting osteoblastogenesis and gene expression, Avpstimulated gene expression is inhibited when the Oxtr is deleted in Avpr1α −/− cells. In contrast, Oxt does not interact with Avprs in vivo in a model of lactation-induced bone loss in which Oxt levels are high. Immunofluorescence microscopy of isolated nucleoplasts and Western blotting and MALDI-TOF of nuclear extracts show that Avp triggers Avpr1α localization to the nucleus. Finally, a specific Avpr2 inhibitor, tolvaptan, does not affect bone formation or bone mass, suggesting that Avpr2, which primarily functions in the kidney, does not have a significant role in bone remodeling.O ver the past decade, we have described direct actions of anterior and posterior pituitary hormones on the skeleton (1-8). We have shown that these actions are exerted via G protein-coupled receptors resident on both osteoblasts and osteoclasts. We also find that the skeleton is highly sensitive to the action of posterior pituitary hormones; for example, mice haploinsufficient in oxytocin (Oxt) have osteopenic bones, but lactation is normal; lactation is impaired only in Oxt −/− mice (2). Likewise, Tshr haploinsufficient mice are completely euthyroid with normal thyroid follicles but display significant osteopenia (4). The exquisite sensitivity of the skeleton to pituitary hormones comes as no surprise, considering that the pituitary gland and the skeleton are both evolutionarily more primitive than target endocrine organs (7).Apart from the known actions of growth hormone on the skeleton, Tsh, Fsh, Acth, Oxt, and vasopressin (Avp) have all been shown to regulate the formation and/or function of both osteoblasts and osteoclasts and thus to control bone remodeling in vivo (2-4, 6-8). The two neurohypophyseal hormones Oxt and Avp have opposing functions (2, 3). Oxt stimulates and Avp inhibits osteoblast formation. Consequently, the genetic deletion of the Oxt receptor (Oxtr) and Avp receptor 1α (Avpr1α) yields opposing phenotypes, notably osteopenia in Oxtr −/− mice and high bone mass in Avpr1α −/− mice (2, 3). These findings may explain the rapid recovery of bone loss at weaning when plasma Oxt levels are high (9) and also the profound loss of bone noted in chronic hyponatremic states, such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), in which serum Avp levels are elevated (3).We find high levels of Oxtr expression on ...

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“…Clinical Study L Holland-Bill and others Hyponatremia severity and mortality risk stress (30). It is possible that even small decreases in serum sodium below 139 mmol/l may be sufficient to induce accumulation of free oxygen radicals and thereby induce damage to proteins, lipids and DNA.…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

Hyponatremia and mortality risk: a Danish cohort study of 279 508 acutely hospitalized patients

Holland-Bill¹,

Christiansen²,

Heide-Jørgensen³

et al. 2015

European Journal of Endocrinology

120

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Objective: We aimed to investigate the impact of hyponatremia severity on mortality risk and assess any evidence of a dose-response relation, utilizing prospectively collected data from population-based registries. Design: Cohort study of 279 508 first-time acute admissions to Departments of Internal Medicine in the North and Central Denmark Regions from 2006 to 2011. Methods: We used the Kaplan-Meier method (1 -survival function) to compute 30-day and 1-year mortality in patients with normonatremia and categories of increasing hyponatremia severity. Relative risks (RRs) with 95% CIs, adjusted for age, gender and previous morbidities, and stratified by clinical subgroups were estimated by the pseudo-value approach. The probability of death was estimated treating serum sodium as a continuous variable. Results: The prevalence of admission hyponatremia was 15% (41 803 patients). Thirty-day mortality was 3.6% in normonatremic patients compared to 7.3, 10.0, 10.4 and 9.6% in patients with serum sodium levels of 130-134.9, 125-129.9, 120-124.9 and !120 mmol/l, resulting in adjusted RRs of 1.4 (95% CI: 1.3-1.4), 1.7 (95% CI: 1.6-1.8), 1.7 (95% CI: 1.4-1.9) and 1.3 (95% CI: 1.1-1.5) respectively. Mortality risk was increased across virtually all clinical subgroups, and remained increased by 30-40% 1 year after admission. The probability of death increased when serum sodium decreased from 139 to 132 mmol/l. No clear increase in mortality was observed for lower concentrations. Conclusions: Hyponatremia is highly prevalent among patients admitted to Departments of Internal Medicine and is associated with increased 30-day and 1-year mortality risk, regardless of underlying disease. This risk seems independent of hyponatremia severity.

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Osteoclast Response to Low Extracellular Sodium and the Mechanism of Hyponatremia-induced Bone Loss

Cited by 159 publications

References 51 publications

An Elderly Patient with Chronic Hyponatremia

An Elderly Patient with Chronic Hyponatremia

Functions of vasopressin and oxytocin in bone mass regulation

Hyponatremia and mortality risk: a Danish cohort study of 279 508 acutely hospitalized patients

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