Hyponatremia Independent of Osteoporosis is Associated with Fracture Occurrence

Kinsella, Sinéad; Moran, Sarah; Sullivan, Miriam O.; Molloy, Michael G.; Eustace, Joseph A.

doi:10.2215/cjn.06120809

Cited by 256 publications

(209 citation statements)

References 31 publications

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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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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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“…The potential implication of chronic hyponatraemia due to over-treatment with desmopressin remains to be quantified. Recent publications have stressed the morbidity associated with chronic hyponatraemia, including gait instability and falls (15), fractures (16,17), and osteoporosis (18), which suggests that even mild hyponatraemia may be detrimental to health. Further prospective studies are warranted to evaluate the nature of some of these morbidities, including defining whether they are an association or a direct result of hyponatraemia.…”

Section: Discussionmentioning

confidence: 99%

Abnormal plasma sodium concentrations in patients treated with desmopressin for cranial diabetes insipidus: results of a long-term retrospective study

Behan

Sherlock

Moyles

et al. 2015

European Journal of Endocrinology

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Context and objective: Patients with cranial diabetes insipidus (CDI) are at risk of developing both hypernatraemia and hyponatraemia, due to the condition itself or secondary to treatment with vasopressin-analogues or during administration of i.v. fluids. We aimed to assess the frequency and impact of dysnatraemias in the inpatient (INPT) and outpatient (OPT) setting in desmopressin-treated CDI, comparing those with normal thirst with those with abnormal thirst. Design: The study included 192 patients with cranial diabetes, who were identified from the Beaumont Pituitary Database, a tertiary referral centre. Retrospective case note audit was performed and the clinical and biochemical information of 147 patients with CDI were available for analysis. Results: A total of 4142 plasma sodium measurements for 137 patients with normal thirst, and 385 plasma sodium measurements for ten patients with abnormal thirst were analysed. In those with normal thirst, the most common OPT abnormality was mild hyponatraemia (pNa C 131-134 mmol/l) in 27%, while 14.6% had more significant hyponatraemia (pNa C %130 mmol/l). Of those patients with normal thirst, 5.8% were admitted due to complications directly related to hyponatraemia. Compared with patients with normal thirst, those with abnormal thirst were more likely to develop significant OPT hypernatraemia (20% vs 1.4%, PZ0.02) and significant INPT hyponatraemia (50% vs 11.1%, P 0.02). Conclusion: OPT management of CDI is complicated by a significant incidence of hyponatraemia. In contrast, OPT hypernatraemia is almost exclusively a complication seen in adipsic CDI, who also had more frequent INPT hyponatraemia. CDI associated with thirst disorder requires increased physician attention and patient awareness of potential complications.

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“…Although there are virtually no data on mortality in SIAD, mortality in all-cause hyponatraemia has been reported to be elevated in almost every paper on the subject [2][3][4]. Hyponatraemic patients are also vulnerable to morbidity related to falls [5], fractures [6] and osteoporosis [7]. In the absence of separate studies in SIAD, it is widely accepted that patients who have hyponatraemia due to SIAD are vulnerable to the same risk of the morbidities and mortality associated with all-cause hyponatraemia.…”

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confidence: 99%

Syndrome of inappropriate antidiuresis should it be managed by specialised endocrinologists?

Garrahy

Thompson

2017

Endocrine

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The syndrome of inappropriate antidiuresis (SIAD) is the commonest cause of hyponatraemia in hospitalised patients, accounting for 43% of patients with a plasma sodium concentration of <130 mmol/l [1]. Although there are virtually no data on mortality in SIAD, mortality in all-cause hyponatraemia has been reported to be elevated in almost every paper on the subject [2][3][4]. Hyponatraemic patients are also vulnerable to morbidity related to falls [5], fractures [6] and osteoporosis [7]. In the absence of separate studies in SIAD, it is widely accepted that patients who have hyponatraemia due to SIAD are vulnerable to the same risk of the morbidities and mortality associated with all-cause hyponatraemia. This has prompted considerable interest in whether treatment of hyponatreamia can improve outcomes in SIAD.Unfortunately, there is little data in the literature upon which to construct evidence based guidelines for the management of hyponatraemia due to SIAD. In the absence of a solid evidence base, there are controversial differences between the US recommendations [8] and the European guidelines [9] on treatment of SIAD. The US recommendations acknowledge that second-line treatment of SIAD, after failure of water restriction can be vaptans, urea or frusemide with sodium chloride supplementation, whereas the European Guidelines specifically advise against vaptans. So where are the gaps in our knowledge in the literature? The mortality in SIAD separately from that due to all-cause hyponatraemia is not known. Mortality studies have assessed the effects of hyponatraemia on death rate, without separating out the relative mortality of SIAD from other causes of hyponatraemia. In addition, as very few studies have firmly ascertained the full diagnostic criteria for SIAD in their study cohorts [10], the accuracy of data from many SIAD studies is questionable.The situation is complicated by the lack of studies on the response of plasma sodium to established treatments for SIAD. There are no prospective randomised-controlled trials which have reported the effects of water restriction, and many second-line treatments, in SIAD. There is however firm data on the response of SIAD-related hyponatraemia to treatment with vaptans; the randomised, placebocontrolled SALT studies showed that a mixed population of patients with SIAD and hypervolaemic hyponatraemia demonstrated a larger rise in plasma sodium concentration in response to tolvaptan than to placebo [11], and a later subgroup analysis confirmed that similar biochemical responses were consistent in the SIAD subgroup [12]. However, we still await the results of trials which compare the proven benefits of vaptans with first-line treatment with water restriction.It is therefore timely to see the results of an intervention study in SIAD patients in this journal [13]; the paper reported the effects of specialised endocrine care on outcomes in SIAD. The authors have a proven track record in the field, and as a group who have highlighted the poor ascertainment of basic diagnosti...

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Hyponatremia Independent of Osteoporosis is Associated with Fracture Occurrence

Cited by 256 publications

References 31 publications

Functions of vasopressin and oxytocin in bone mass regulation

Functions of vasopressin and oxytocin in bone mass regulation

Abnormal plasma sodium concentrations in patients treated with desmopressin for cranial diabetes insipidus: results of a long-term retrospective study

Syndrome of inappropriate antidiuresis should it be managed by specialised endocrinologists?

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