I. Chiodini Dpt. of Clinical Sciences & Community Health ......pathway, not only in cultured RAW...

I. Chiodini Dpt. of Clinical Sciences & Community Health, University of Milan. Unit for Bone Metabolism Diseases and Diabetes & Lab of Endocrine and Metabolic Research, IRCCS Istituto Auxologico Italiano

Iacopo Chiodini

Il sottoscritto Iacopo Chiodini in qualità di relatore, ai sensi dell’Accordo tra il Governo, le Regioni e le Province autonome di Trento e Bolzano sul documento “LA FORMAZIONE CONTINUA NEL SETTORE «SALUTE»” del 02/02/2017 e allegato "Criteri per l'assegnazione dei crediti alle attività ECM" che costituisce parte integrante dello stesso, per conto della MuseiOn Soc. Coop. di Fermo DICHIARA che negli ultimi due anni ha avuto i seguenti rapporti anche di finanziamento con soggetti portatori di interessi commerciali in campo sanitario: - Eli Lilly - Abiogen - Italfarmaco - Kyowa Kirin - Savio

DISCLOSURES



• The association of hyponatremia with falls and fractures in elders is well documented. • Both hyponatremia and falls are associated with increased morbidity and mortality. • Hyponatremia and falls adversely impact hospitalization costs. • On the basis of this evidence, we propose inclusion of hyponatremia, in all fall risk

assessment tools for hospitalized older adults J Am Geriatr Soc 2019, epub

HYPONATREMIA Epidemiology

1. Ellison DH, Berl T. N Engl J Med.2007;356:2064-2072. 2. Hoorn EJ, et al. Nephrol Dial Transplant.2006;21:70-76. 3. Weir MR, Rolfe M. Clin J Am Soc Nephrol.2010;5(3):531-548.

Disorder Prevalence

Hyponatremia

- Mild (Na+ 135-130 mmol/L) 15-22% inpatients1

7% outpatients

- Moderate (Na+ 125-130 mmol/L) 7% inpatients1

- Severe (Na+ <125 mmol/L) 3% inpatients2

Hyperkalemia 2-5% patients3

Hypercalcemia 1-2% after 60 years

Na+ normal values: 135-145 mmol/L


Aetiology of hyponatraemia (serum [Na+] < 130 mmol/L) at the Medical University Hospital of Würzburg

HYPONATREMIA: PREVALENCE OF DIFFERENT CAUSES

Fenske W, et al. Am J Med. 2010;123:652-657.


Ayus JC et al, Nephrol Dial Transplant 2012

OVERVIEW OF THE PATHOPHYSIOLOGY OF HYPONATREMIA ASSOCIATED SIGNS AND SYMPTOMS IN MULTIPLE ORGANS

Diuretics; Antidepressants ; Antiepileptics; Proton pump inhibitors (PPI); antipsychotics ; chemotherapeutics ; Voriconazole; Recreational party drugs


SODIUM, GAIT AND SENESCENCE


Hannon J & Verbalis J Curr Opin Nephrol Hyperten 2014

• Even mild hyponatremia may induce gait instability in the elderly

• Initially, chronic hyponatremia leads to cellular loss of electrolytes (potassium, sodium, and chloride) from the brain to the ECF.

• Subsequently, there is a loss of organic osmolytes, largely amino acids, including glutamate (the most prevalent excitatory neurotransmitter in the brain).

• Loss of intracellular glutamate may impair the neurotransmission in motor neurons important for the maintenance of postural muscle tone.

• 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.

Renneboog B et al, Am J Med 2006


MILD CHRONIC HYPONATREMIA IS ASSOCIATED WITH FALLS, UNSTEADINESS, AND ATTENTION DEFICITS


FOREST PLOT ASSESSING HYPONATREMIA AND RISK OF OSTEOPOROSIS

Retrospective

Cross-sectional

Murthy K…Verbalis JG, Endocr Pract 2019


FOREST PLOT ASSESSING HYPONATREMIA AND RISK OF HIP FRACTURES COMPARED TO OTHER FRACTURES

Hip fracture

Any fracture



FOREST PLOT ASSESSING MORTALITY RISK AMONG STUDIES REPORTING HYPONATREMIA AND FRACTURES

Retrospective

Prospective


Hoorn EJ et al, Nat Rev Endocrinol 2011

POSSIBLE RELATIONSHIPS BETWEEN HYPONATREMIA, OSTEOPOROSIS, AND FRACTURES


INCREASED FRACTURE RISK IN HYPONATREMIA IS INDEPENDENT OF FALLS

Hoorn EJ et al, J Bone Miner Res 2011


SODIUM AND BONE


Hannon J & Verbalis J Curr Opin Nephrol Hyperten 2014

• Bone mineral is extremely rich in sodium, 40% exchangeable with ECF [Forbes GB

&Perley A, J Clin Invest 1951].

• Bone is the only tissue in which the sodium concentration is actually higher than in the extracellular fluid [Harrison HE et al, Biol Chem 1936].

• Possibility of bone acting as an internal sodium ‘reservoir’?

RISK OF BONE FRACTURE IN RELATION TO SERUM SODIUM IN PATIENTS WITH CHRONIC KIDNEY DISEASE IS INDEPENDENT OF BMD

Kinsella S et al. Clin J Am Soc Nephrol. 2010

Adjusted for: • age • T-score • CKD stage • OP risk factors • OP therapy

59 hyponatremic subjects 1349 normonatremic subjects


Verbalis JG et al, J Bone Miner Res 2010

Na: 141±1 135±2 110±2 115±3 mmol/L

3 months

BMD IS DECREASED IN CHRONICALLY HYPONATREMIC RATS


Liquid: liquid diet Solid: solid diet VD: vitamin D


BONE QUALITY IS REDUCED IN CHRONICALLY HYPONATREMIC RATS

Von Kossa

Von Kossa




HYPONATREMIA INCREASED BONE RESORPTION AND DECREASED BONE FORMATION

Bone formation:

- a tendency toward lower mineral apposition rate in hyponatremic rats.

- Mineralizing surface per bone surface not different

- Osteocalcin significantly decreased in hyponatremic rats compared with normonatremic controls.



Barsony J et al, J Biol Chem 2011

OSTEOCLAST RESPONSE TO LOW EXTRACELLULAR SODIUM AND THE MECHANISM OF HYPONATREMIA-INDUCED BONE LOSS

Osteoclastogenic effect of hyponatremia is related to low sodium

levels rather than low osmolality

[Na]-dependent decreases of cytosolic

[Ca2]

Lowering [Na] dose-dependently reduced ascorbic acid uptake

Removal of ascorbic acid stimulates resorbing activity


LOWERING [NA] INCREASES ACCUMULATION OF REACTIVE OXYGEN SPECIES AND ELICITS OXIDATIVE STRESS RESPONSE IN CELLULAR AND ANIMAL

MODELS OF HYPONATREMIA Barsony J et al, J Biol Chem 2011

RANKL signalling

RANKL and ROS signalling

Lowering [Na] increased ROS

A low [Na] triggers osteoclastic bone

resorption by signaling through the

oxidative stress pathway, not only in cultured RAW 264.7 cells but also in rat

model of SIADH


REGULATION OF BONE REMODELLING BY VASOPRESSIN EXPLAINS THE BONE LOSS IN HYPONATREMIA

Tamma R et al, PNAS 2013

Bone cells express Avprs. Immunofluorescence micrographs


AVP (Avpr1) REGULATES OSTEOCLAST FORMATION AND FUNCTION



AVP (Avpr1) REGULATES OSTEOBLASTOGENESIS




HYPONATREMIA AFFECTS BONE TISSUE REGARDLESS OF AVP LEVELS IN RATS

Same DDVAP levels Different Na+ levels

Na+ 110 mmol/L

Na+ 141 mmol/L

Na+ 141 mmol/L

Na+ 110 mmol/L

Same DDVAP levels Different Na+ levels

Verbalis JG et al, JBMR 2010

However, the drawback of this SIADH model is that it used DDAVP, and, although DDAVP has potent agonist activity at the Avpr2 receptor, it has only minor effects on the Avpr1α receptor. Avpr2 primarily functions in the kidney and does not have a significant role in bone remodeling. Vaptans (Avpr2 agonists) have no effect on bone.

Modified from Ayus JC et al, Nephrol Dial Transplant 2012

MECHANISM OF BONE DISEASE INDUCED BY HYPONATREMIA

AVP increase



IN HUMANS HYPONATREMIA IS A SIGN OF SEVERAL DIFFERENT DISEASES THAT PER SE MAY IMPACT ON BONE HEALTH.

Thus, although these data are interesting, in humans the independent role of hyponatremia on bone tissue is still to be

understood.

Fenske W, et al. Am J Med. 2010;123:652-657.


SHOULD SERUM SODIUM BE VIEWED AS A NOVEL RISK FACTOR FOR GAIT DISTURBANCES AND BONE DISEASE, ESPECIALLY IN THE ELDERLY?

• Tolvaptan was effective in reversing mild to moderate chronic asymptomatic hyponatremia, and this correlated with improvements of neurocognition tests

Verbalis JG, et al, Am J Kidney Dis. 2016

Measuring serum sodium can only be recommended if treatment of hyponatremia corrects gait disturbances and bone abnormalities and/or if

impacts on mortality.

• Sejling et al. described a man with SIADH-induced severe osteoporosis associated sinus esthesioneuroblastoma. After the tumor was removed, ADH and sodium levels normalized, and a DXA scan 7 months later showed significant improvement of BMD in the lumbar vertebrae.

Sejling AS et al, J Clin Endocrinol Metab. 2014

• Hyponatremia is associated with increased mortality: causative role? Wald R et al, Arch It Med 2010; Chawla A et al, Clin J Am Soc Nephrol 2011

Because data on bone parameters or fractures during treatment of hyponatremia are lacking, one could argue that, at present, no clear indication for screening exists.

However

- The gait disorders during hyponatremia are reversible after treatment - Interventions for hyponatremia are sometimes easy (thiazide, SSRI) - Hyponatremia could be a early sign of diseases (i.e cancer or adrenal failure) - Serum sodium is a readily available and affordable measurement.

Nat Rev Endocrinol 2011


Negri AL, Ayus JC, Rev Endocr Metab Disord 2017


• In an osteoporosis clinic, serum sodium could be included as part of general risk factor screening, similar to the approach used for vitamin D. For many patients in whom hyponatremia is detected, treatment is simple: thiazide diuretic or SSRI antidepressant medications, which are frequent causes of hyponatremia, can be discontinued or switched to another drug.

• In the ambulatory care setting, when patients are found to have chronic

hyponatremia (most commonly elderly individuals, often with SIADH), determination of BMD should be considered.

A PRAGMATIC APPROACH


GRAZIE PER L’ATTENZIONE

Unit for Bone Metabolism Diseases and Diabetes Lab of Endocrine and Metabolic Research

I. Chiodini Dpt. of Clinical Sciences & Community Health ......pathway, not only in cultured RAW...

Documents

Transcript of I. Chiodini Dpt. of Clinical Sciences & Community Health ......pathway, not only in cultured RAW...