Endocrine Abstracts

Introduction: Hyponatremia is the most common electrolyte disorder encountered in clinical practice and is associated with increased mortality and morbidity, including an increased risk for osteoporosis and fragility fractures. Preclinical studies suggest osteoclast upregulation whereas a clinical study showed improved osteoblast fuction after hyponatremia normalization in hospitalized patients with SIAD.

Methods: This is a secondary analysis of a double-blind, crossover, placebo-controlled trial investigating the effect of 4-week treatment with empagliflozin 25mg/day as compared to placebo in outpatients with chronic SIAD (SANDx Trial, NCT03202667). The primary objective was to investigate the relationship between the change in bone formation index (BFI), defined as PINP/CTX, and the change in plasma sodium levels. Secondary objectives included the relationship between the change in the osteoblasts markers procollagen type 1 N (P1NP) and osteocalcin and the osteoclasts markers C-telopeptide crosslink (CTX), and the change in plasma sodium levels over the treatment periods. Linear mixed models were built with the bone markers as dependent variables, patients as random-effect and the following fixed-effects: week of treatment, serum cortisol, 25-OH vitamin D and bone marker concentration at baseline, age, gender and smoking status. Spearman correlation coefficients between bone markers and sodium levels were calculated.

Results: Six out of the 11 outpatients with a chronic SIAD were female (median [IQR] age 73 years [66, 78]). A sodium increase of 1 mmol/l was associated with an increase of 5.21 in BFI (95%-CI: 1.41, 9.00, P=0.013) and with an increase of 1.48 ug/l in P1NP (95%-CI: 0.26, 2.62, P=0.03). Plasma sodium concentration was not associated with a change in osteocalcin (β = 0.32; 95%-CI: -0.09, 0.72, P=0.18), nor with a change in CTX (β = 0.003; 95%-CI: -0.008, 0.014, P=0.324). The effect of sodium on bone markers was independent from empagliflozin. Changes in plasma sodium were positively correlated with changes in BFI and P1NP (BFI:ρ = 0.55, P<0.001; P1NP:ρ = 0.45, P=0.004) but not with CTX and osteocalcin (CTX:ρ = -0.21, P=0.184; Osteocalcin:ρ = 0.34, P=0.149).

Conclusion: An increase in plasma sodium levels in outpatients with chronic SIAD was associated with an increase in bone formation index (P1NP/CTX), which was triggered by an increase in the osteoblast marker P1NP. This supports the importance of treating hyponatremia, particularly in older adults in whom chronic hyponatremia is also associated with falls.