An Increase in Plasma Sodium Levels Is Associated With an Increase in Osteoblast Function in Chronic SIAD

Abstract

Context Hyponatremia is associated with increased risk for osteoporosis. Preclinical studies in untreated hyponatremia suggest osteoclast upregulation whereas a clinical study showed improved osteoblast fuction after hyponatremia normalization in hospitalized patients with syndrome of inappropriate antidiuresis (SIAD). Objective To investigate the impact of sodium increase on bone turnover, i.e. the ratio of the osteoblast marker procollagen type 1 N (P1NP) to the osteoclast marker C-telopeptide crosslink (CTX), in outpatients with chronic SIAD. Design Predefined secondary analysis of the two-month double-blind, crossover, placebo-controlled SANDx Trial (NCT03202667) performed from 12/2017 to 08/2021. Setting and Patients 11 outpatients with chronic SIAD, 6 females, median age 73 years. Intervention 4-week treatment with 25 mg empagliflozin or placebo. Main Outcome Measure Relationship between the change in bone formation index (BFI), defined as P1NP/CTX, and the change in plasma sodium levels. Results Changes in 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 (p = 0.184) and osteocalcin (p = 0.149). 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 µg/L in P1NP (95%-CI: 0.26, 2.62, p = 0.03). The effect of sodium change on bone markers was independent of the study medication empagliflozin. Conclusion An increase in plasma sodium levels in outpatients with chronic hyponatremia due to SIAD, even when mild, was associated with an increase in bone formation index (P1NP/CTX) triggered by an increase in P1NP, a surrogate marker of osteoblast function.

Extracellular sodium regulates fibroblast growth factor 23 (FGF23) formation

“…Moreover, the tonicity response to Fgf23 was not completely abolished in NFAT5 KO Osmoregulation and [Na + ] sensing mechanisms were mainly studied for cells in the hypothalamus (reviewed in 47 ). In line with studies from others 29,30,32 , we found that osteoblasts can sense osmotically relevant changes in [Na + ] and respond with an altered expression of several genes including Fgf23. Studies in RAW264.7 pre-osteoclastic cells showed increased osteoclast formation and resorptive activity in response to low [Na + ] concentration 20,21 .…”

“…On a mechanistic level, both high AVP 26,27 and low [Na+] levels 19,28 are postulated to promote osteoclastogenesis and inhibit osteoblastogenesis, leading to bone loss in hyponatremia. Correction of hyponatremia in hospitalized patients has a positive impact on osteoblast function 29,30 . On the other hand, high [Na + ] may also enhance bone loss through an increase in osteoclastic resorption 31 .…”

Halofuginone Inhibits Osteoclastogenesis and Enhances Osteoblastogenesis by Regulating Th17/Treg Cell Balance in Multiple Myeloma Mice with Bone Lesions

“…However, in another study researchers found that when the doses of halofuginone were less than 10 μg/ml, no effect of halofuginone was evident on osteoclast abundance or morphology, reflecting that halofuginone had no direct effect on osteoclast formation, but was mediated by other factors [ 21 ]. P1NP is a byproduct of type I collagen synthesis and an indicator of bone formation and osteoblast function [ 22 , 23 ], and its serum concentration can reflect osteoblast activity and differentiation directly. We found that both the ALP + osteoblasts and the serum P1NP concentration increased obviously in the HF group, suggesting that halofuginone enhanced osteoblastogenesis by increasing osteoblast formation and activity.…”