Increased bone mineral density (BMD), hypocalciuria and hypophosphatemia have been reported in hypertensive patients with chronic thiazide treatment and in Gitelman syndrome; a salt-wasting hypotensive disease caused by reduced renal thiazide-sensitive Na+-Cl- cotransporter (NCC) activity. SPAK phosphorylates NCC increasing activity and our SPAK T243A loss-of-function knock-in (SPAK-KI) mice recapitulate the human Gitelman syndrome by reducing phospho-NCC. We hypothesised that SPAK-KI mice would have increased BMD. Earlier work in our lab showed hypophosphatemia is specific to male SPAK-KI (Table 1). Therefore, our aim was to investigate potential sex differences in BMD. Whole body (excluding skull) areal BMD of age matched SPAK-KI and wildtype (WT) C57Bl/6 littermates were measured by dual energy x-ray absorptiometry in vivo under terminal anaesthesia by intraperitoneal injection of ketamine [400mg/kg BW] and xylazine [40mg/kg BW], with death later confirmed by exsanguination and cervical dislocation. In a subset of mice, tibiae were excised and the mid- and proximal-shafts used as markers of cortical and trabecular bone, respectively. Compared to WT males (n=11), SPAK-KI (n=11) had significantly higher whole body [3.7%] and cortical BMDs [11.9%] (p<0.05), but trabecular BMD [7.9%] was not significant. No significant BMD differences were found between WT (n=12) and SPAK-KI (n=10) females (Fig 1). Data are presented as means with SEM, data was analysed by two-way ANOVA with bonferroni post-hoc test.In conclusion, only SPAK-KI males have increased BMD with hypophosphatemia. We postulate this could be a compensatory response to hypocalciuria, maintaining the Ca2+ X PO43- product to prevent calciphylaxis. In light of these results, the implications of sex differences should be investigated in Gitelman syndrome and chronic thiazide users