Sex Differences in Phosphate Homeostasis: Females Excrete More Phosphate and Calcium After an Oral Phosphate Challenge

Abstract

Context Dietary consumption of phosphate is increasing, and elevated serum phosphate is associated with increased cardiovascular disease (CVD) risk. Sex differences in phosphate homeostasis and response to changes in dietary phosphate intake, which are not captured by clinically measured analytes, may contribute to differences in CVD presentation and bone disease. Objective To assess sex differences in acute phosphate homeostasis in response to a single oral phosphate challenge. Design Cross-sectional. Setting General community. Participants : 78 participants (40-76y) with measured GFR >60 mL/min/1.73m2 and no clinically diagnosed CVD and 14 young healthy adults. Main Outcome Measures To elucidate subtle alterations in phosphate homeostasis, we employ an acute challenge whereby the hormonal response, circulating mineral levels, and urinary excretion are assessed following an oral challenge of phosphate. Results Although both males and females had similar changes in circulating phosphate, calcium, and parathyroid hormone in response to the challenge, females excreted ∼1.9x more phosphate and ∼2.7x more calcium than males, despite not consuming calcium. These sex differences were recapitulated in healthy young adults. This excretion response did not correlate to age, serum phosphate, or estradiol levels. The females with greater excretion of phosphate had higher levels of bone resorption markers compared to formation markers. Conclusions Taken together, these data identify sex differences in acute phosphate homeostasis, specifically that females may mobilize and excrete endogenous sources of calcium and phosphate in response to oral phosphate compared to males. While high levels of dietary phosphate negatively impact bone, our results suggest that females may incur more risk from these diets.

Urinary phosphate is associated with cardiovascular disease incidence

“…Furthermore, these previous studies have been carried out in men, whereas our cohort includes women. A greater excretion of P in females than in males in response to oral challenge of P has been reported [53], but any sex‐specific differences in P‐homeostasis or susceptibility to large intakes of P in relation CVD risk can only be speculated.…”

Obesity attenuates acute phosphate excretion after an oral challenge in females: A sex‐specific effect of obesity on phosphate handling

“…We previously demonstrated in this cohort that a higher ratio of bone resorption to bone formation biomarkers was associated with greater de novo phosphate excretion in female participants, suggesting that some excreted minerals may have originated from bone. 7 In response to dietary phosphate, females with obesity may have a protective skeletal advantage due to reduced mobilization of endogenous calcium. This is consistent with the documented association of weight loss with lower bone mass and increased bone resorption in postmenopausal females.…”

“…Methods of measurement within this study cohort have been previously reported. 7 Jaya K. Sharma and Mandy E. Turner are shared primary contribtors.…”

“…We recently reported that females excrete more urinary calcium and phosphate than males following an oral phosphate challenge. 7 Thus, there is a need to examine obesity-related alterations in phosphate handling separately by sex.…”

“…This challenge facilitates more sensitive detection of differences in phosphate homeostasis and handling than static clinical measurements. 7…”