Serum Phosphate, BMI, and Body Composition of Middle-Aged and Older Adults: A Cross-Sectional Association Analysis and Bidirectional Mendelian Randomization Study.

BACKGROUND: Observational studies have reported associations between serum phosphate and BMI in specific clinical settings, but the nature of this relation in the general population is unclear. OBJECTIVES: The aim of this study was twofold: to investigate the association between serum phosphate and BMI and body composition, as well as to explore evidence of causality through a bidirectional one-sample Mendelian randomization (MR) in the population-based Rotterdam Study (RS). METHODS: Observational associations between phosphate (mg/dL) and BMI, lean mass, and fat percentage (fat%), estimated by DXA, were analyzed using multivariable regression models in 9202 participants aged 45-100 y from 3 RS cohorts. The role of serum leptin was examined in a subgroup of 1089 participants. For MR analyses, allele scores with 6 single-nucleotide polymorphisms (SNPs) for phosphate and 905 SNPs for BMI were constructed in 7983 participants. RESULTS: Phosphate was inversely associated with BMI in the total population (ß: -0.89; 95% CI: -1.17, -0.62), and stronger in women (ß: -1.92; 95% CI: -2.20, -1.65) than in men (ß: -0.37; 95% CI: -0.68, -0.06) (P-interaction < 0.05). Adjustment for leptin did not change results in men. In women, adjustment for leptin attenuated the association, but it was not abolished (ß: -0.94; 95% CI: -1.45, -0.42). Phosphate was inversely associated with fat%, but not with lean mass, in both sexes. MR analyses suggested a causal effect of BMI on serum phosphate (ß: -0.01; 95% CI: -0.02, 0.00) but not vice versa. CONCLUSIONS: Serum phosphate was inversely associated with BMI and fat% in a population-based study of middle-aged and older adults, with a stronger effect in women than in men. Adjusting for leptin attenuated this relation in women only. MR results suggest a causal effect of BMI on phosphate but not vice versa. An underlying sex dimorphism in phosphate homeostasis should be further explored.

Tumor-Induced Osteomalacia: A Systematic Clinical Review of 895 Cases.

Tumor-induced osteomalacia (TIO) is a rare and largely underdiagnosed paraneoplastic condition. Previous reviews often reported incomplete data on clinical aspects, diagnosis or prognosis. The aim of this study was to present a systematic clinical review of all published cases of TIO. A search was conducted in Pubmed, Embase, Web of Science from inception until April 23rd, 2020. We selected case reports and case series of patients diagnosed with TIO, with information on tumor localization and serum phosphate concentration. Two reviewers independently extracted data on biochemical and clinical characteristics including bone involvement, tumor localization and treatment. 468 articles with 895 unique TIO cases were included. Median age was 46 years (range 9 months-90 years) and 58.3% were males. Hypophosphatemia and inappropriately low or normal 1,25-dihydroxyvitamin D levels, characteristic for TIO, were present in 98% of cases. Median tumor size was 2.7 cm (range 0.5 to 25.0 cm). Serum fibroblast growth factor 23 was related to tumor size (r = 0.344, P < 0.001). In 32% of the cases the tumor was detected by physical examination. Data on bone phenotype confirmed skeletal involvement: 62% of cases with BMD data had a T-score of the lumbar spine ≤ - 2.5 (n = 61/99) and a fracture was reported in at least 39% of all cases (n = 346/895). Diagnostic delay was longer than 2 years in more than 80% of cases. 10% were reported to be malignant at histology. In conclusion, TIO is a debilitating disease characterized by a long diagnostic delay leading to metabolic disturbances and skeletal impairment. Increasing awareness of TIO should decrease its diagnostic delay and the clinical consequences.

Diuretic Use and Serum Phosphate: Rotterdam Study and UK Biobank.

Purpose: Hypophosphatemia (serum phosphate < 0.80 mmol/L) leads to musculoskeletal complaints. The most common drugs linked to hypophosphatemia are thiazide and loop diuretics, but studies in the general population are lacking. Our aim was to study associations between diuretic use and serum phosphate in the Rotterdam Study (RS), a population-based cohort study, with replication in UK Biobank (UKBB). Methods: Associations between thiazide and loop diuretic use and serum phosphate and odds of hypophosphatemia were analyzed with cross-sectional multivariate linear and logistic regression in participants without chronic kidney disease in the RS and UKBB. Analyses were adjusted for age, sex, and body mass index (BMI) and pooled in 3 RS cohorts with further adjustment for cohort and serum potassium, which was not available in UKBB. Results: Thiazide diuretics were associated with lower serum phosphate in both sexes. This association lost significance in RS females after adjustment for BMI and in males after adjustment for serum potassium. Thiazide diuretics increased odds of hypophosphatemia in females in both cohorts and in males in UKBB only. Loop diuretics were associated with lower serum phosphate in females but not males. Adjustment for BMI attenuated these associations. Associations between loop diuretics and increased odds of hypophosphatemia in females lost significance after BMI adjustment. Conclusion: Thiazides, but not loop diuretics, and increased BMI and decreased serum potassium should be considered as contributing factors in subjects with hypophosphatemia. Further studies are needed to replicate the findings and elucidate the potential role of hypokalemia as a mediator of this effect.

Thermal Ablation for Treating Tumor-induced Osteomalacia in a Patient With IV Phosphate Dependency.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome associated with tumors secreting fibroblast growth factor 23 that can be cured with complete surgical resection of the tumor. However, when these tumors are at difficult locations, less invasive modalities such as thermal ablation (TA) might be a good alternative. A 40-year-old woman was seen for a second opinion because of severe hypophosphatemia with complaints of fatigue, myalgia, and muscle weakness for which she needed IV phosphate for 15 to 18 hours per day in addition to oral alfacalcidol and phosphate. Initial laboratory results revealed hypophosphatemia (0.59 mmol/L [1.83 mg/dL]; reference range, 0.90-1.50 mmol/L [8.40-10.2 mg/dL]), increased fibroblast growth factor 23 levels (137 RU/mL; reference range, <125 RU/mL), and a reduced TmP-GFR (0.47 mmol/L; reference range, 0.8-1.4 mmol/L). Gallium-positron emission tomography/computed tomography (CT) showed moderately increased uptake at thoracic vertebra (Th) 8 and mildly increased uptake at Th7, suggestive of TIO. Complete tumor removal would have required resection of at least 1 vertebral body. Therefore, CT-guided TA was performed at Th8. No complications were observed, and in the months after, treatment with IV phosphate could be discontinued, indicating a satisfying result from the procedure. This extreme TIO case demonstrates that CT-guided TA can be an alternative to extensive or risky classical surgery.

Case Report: Unexplained Mild Hypophosphatemia and Very High Serum FGF23 Concentrations.

Fibroblast growth factor (FGF)23 is one of the major regulators of phosphate homeostasis. Hypophosphatemia can lead to muscle weakness, fatigue, and osteomalacia. In the setting of hypophosphatemia, serum FGF23 can be measured to differentiate between FGF23-mediated and non-FGF23-mediated renal phosphate wasting. C-terminal FGF23 (cFGF23) assays detect both cFGF23 and intact FGF23 (iFGF23). Circulating FGF23 is regulated by 1.25-dihydroxy-vitamin D, parathyroid hormone (PTH), serum phosphate, and serum calcium but also by, for example, iron status, inflammation, erythropoietin, and hypoxia-inducible-factor-1-α. We present the case of a 48-year-old woman with unexplained mild hypophosphatemia, very high cFGF23, and normal iFGF23. The patient proved to have an iron deficiency. Iron deficiency alters the iFGF23-to-cFGF23 ratio. After initiation of iron treatment, cFGF23 strongly decreased. This case report illustrates the limitation of cFGF23 assays and urges clinicians to be aware that cFGF23 concentrations do not necessarily reflect iFGF23 concentrations and that alternative causes for its elevation should be considered (eg, iron deficiency). © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

Sexual dimorphisms in serum calcium and phosphate concentrations in the Rotterdam Study.

Sex differences in serum phosphate and calcium have been reported but the exact nature and underlying regulatory mechanisms remain unclear. We aimed to compare calcium and phosphate concentrations between sexes, and explore potential covariates to elucidate underlying mechanisms of sex differences in a prospective, population-based cohort study. Pooled data of subjects > 45 years from three independent cohorts of the Rotterdam Study (RS) were used: RS-I-3 (n = 3623), RS-II-1 (n = 2394), RS-III-1 (n = 3241), with separate analyses from an additional time point of the first cohort RS-I-1 (n = 2688). Compared to men, women had significantly higher total serum calcium and phosphate concentrations which was not explained by BMI, kidney function nor smoking. Adjustment for serum estradiol diminished sex differences in serum calcium while adjustment for serum testosterone diminished sex differences in serum phosphate. Adjustment for vitamin D and alkaline phosphatase did not change the association between sex and calcium or phosphate in RS-I-1. In the sex-combined group, both serum calcium and phosphate decreased with age with a significant interaction for sex differences for serum calcium but not phosphate. In sex-stratified analyses, serum estradiol but not testosterone was inversely associated with serum calcium in both sexes. Serum estradiol was inversely associated with serum phosphate in both sexes to a similar degree, while serum testosterone was inversely associated with serum phosphate in both sexes with an apparent stronger effect in men than in women. Premenopausal women had lower serum phosphate compared to postmenopausal women. Serum testosterone was inversely associated with serum phosphate in postmenopausal women only. In conclusion, women > 45 years have higher serum calcium and phosphate concentrations compared to men of similar age, not explained by vitamin D or alkaline phosphatase concentrations. Serum estradiol but not testosterone was inversely associated with serum calcium while serum testosterone was inversely associated with serum phosphate in both sexes. Serum testosterone may in part explain sex differences in serum phosphate while estradiol could partly explain sex differences in serum calcium.

Genetic Evidence for a Causal Role of Serum Phosphate in Coronary Artery Calcification: The Rotterdam Study.

Background Hyperphosphatemia has been associated with coronary artery calcification (CAC) mostly in chronic kidney disease, but the association between phosphate levels within the normal phosphate range and CAC is unclear. Our objectives were to evaluate associations between phosphate levels and CAC among men and women from the general population and assess causality through Mendelian randomization. Methods and Results CAC, measured by electron-beam computed tomography, and serum phosphate levels were assessed in 1889 individuals from the RS (Rotterdam Study). Phenotypic associations were tested through linear models adjusted for age, body mass index, blood pressure, smoking, prevalent cardiovascular disease and diabetes, 25-hydroxyvitamin D, total calcium, C-reactive protein, glucose, and total cholesterol : high-density lipoprotein cholesterol ratio. Mendelian randomization was implemented through an allele score including 8 phosphate-related single-nucleotide polymorphisms. In phenotypic analyses, serum phosphate (per 1 SD) was associated with CAC with evidence for sex interaction (Pinteraction=0.003) (men ß, 0.44 [95% CI, 0.30-0.59]; P=3×10-9; n=878; women ß, 0.24 [95% CI, 0.08-0.40]; P=0.003; n=1011). Exclusion of hyperphosphatemia, chronic kidney disease (estimated glomerular filtration rate <60 mL/min per 1.73 m2) and prevalent cardiovascular disease yielded similar results. In Mendelian randomization analyses, instrumented phosphate was associated with CAC (total population ß, 0.93 [95% CI: 0.07-1.79]; P=0.034; n=1693), even after exclusion of hyperphosphatemia, chronic kidney disease and prevalent cardiovascular disease (total population ß, 1.23 [95% CI, 0.17-2.28]; P=0.023; n=1224). Conclusions Serum phosphate was associated with CAC in the general population with stronger effects in men. Mendelian randomization findings support a causal relation, also for serum phosphate and CAC in subjects without hyperphosphatemia, chronic kidney disease, and cardiovascular disease. Further research into underlying mechanisms of this association and sex differences is needed.

Cortisol and Phosphate Homeostasis: Cushing's Syndrome Is Associated With Reversible Hypophosphatemia.

Objectives: The influence of hypercortisolism on phosphate homeostasis is relatively unknown. A few previous studies have reported on patients with Cushing's syndrome (CS) with hypophosphatemia in whom serum phosphate normalized after initiation of treatment for CS. We aimed to investigate the prevalence of hypophosphatemia in CS, the association between the degree of hypercortisolism and serum phosphate and the change in serum phosphate after remission of CS. We compared the prevalence of hypophosphatemia in CS with the prevalence in the population-based Rotterdam Study (RS). Methods: Patients diagnosed with CS and treated at the Department of Endocrinology of Erasmus MC in the period of 2002-2020 were included and data was collected on age at diagnosis, sex, serum phosphate, calcium and potassium levels, kidney function and BMI. Using multivariate linear regression, we analyzed the association between 24h urinary free cortisol excretion (UFC) and serum phosphate. Changes in serum phosphate and covariates were tested with a repeated measurement ANOVA, using mean levels of laboratory values for the periods before remission, and 0-14 days and 15-180 days after remission. Results: Hypophosphatemia before treatment was present in 16% of the 99 CS patients with data on serum phosphate, 24h UFC and covariates. In comparison, the prevalence of hypophosphatemia in RS was 2.0-4.2%. Linear regression showed a negative association between the level of UFC and serum phosphate at diagnosis, which remained significant after adjusting for covariates [ß -0.002 (95%CI -0.004; -0.0004), p=0.021]. A subset of 24 patients had additional phosphate measurements at 0-14 days and 15-180 days after remission. In this subgroup, serum phosphate significantly increased from 1.03 ± 0.17 mmol/L prior to remission to 1.22 ± 0.25 mmol/L 15-180 days after remission (p = 0.008). BMI decreased after remission [-1.1 kg/m2, (95%CI -2.09 to -0.07), p=0.037]. Other covariates did not show an equivalent change over time. Conclusion: In this retrospective study, we found that 16% of patients with CS had hypophosphatemia. Moreover, serum phosphate was related to the level of cortisoluria and increased after remission of CS. Potential underlying mechanisms related to urinary phosphate excretion and possibly involving FGF23, BMI and parathyroid hormone levels should be further explored.