In this article, we briefly summarized evidence that cellular phosphate burden from phosphate toxicity is a pathophysiological determinant of cancer cell growth. Tumor cells express more phosphate cotransporters and store more inorganic phosphate than normal cells, and dysregulated phosphate homeostasis is associated with the genesis of various human tumors. High dietary phosphate consumption causes the growth of lung and skin tumors in experimental animal models. Additional studies show that excessive phosphate burden induces growth-promoting cell signaling, stimulates neovascularization, and is associated with chromosome instability and metastasis. Studies have also shown phosphate is a mitogenic factor that affects various tumor cell growth. Among epidemiological evidence linking phosphate and tumor formation, the Health Professionals Follow-Up Study found that high dietary phosphate levels were independently associated with lethal and high-grade prostate cancer. Further research is needed to determine how excessive dietary phosphate consumption influences initiation and promotion of tumorigenesis, and to elucidate prognostic benefits of reducing phosphate burden to decrease tumor cell growth and delay metastatic progression. The results of such studies could provide the basis for therapeutic modulation of phosphate metabolism for improved patient outcome.

Phosphate homeostasis is coordinated and regulated by complex cross-organ talk through delicate hormonal networks. Parathyroid hormone (PTH), secreted in response to low serum calcium, has an important role in maintaining phosphate homeostasis by influencing renal synthesis of 1,25-dihydroxyvitamin D, thereby increasing intestinal phosphate absorption. Moreover, PTH can increase phosphate efflux from bone and contribute to renal phosphate homeostasis through phosphaturic effects. In addition, PTH can induce skeletal synthesis of another potent phosphaturic hormone, fibroblast growth factor 23 (FGF23), which is able to inhibit renal tubular phosphate reabsorption, thereby increasing urinary phosphate excretion. FGF23 can also fine-tune vitamin D homeostasis by suppressing renal expression of 1-alpha hydroxylase (1a(OH)ase). This review briefly discusses how FGF23, by forming a bone-kidney axis, regulates phosphate homeostasis, and how its dysregulation can lead to phosphate toxicity that induces widespread tissue injury. We also provide evidence to explain how phosphate toxicity related to dietary phosphorus overload may facilitate incidence of noncommunicable diseases including kidney disease, cardiovascular disease, cancers and skeletal disorders.

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In testimony before U.S. Congress on March 11, 2020, members of the House Oversight and Reform Committee were informed that estimated mortality for the novel coronavirus was ten-times higher than for seasonal influenza. Additional evidence, however, suggests the validity of this estimation could benefit from vetting for biases and miscalculations. The main objective of this article is to critically appraise the coronavirus mortality estimation presented to Congress. Informational texts from the World Health Organization and the Centers for Disease Control and Prevention are compared with coronavirus mortality calculations in Congressional testimony. Results of this critical appraisal reveal information bias and selection bias in coronavirus mortality overestimation, most likely caused by misclassifying an influenza infection fatality rate as a case fatality rate. Public health lessons learned for future infectious disease pandemics include: safeguarding against research biases that may underestimate or overestimate an associated risk of disease and mortality; reassessing the ethics of fear-based public health campaigns; and providing full public disclosure of adverse effects from severe mitigation measures to contain viral transmission.

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Relative risk reduction and absolute risk reduction measures in the evaluation of clinical trial data are poorly understood by health professionals and the public. The absence of reported absolute risk reduction in COVID-19 vaccine clinical trials can lead to outcome reporting bias that affects the interpretation of vaccine efficacy. The present article uses clinical epidemiologic tools to critically appraise reports of efficacy in Pfzier/BioNTech and Moderna COVID-19 mRNA vaccine clinical trials. Based on data reported by the manufacturer for Pfzier/BioNTech vaccine BNT162b2, this critical appraisal shows: relative risk reduction, 95.1%; 95% CI, 90.0% to 97.6%; p = 0.016; absolute risk reduction, 0.7%; 95% CI, 0.59% to 0.83%; p < 0.000. For the Moderna vaccine mRNA-1273, the appraisal shows: relative risk reduction, 94.1%; 95% CI, 89.1% to 96.8%; p = 0.004; absolute risk reduction, 1.1%; 95% CI, 0.97% to 1.32%; p < 0.000. Unreported absolute risk reduction measures of 0.7% and 1.1% for the Pfzier/BioNTech and Moderna vaccines, respectively, are very much lower than the reported relative risk reduction measures. Reporting absolute risk reduction measures is essential to prevent outcome reporting bias in evaluation of COVID-19 vaccine efficacy.

Phosphate is an essential mineral component of the human body, and therefore, its dysregulation can affect the functionality of almost all the organ systems. Both organic and inorganic forms of phosphate are routinely consumed through meats, fish, eggs, milk/dairy products, and vegetables. The amount of total phosphate ingestion is significantly increased by the consumption of processed food and drinks in which phosphate metabolites are used as additives. Of clinical significance, phosphate additives are almost entirely absorbed in the intestine, whereas about 60 % is absorbed from naturally available sources [1]. Normal phosphate homeostasis is tightly controlled by numerous endocrine factors, including fibroblast growth factor 23 (FGF23), parathyroid hormone (PTH), vitamin D and klotho [2][3][4][5][6][7][8][9]. FGF23, through the activation of FGF receptors, acts as a counter regulatory hormone to suppress renal 1a-hydroxylase and activities of sodium-phosphate cotransporters (NaPi2a and NaPi2c) which influence systemic phosphate balance [7]; such receptor activation by FGF23 needs klotho, as a cofactor to generate downstream signaling events [10]. Moreover, PTH can induce FGF23 transcription in bone cells to influence systemic phosphate balance [11].In an average healthy 70 kg adult individual, the total body phosphorus content is around 700 g, more than 80 % of which is present in the bone and tooth (calcium-phosphate hydroxyapatite), about 9 % in the skeletal muscle, around 10 % in various internal organs, and less than 1 % in the extracellular fluid [12]. In general, serum inorganic phosphate is actively transported through the cellular membrane, often against a molecular concentration gradient and involving glucose metabolism. Type III sodium-phosphate cotransporters (SLC20 family; also called Pit-1 and Pit-2), alongside Type I (SLC17 family) and Type II (SLC34 family) are believed to be involved in cellular phosphate transport in various organs. Pit-1 and Pit-2 are mostly expressed on the basolateral membranes of the epithelial cells, where these transporters are likely to be involved in cellular phosphate transport. Although measuring extracellular serum phosphate is the gold standard to estimate the overall phosphate status of the body, the amount of intracellular phosphate distribution or phosphate storage or the amount of phosphate uptake is not taken into consideration in such traditional methods of serum measurement. Moreover, lack of public awareness of getting too much dietary phosphorus [13,14], which might not always be reflected by serum phosphate levels, is gradually becoming a public health concern as dietary phosphate burden from consumption of an unhealthy diet is linked to various non-communicable diseases and eventual mortality [15].

The regulation of phosphate homeostasis is biologically important because inorganic phosphorus performs many functions within the body. [15][16][17][18][19] Phosphate is a component of nucleic acids, DNA and RNA, and it is incorporated in the structure of phospholipids in cell membranes. As an intracellular anion, phosphate is involved in the activation and inactivation of enzymes and coenzymes. Phosphate also plays roles in cell signaling through phosphorylation, in energy metabolism as ATP, and in bone mineralization as a principal element within hydroxyapatite. Endocrine regulation of phosphate depends on a delicate balance among circulating factors like 1,25(OH) 2 D 3 (calcitriol, the active form of vitamin D), parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23). Dysregulation of these factors can induce phosphorus imbalances which can affect the functionality of almost every human system, including musculoskeletal and cardiovascular systems, ultimately leading to an increase in morbidity and mortality. Through the action of PTH, vitamin D, and FGF23, phosphate homeostasis is maintained by regulating the amount of phosphate absorbed in the intestines, reabsorbed in the kidney, and resorbed from bone (Fig. 31.1).