The global burden of periodontal disease, which accounts for the majority of the 442 billion USD spent on oral disease costs, share risk factors, and social determinants with other non-communicable diseases such as diabetes, heart disease, and cancer [1]. Recent studies investigating the link between periodontal disease and various cancers include meta-analyses of periodontal disease and cancer ^[2][3][2,3], studies of periodontal disease and cancer in postmenopausal women ^[4][5][4,5], in male non-smokers [6], and studies and meta-analyses of periodontal disease linked to specific cancers including breast cancer ^[7][8][7,8], pancreatic cancer ^[9][10][9,10], oral cancer ^[11][12][11,12], colorectal cancer ^[13][14][13,14], lymphoma ^[14][15][14,15], head and neck cancer [16], lung cancer ^[17][18][17,18], prostate cancer [19], and gastric cancer [20]. To the author’s knowledge, no findings from major studies published within the last five years have failed to support an association of periodontal disease with at least some type of cancer risk. Discrepancies between studies regarding specific cancers may be accounted for by the study design, population studied, and method used to measure periodontal disease [5].

2. Phosphate Toxicity as a Global Health Burden

Phosphorus, an essential dietary micronutrient, is ingested as phosphate in food and food additives. The highest amount of phosphate within the body is stored in bone as calcium phosphate. Levels of serum phosphate are regulated through a hormonal network, involving the kidneys, parathyroid glands, intestines, and the skeletal system [21]. Bioactive vitamin D, 1,25(OH)₂D₃, increases intestinal absorption of dietary phosphate, mainly through enhanced expression of sodium-phosphate 2b cotransporters. Fibroblast growth factor 23 (FGF23) is produced within osteocytes and osteoblasts of bone. Working in conjunction with its co-factor, Klotho, FGF23 lowers serum phosphate levels, and increases urinary phosphate excretion by suppressing reabsorption through action of sodium-phosphate cotransporters in the kidneys. Phosphorus renal reabsorption is also decreased by parathyroid hormone (PTH). If phosphate is dysregulated due to kidney burden and excessive dietary phosphate intake, serum phosphate levels may rise (hyperphosphatemia) and excessive phosphate may be sequestered in cellular tissue producing a pathological condition called phosphate toxicity. Phosphate toxicity is emerging as a global health concern as average amounts of dietary phosphate intake increase to approximately double the Recommended Dietary Allowance of 700 mg per day for an adult [22]. An excessive amount of phosphate stored in the body tissue may not always correlate with serum levels. It is possible that phosphate toxicity may be present in the body cells even in normophosphatemia, disturbing the function of almost every system in the body, including the muscular, skeletal, and vascular systems, and increasing morbidity and mortality [23]. Genetic evidence from animal experiments shows that phosphate toxicity may also accelerate mammalian aging [24], and phosphate toxicity is associated with tumorigenesis [25].

3. Dysregulated Phosphate Metabolism and Cancer

Evidence supporting the role of dysregulated phosphate metabolism and phosphate toxicity in tumorigenesis has been detailed elsewhere ^[26][27][26,27]; a very brief summary of that evidence with important relevance to periodontal disease is presented here. Cancer cells express more phosphate cotransporters within their cell membranes than normal cells [28], which allow cancer cells to absorb and retain greater amounts of phosphate from the tumor microenvironment. Solid tumors have filopodia and lamellipodia that extend cancer cell membranes throughout the tumor microenvironment [29]. Phosphorus is a limiting factor in biological growth [30] and is the least abundantly supplied element in the formation of nucleic acids DNA and RNA. The sequestration of dysregulated amounts of phosphorus in cancer cells is associated with additional biosynthesis of ribosomal RNA [31], which increases protein synthesis necessary for cancer cell growth and tumorigenesis. Of relevance, detection of the overexpression of circulating microRNA fragments associated with dysregulated RNA biogenesis has potential as a cancer biomarker [32]. While serum phosphorus levels are not always a reliable indicator of phosphate stored in the body, a study of cancer patients found that they had abnormally higher serum phosphate levels compared to control patients [33]. The Health Professionals Follow-Up Study found that high-grade prostate cancer was associated with high dietary phosphate levels [34]. High dietary phosphorus fed to experimental animals caused skin cancer [35] and lung tumors [36]. Of relevance, experimental studies showing causative effects of cancer from feeding the milk protein casein [37] may not have controlled for high levels of phosphorus within casein, which is classified as a phosphoprotein [38]. Other studies have shown that high amounts of phosphate stimulate tumor neovascularization [39] and cell signaling in cancer growth [40], and are associated with chromosome instability [41] and metastasis [42]. Phosphate toxicity also contributes to systemic inflammation and malnutrition [43], which is seen in terminally ill cancer patients with cachexia.

4. Periodontal Disease

The periodontium functions to connect teeth to bone; its structures consist of the cementum, periodontal ligament, gingiva, and alveolar bone. Periodontal disease is the most common cause of adult tooth loss [44]. Many mediators of inflammation in periodontal disease are associated with cancer risk, such as C-reactive protein (CRP), Matrix metalloprotenases (MMP), Tumor Necrosis Factor (TNF), and Interluekin (IL) [45]. Inflammation within the periodontium may begin as gingivitis and eventually progress to periodontitis, which is usually associated with the accumulation of dental plaque or calculus. Dental calculus is formed supragingvally and subgingivally when biofilms rich in bacteria are mineralized with various crystals of calcium phosphate, including octacalcium phosphate = Ca₄H(PO₄)₃ · 2H₂O, brushite = CaH(PO₄) · 2H₂O, hydroxyapatite = Ca₅(PO₄)₃(OH), and whitlockite that contains a small amount of magnesium and other elements = β-Ca₃(PO₄)₂ [46]. While growth of bacteria in the oral microbiota is associated with periodontal disease, there is currently insufficient evidence to either support or exclude a causative role of bacterial invasion in the etiology of periodontal disease [47]. As an alternative explanation for the development of periodontal disease and its association with cancer, Figure 1 in this peresearchspective article shows that excessive dietary phosphate and renal burden may increase the risk for dysregulated phosphate metabolism. It is hypothesized that this systemic metabolic pathology could mediate the association of tumorigenesis with periodontal disease through separate causal pathways involving phosphate toxicity and systemic chronic kidney disease-mineral and bone disorder (CKD-MBD), respectively.

5. Chronic Kidney Disease-Mineral and Bone Disorder

Phosphate metabolism is often dysregulated in chronic kidney disease (CKD), and hyperphosphatemia contributes to patient morbidity and mortality [48]. CKD is often comorbid with cancer [49], and an association of periodontal disease with CKD has been confirmed in observational studies ^[50][51][52][50,51,52]. As in cancer, it is plausible that the association of periodontal disease with CKD also involves dysregulated phosphate and calcium metabolism, seen in systemic CKD-MBD [53]. In addition to endocrine disturbances in the metabolism of ions and hormones associated with bone, characterization of chronic kidney disease-mineral and bone disorder (CKD-MBD) includes abnormalities in bone mineralization, bone growth, and bone turnover. Jaw bones affected with CKD-MBD increase the risk of bone loss in periodontitis [54]. While severity of periodontal disease was found to increase with stages of CKD, serum albumin levels declined as periodontal disease severity increased [55]. Of relevance, increasing hyperphosphatemia in CKD is also associated with declining serum albumin levels [56], implying that hyperphosphatemia may also be positively associated with periodontal disease severity. It has been observed that dental calculus formation appears to be similar to ectopic calcification such as that which occurs in kidney stone formation [57], and an association has been found between calculus formation and renal calculi [58]. Of relevance, ectopic calcification, including calcification of the vascular system, is associated with dysregulated phosphate metabolism and hyperphosphatemia [27]. Hyperphosphatemia is a common condition in dialysis patients [59], and dialysis patients were found to have a higher rate of dental calculus formation compared to healthy controls [60], further implying a role for high serum phosphate levels in calculus formation. Calculus that formed in closer proximity to salivary gland ducts was also found to contain more calcium and phosphate than calculus in other oral locations [46]. Increased phosphate and calcium in saliva has been associated with higher risk for inflammation of the periodontium [61], and high levels of phosphorus have been linked to systemic inflammation [43], which is often present in periodontal disease and cancer. Of relevance, detection of ribose nucleic acids in saliva is used in oral cancer diagnosis [62], and as previously mentioned, phosphorus is a key element in the formation of nucleic acids detected in circulating microRNA [32]. Furthermore, increased periodontal risk has been associated with carotid artery calcifications [63] and increased aortic arch plaque thickness [64], which may be related to vascular ectopic calcification caused by elevated serum phosphate associated with periodontal disease.