Compendium of the most significant studies with reference to properties, intake, effects.

Zhang Y, Yang S, Zhou W, Fu H, Qian L, Miron RJ. Addition of a Synthetically Fabricated Osteoinductive Biphasic Calcium Phosphate Bone Graft to BMP2 Improves New Bone Formation. Clin Implant Dent Relat Res. 2016 Dec;18(6):1238-1247. doi: 10.1111/cid.12384.

Abstract. The aim of the present study was to assess whether the combination of Bone morphogenetic protein-2 with this novel Biphasic Calcium Phosphate (BCP) scaffold may additionally promote new bone regeneration.

O'Shea FD, McCarthy GM. Basic calcium phosphate deposition in the joint: a potential therapeutic target in osteoarthritis. Curr Opin Rheumatol. 2004 May;16(3):273-8. doi: 10.1097/00002281-200405000-00018. 

Abstract. Basic calcium phosphate crystals are responsible for a number of clinical syndromes. The study of basic calcium phosphate crystal deposition diseases has been hindered by a lack of readily available, accurate, diagnostic tests. Recent data have provided further understanding of the mechanisms by which basic calcium phosphate crystals induce inflammation and degeneration within the joint, as well as their potential role in other conditions such as cancer and atherosclerosis.

van Houdt CI, Preethanath RS, van Oirschot BA, Zwarts PH, Ulrich DJ, Anil S, Jansen JA, van den Beucken JJ. Toward accelerated bone regeneration by altering poly(D,L-lactic-co-glycolic) acid porogen content in calcium phosphate cement. J Biomed Mater Res A. 2016 Feb;104(2):483-92. doi: 10.1002/jbm.a.35584.

Abstract. This work aimed to compare in vitro degradation of dense PLGA microspheres and milled PLGA particles as porogens within CPC, considering that the manufacturing of milled PLGA is more cost-effective when compared with PLGA microspheres.

Kanzaki N, Treboux G, Onuma K, Tsutsumi S, Ito A. Calcium phosphate clusters. Biomaterials. 2001 Nov;22(21):2921-9. doi: 10.1016/s0142-9612(01)00039-4. 

Abstract. The potential energy surfaces associated with [Ca3(PO4)2n clusters are analyzed in detail using ab initio calculations for n ranging from one to four. Considering separated clusters, energy criteria favor the so-called Posner's cluster Ca9(PO4)6, which is the core of the actual structural model of amorphous calcium phosphate. This is rationalized through the existence of a distinct CaO bonding pattern in this cluster. Considering aggregated clusters as a possible model for amorphous calcium phosphate, the aggregation of Ca3(PO4)2 clusters appears as an alternative to Posner's hypothesis.

Suarez GMG, Merino-Ribas A, Haro MC, Freiría XB, Alemany NM, Bover B, Mendez IG, Paez CN, Devia CMC, Teran MP, Escuder PT, Martinez JC. Multi-organ involvement and intratubular calcium phosphate deposition in the kidney biopsy: what should we investigate? Eat Weight Disord. 2022 May 12. doi: 10.1007/s40519-022-01406-6. 

Abstract. Anorexia nervosa is frequently associated with alcohol use disorder. Both of them may adversely affect almost every body system, leading to worse clinical outcomes and high mortality risk. Nonetheless, there is little evidence interrelating anorexia nervosa, alcohol use disorder, and kidney failure.

Seifert A, Tylek T, Blum C, Hemmelmann N, Böttcher B, Gbureck U, Groll J. Calcium phosphate-based biomaterials trigger human macrophages to release extracellular traps. Biomaterials. 2022 Apr 23;285:121521. doi: 10.1016/j.biomaterials.2022.121521. 

Abstract. In this study, the response of human monocyte-derived macrophages in vitro to two different CaPs (α-tricalcium phosphate (α-TCP) and calcium deficient hydroxyapatite (CDHA)) as well as different pore structures was investigated.

Sebastian R, Paul ST, Azher U, Reddy D. Comparison of Remineralization Potential of Casein Phosphopeptide: Amorphous Calcium Phosphate, Nano-hydroxyapatite and Calcium Sucrose Phosphate on Artificial Enamel Lesions: An In Vitro Study. Int J Clin Pediatr Dent. 2022 Jan-Feb;15(1):69-73. doi: 10.5005/jp-journals-10005-2339.

Abstract. To evaluate and compare the remineralization potential of CPP-ACP, nano-hydroxyapatite, and calcium sucrose phosphate toothpaste on artificial enamel caries lesions by means of microhardness testing.

Yoshikawa Y, Tamura A, Tsuda S, Domae E, Zhang S, Yui N, Ikeo T, Yoshizawa T. Calcium phosphate-adsorbable and acid-degradable carboxylated polyrotaxane consisting of β-cyclodextrins suppresses osteoclast resorptive activity. Dent Mater J. 2022 May 19. doi: 10.4012/dmj.2021-331. 

Abstract. In this study, we investigated whether carboxymethyl carbamate-modified AdPRX (CMC-AdPRX) can be used for adsorption to calcium phosphate to treat bone diseases. 

Zakowiecki D, Hess T, Cal K, Mikolaszek B, Garbacz G, Haznar-Garbacz D. Directly compressible formulation of immediate release rosuvastatin calcium tablets stabilized with tribasic calcium phosphate. Pharm Dev Technol. 2022 May 8:1-10. doi: 10.1080/10837450.2022.2073370.

Abstract.  In the present study, a special grade of tribasic calcium phosphate excipient was used to chemically stabilize RSC in a directly compressible immediate release tablet formulation.

Köse N, Asfuroğlu ZM, Köse A, Şahintürk V, Gürbüz M, Doğan A. Silver ion-doped calcium phosphate-based bone-graft substitute eliminates chronic osteomyelitis: An experimental study in animals. J Orthop Res. 2021 Jul;39(7):1390-1401. doi: 10.1002/jor.24946.

Abstract. Despite the latest technologies and advances in microbiology and orthopedic surgery, chronic osteomyelitis is still a challenging disorder. Antibiotic resistance and bacterially induced bone destruction can have very serious consequences. We hypothesized that calcium phosphate-based bone graft substitution with silver ion doping would simultaneously treat bone infection and the bony defect in the chronic osteomyelitis.

Calcium phosphate  is a chemical compound, calcium salt of phosphoric acid.

The name defines the structure of the molecule:

• Calcium is a chemical element with the symbol Ca and the atomic number 20. It is a soft, gray alkaline metal, and is the fifth most abundant element by mass in the Earth’s crust.
• Phosphate refers to the phosphate ion (PO4 3-), a polyatomic ion with a charge of -3. Phosphates are important in biochemistry for their role in storing and transferring energy within cells.

The synthesis process takes place in several stages:

• Reactive sources of calcium and phosphate. In the first phase a reaction is expected between a source of calcium, such as calcium chloride and a source of phosphate, such as phosphoric acid or ammonium phosphate. This reaction produces calcium phosphate and a by-product, which could be ammonium chloride or water, depending on the phosphate source used.
• Precipitation. Calcium phosphate is precipitated out of the solution by adjusting the pH of the solution, often with a base such as sodium hydroxide. Calcium phosphate precipitates from the solution as a solid.
• Filtration and washing. The precipitated calcium phosphate is filtered from the solution and washed to remove any remaining impurities.
• Drying and grinding. The filtered calcium phosphate is dried and ground into a fine powder ready for use.

It appears as an odourless, tasteless, white powder that is stable in air. Insoluble in water and alcohol, it is easily soluble in dilute hydrochloric and nitric acids.

What it is used for and where

Food

It is used in food in a variety of applications and is labelled as E341 in the European food additives list as an acidity regulator.

• table salt
• seasonings
• food supplements
• bakery products

with antioxidant functions to prevent browning and is also used as a leavening agent.

As a food additive it is distinguished into:

• E341 (i) Calcium dihydrogen phosphate 
• E341 (ii) Calcium hydrogen phosphate 
• E341 (iii) Tricalcium phosphate

Medical

In medical applications it is used in bone treatment (1), in odontostomatology to protect tooth enamel (2) and to treat granulomas or periapical lesions (3) and to correct intrabony periodontal filling defects (4).

Another interesting technique is the subchondral injection of calcium phosphate, which consists of the application of a synthetic calcium-phosphate bone substitute into the bone marrow with the aim of improving the structural quality of the subchondral bone in order to achieve a modification of the bone to prevent the progression of arthritis and eventual bone collapse (5).

This article reviews the classification of calcinosis, a rheumatic disorder, with the mechanisms that may contribute to the pathogenesis of calcinosis and summarises the evidence evaluating non-pharmacological and pharmacological interventions for the treatment of calcinosis involving hydroxyapatite and calcium phosphate (6).

Bones are an important area of application for biomaterials and grafts to achieve healing from critical size defects are composed of calcium phosphates.

Safety

The Panel on Food Additives and Flavourings added to Food (FAF) provided a scientific opinion re-evaluating the safety of phosphates (E 338–341, E 343, E 450–452) as food additives. The Panel considered that (1). The Panel considered that phosphates have low acute oral toxicity and there is no concern regarding genotoxicity and carcinogenicity. The Panel calculated a group Acceptable Daily Intake (ADI) for phosphates expressed as phosphorus of 40 mg/kg body weight (bw) per day and concluded that this ADI is protective for the human population (7).

Animal nutrition

It increases body weight, reproduction rate and survival rate, shortens the fattening period and improves the defence against diseases such as chondropathy, dysentery and paralysis.

Cosmetics

Abrasive agent. It contains abrasive particles to remove stains or biofilm that accumulate on the stratum corneum or teeth. Baking soda, kieselguhr, silica and many others have abrasive properties. Peeling or exfoliating products used in dermatology or cosmetic applications contain abrasive agents in the form of synthetic microspheres, however these microspheres or abrasive particles are not biodegradable and create pollution in aquatic ecosystems.

Antiplaque agent. This ingredient has the property of preventing the onset of caries by fighting the bacteria responsible for acid corrosion of teeth.

Buffering agent. It is an iingredient that can bring an alkaline or acid solution to a certain pH level and prevent it from changing, in practice a pH stabiliser that can effectively resist instability and pH change.

Bulking agent. It regulates the water content, dilutes other solids, can increase the volume of a product for better flow, acts as a buffer against organic acids, helps to keep the pH of the mixture within a certain level.

Oral care agent. This ingredient can be placed in the oral cavity to improve and/or maintain oral hygiene and health, to prevent or improve a disorder of the teeth, gums, mucous membrane.

Viscosity control agent. It controls and adapts viscosity to the required level for optimal chemical and physical stability of the product and dosage in gels, suspensions, emulsions, solutions. 

The most relevant studies on this ingredient have been selected with a summary of their contents:

    Calcium phosphate studies

Typical commercial product characteristics Calcium phosphate

• Molecular Formula   CaHO₄P      Ca₃O₈P₂
• Molecular Weight   136.06
• Exact Mass   135.923843
• CAS   7757-93-9
• UNII    K4C08XP666
• EC Number   231-826-1   
• DSSTox Substance ID  DTXSID1049803
• IUPAC  tricalcium;diphosphate
• InChI=1S/3Ca.2H3O4P/c;;;2*1-5(2,3)4/h;;;2*(H3,1,2,3,4)/q3*+2;;/p-6 
• InChl Key      QORWJWZARLRLPR-UHFFFAOYSA-H
• SMILES   [O-]P(=O)([O-])[O-].[O-]P(=O)([O-])[O-].[Ca+2].[Ca+2].[Ca+2]
• MDL number  MFCD00010909
• PubChem Substance ID    24892950
• ChEBI  9679
• FEMA   3081   
• NACRES   NA.25   
• RTECS  

Synonyms

• Dicalcium phosphate
• Monohydrogen calcium phosphate
• dibasic calcium phosphate
• Calcium hydrogen phosphate
• Calcium phosphate, dibasic
• calcium,hydrogen phosphate

References____________________________________________________________

(1) Kawata M, Azuma K, Izawa H, Morimoto M, Saimoto H, Ifuku S. Biomineralization of calcium phosphate crystals on chitin nanofiber hydrogel for bone regeneration material. Carbohydr Polym. 2016 Jan 20;136:964-9. doi: 10.1016/j.carbpol.2015.10.009. 

(2) Shen P, Bagheri R, Walker GD, Yuan Y, Stanton DP, Reynolds C, Reynolds EC. Effect of calcium phosphate addition to fluoride containing dental varnishes on enamel demineralization. Aust Dent J. 2016 Sep;61(3):357-65. doi: 10.1111/adj.12385. 

(3) Mostafa AA, Zaazou MH, Chow LC, Mahmoud AA, Zaki DY, Basha M, Abdel Hamid MA, Khallaf ME, Sharaf NF, Hamdy TM. Injectable nanoamorphous calcium phosphate based in situ gel systems for the treatment of periapical lesions. Biomed Mater. 2015 Nov 6;10(6):065006. doi: 10.1088/1748-6041/10/6/065006. 

Abstract. Nonsurgical local treatment of a periapical lesion arising from trauma or bacterial infection is a promising innovative approach. The present study investigated the feasibility of developing injectable amorphous calcium phosphate nanoparticles (ACP NPs) and ACP NPs loaded with an anti-inflammatory drug; ibuprofen (IBU-ACP NPs) in the form of thermoreversible in situ gels to treat periapical lesions with the stimulation of bone formation. NPs were produced by a spray-drying technique. Different formulations of Poloxamer 407 were incorporated with/without the produced NPs to form injectable gels. A drug release study was carried out. A 3 month in vivo test on a dog model also was assessed. Results showed successful incorporation of the drug into the NPs of CP during spray drying. The particles had mean diameters varying from 100 to 200 nm with a narrow distribution. A drug release study demonstrated controlled IBU release from IBU-ACP NPs at a pH of 7.4 over 24 h. The gelation temperature of the injectable in situ gels based on Poloxamer 407 was measured to be 30 °C. After 3 months of implantation in dogs, the results clearly demonstrated that the inclusion of ACP NPs loaded with IBU showed high degrees of periapical bone healing and cementum layer deposition around the apical root tip.

(4) Stevanović M, Biočanin V, Nedkić M, Ignjatović N. Efficacy of nanocrystalline bone substitute biphasic calcium phosphate/poly-DL-lactide-co-glycolide for periodontal intrabony defects filling. Vojnosanit Pregl. 2015 Aug;72(8):689-95. doi: 10.2298/vsp140528049s. 

Abstract. Background/aim: Different bone substitutes have been used for filling and reparation of intrabony defects. The aim of this study was to compare nanocrystalline material, biphasic calcium phosphate poly-DL-lactide-co-glycolide (BCP/PLGA) with deproteinised bovine bone (DPBB) and beta-tricalcium phosphate (P-TCP) in the treatment of periodontal intrabony defects....Conclusion: Significant reductions of PPD and CEJ were registered in the group with BCP/PLGA when compared to the beta-TCP group.

 (5) Winge MI, Reikerås O, Røkkum M. Calcium phosphate bone cement: a possible alternative to autologous bone graft. A radiological and biomechanical comparison in rat tibial bone. Arch Orthop Trauma Surg. 2011 Aug;131(8):1035-41. doi: 10.1007/s00402-011-1271-z.

Abstract. Background: Donor site morbidity is a problem after autologous bone transplantation. An injectable CaP bone cement indicates properties similar to bone....Conclusion: The injectable CaP bone cement confirms its similarities to bone, implying that it can be used as an adjunct to secure bone fragments and as a possible alternative to autologous bone transplantation in clinical practice.

(6) Elahmar H, Feldman BM, Johnson SR. Management of calcinosis cutis in rheumatic diseases. J Rheumatol. 2022 May 15:jrheum.211393. doi: 10.3899/jrheum.211393.

(7) EFSA Panel on Food Additives and Flavourings (FAF); Younes M, Aquilina G, Castle L, Engel KH, Fowler P, Frutos Fernandez MJ, Fürst P, Gürtler R, Husøy T, Mennes W, Moldeus P, Oskarsson A, Shah R, Waalkens-Berendsen I, Wölfle D, Aggett P, Cupisti A, Fortes C, Kuhnle G, Lillegaard IT, Scotter M, Giarola A, Rincon A, Tard A, Gundert-Remy U. Re-evaluation of phosphoric acid-phosphates - di-, tri- and polyphosphates (E 338-341, E 343, E 450-452) as food additives and the safety of proposed extension of use. EFSA J. 2019 Jun 12;17(6):e05674. doi: 10.2903/j.efsa.2019.5674.