REVIEW ARTICLE 1.TASTE MASKING BONE IS NOT JUST ...2019/04/12 · REVIEW ARTICLE INTRODUCTION The...

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BONE IS NOT JUST CALCIUM AND VITAMIN D-A REVIEW OF ESSENTIAL NUTRIENTS REQUIRED FOR

BONE HEALTHSana Lodhi1, Saeeda Baig1, Danial Arshad2

1Department of Biochemistry, Ziauddin University, 2MediDent Clinics, Karachi.

REVIEW ARTICLE

INTRODUCTION

The emergence of new data on vitamins and minerals suggests that their potential benefits for the body are beyond than what is being anticipated for the past 100 years or so. The human body, besides having many vital organs, has 270 bones,1 many fuse during growth, leaving 206 separate bones in an adult2. Adult bones need constant maintenance and hence, undergo a continuous state of remodeling, which happens in a certain pattern by the two important cells osteoclasts and osteoblasts along with connective tissue blood vessels and nerves. Osteoclasts degrade the organic matrix, does the resorption of bone by removing the mineral content. Osteoblasts on the other hand, migrate to resorption site and synthesize and mineralize the new bone matrix through a process called coupling3,4. This process is based on series of metabolic reactions, and requires, besides calcium and vitamin D, a constant supply of many dietary nutrients including proteins, minerals like Mg, P, K,

Mn, Cu, Fe, Bo, Zn, and vitamins like A, K, C, and the B complex. Cortical bone has a network of capillaries, the intracortical canals links the periosteum and endosteum, it consists of transverse Volkmann canals and longitudinal Haversian canals5,6. A sufficient blood supply is essential for bone strength it transports oxygen, metabolic wastes, nutrients, minerals and oxygen required for mineralization5-7. During modeling the endothelial cells form a vascular channel for nutrient supply to enter from the growth plate region of cartilage and provide a site for new bone formation5,8. Blood vessels present at the bone remodeling site enable the coupling reaction9,10. The two principal components of bones are collagen and calcium phosphate that make up the individual bones of the human skeletal system. Information regarding the elements involved in bone formation was retrieved through studies published from 1990 to 2018 in PubMed, Medline and other authentic search engines available in the

University. The theme of this review is to highlight the individual roles of specific vitamins and minerals at the respective steps of bone formation.

DISCUSSION

Our skeletal system, in early years, is the most neglected part of the body till we reach the twilight zone. Then comes the recognition of the success story of this unsung hero in shaping, storing, protecting and producing various metabolites as well as enabling the movement of the body for work and play. Like the rest of the body, bone tissues constantly break down and regenerate. It is important to understand factors that have a great influence on bone formation to maintain a healthy skeletal system. Diet of all the factors remains utmost in this endeavor. Vitamins and minerals, the naturally occurring chemical compounds, are supreme in supporting bone modelling.

A series of events occur in the remodeling of bone. It begins with the activation followed by resorption carried out by the osteoclasts, then there is breakdown and removal of bone and eventually new bone is laid by the osteoblast cells. Later there is an inactive phase. In the process of remodeling, paracrine and endocrine factors have an effect on osteoblastic and osteoclastic activities11,12. Preosteoclasts formation is stimulated by monocytes/macrophages12. Preosteoclasts then fuse and become osteoclasts12,13. Preosteoclasts are present in abundance on the surface of periosteum, at active growth sites14,15.Runx2 is an essential transcription factor which initiates the differentiation of osteoblasts and forms preosteoblasts. Growth factors, like transforming

growth factor-beta (TGF-β) and insulin-like growth factor type 1 (IGF-1) contribute in the formation of new bone16,17. Formation and resorption of bone occurs independently.

Stimulators and Inhibitors of Bone ResorptionParathyroid hormone causes bone formation but can also resorb bone. It attaches to a receptor, PTH/PTHrP type 1 to activate signaling pathway, which includes the canonical Wnt-signaling pathway that has catabolic as well as anabolic effects18. Teriparatide is known for increasing cancellous and endocortical ossification, at sites which are actively remodeling bone. However it increases cortical porosity19. PTHrP 1 and its analog abaloparatide, binds to PTH/PTHrP 1 receptor, increases the markers of bone formation and resorpion, but not as much as teriparatide20,21.

Process of resorption is primarily inhibited by substances that decrease the bone turn over, such as denosumab, bisphosphonates, and selective estrogen receptor modulators (SERMs). Various humans and animals studies with osteopetrosis proved that reduction in resorption of bone does not always have an association with reduced bone formation if the osteoclasts remain together22-24. A protease Cathepsin K (CatK), found abundantly in osteoclasts plays a role in degrading bone’s organic matrix.

ROLE OF VITAMINS:Vitamins being crucial nutrients are essential to perform various biochemical and physiological functions. It is important to include vitamins in our diet. Vitamins play an integral role in the formation of bone be it water soluble such as B complex and vitamin C or fat soluble such as vitamins A, D, E and K.

PAKISTAN JOURNAL OF MEDICINE AND DENTISTRY 2019, VOL. 8 (02)

ABSTRACT

Bone formation is a constant procedure in which osteoblasts lay new bone and osteoclasts resorb it. Mineralization takes place at active bone formation sites where the extracellular matrix vesicles, the major sites of apatite mineral deposition, are present. Turnover of bone, which maintains its structure and integrity, has several events such as activation, resorption and osteogenesis by osteoblasts. The bone crystals proliferation depends on the presence of collagen, hormones, minerals and vitamins such as phosphorus, magnesium, calcium, zinc, fluoride, potassium, manganese, boron, copper, iron, calcium and a number of vitamins such as B,K,C,A,D, etc. Information regarding the elements involved in bone formation was retrieved through studies published up to 2017 in PubMed, Medline and other authentic search engines available in the University. This review highlights the individual roles of specific vitamins and minerals at the respective steps of bone formation, insufficiency at all particular stages result in various bone pathologies, leading to deficiency disorders, fractures and poor friable bones. Since the role of vitamin D and calcium is well established therefore these were not included in this review.

Keywords: Osteoblasts, Osteoclasts, Vitamins, Minerals, Osteogenesis, Collagen, RANK Ligand.

Corresponding Author: Dr. Sana LodhiDepartment of Biochemistry, Ziauddin University, Karachi.Email: [email protected] INTRODUCTION

Pharmaceutical dosage forms and drug delivery systems are designed by formulation scientists as well as by various pharmaceutical manufacturing companies so that the required amount of the medicament can be delivered to the patients in a safer, precise and effective manner. For this reason several challenges and strategies are adopted and faced during the development phase of such formulations to make them targeted, efficient and stable throughout the shelf life period of the drug product.1 Among all the drug delivery system presented in terms of oral solid dosage form tablets and capsules in the current era still have gained considerable importance and acceptance by the formulation scientists, physicians and the patients due to its numerous advantages which includes easy self-administration and cost effectiveness experienced by the patients.2 However the drug delivery through the tablet dosage is no doubt, associated with potential drawbacks which include difficulty for the older and pediatric patients to swallow (dysphagia), low fraction of drug available for absorption in the bloodstream due to first pass hepatic effect, and a slower therapeutic outcome in patients.3

DISCUSSION

FAST DISSOLVING TABLETSFast and rapid drug delivery to the site of action with minimum side effects has attracted pharmaceutical industries to formulate and designed a tablet dosage form that can dissolve, disintegrate in the mouth cavity or disperses in water as quickly as possible. Thus readily absorbs in the bloodstream.4 According to survey fifty percent of population belonging to the class of geriatric and pediatric population find difficult to swallow the tablet dosage form.5 So for this purpose fast dissolving tablets have been emerged as a newer concept, in novel drug delivery systems that offers not only an alternative to conventional tablet dosage form, but also provide better therapeutic outcome ,ultimate solution and a better option for the problem faced by the patients of such age group and diseases.6

APPROACHES FOR DEVELOPMENT OF FAST DISPERSIBLE TABLETS Following are the two approaches utilized:1. Mouth dissolving tablets2. Water dispersible tablets

1. Mouth Dissolving TabletsThis approach works by melting or disintegrating in the mouth cavity or by dissolving orally without the need of intake of water.7

2. Water Dissolving TabletsThis approach is designed and formulated in a way to disperse rapidly in water to form a homogenous dispersion.8

REASONS FOR FORMULATING FAST DISPERSIBLE TABLETS•Taste masking by the incorporation of various flavoring and sweetening agents.•Enhanced patient compliance due to acceptability by the patients.•Faster rate of disintegration in a matter of seconds.•Ease of manufacturing with low cost.•Offers the advantage of being stable due to change in humidity and temperature. 9

•Provides benefit in targeting pediatric and geriatric population to swallow both with and without the need of using water.10

POTENTIAL CANDIDATES FOR FAST DISSOLVING TABLETSFollowing are the ideal characteristics which should be incorporated in formulation development of fast dissolving tablets.•The drug should exhibit better solubility in both water and saliva as compared to others.•The fast dissolving tablet must cross, diffuse and should be able to enter by means of partioning into the epithelial lining of upper part of GIT with (log P value be greater than one, or preferably greater than two).•Must have shorter biological half-life and frequent dosing. •It should be able to permeate the tissue of oral mucosa. •Molecular weight of the drug must be moderate to smaller in size.11

FACTORS INFLUENCING FORMULATION DEVELOPMENT OF FAST DISSOLVING TABLETS•Physical and chemical properties of active ingredient.•Both the type and nature of active ingredient incorporated.•Method employed during manufacturing.12

•The physical and chemical properties of the excipients which play an important role and therefore should be evaluated before formulation design and manufacturing.•The design of formulation and the technique employed in manufacturing should be taken into consideration into order to avoid fluctuation in blood levels.

SALIENT FEATURES AND DEVELOPMENTAL CHALLENGES IN DEVELOPMENT OF FAST DISSOLVING TABLETS

1.TASTE MASKINGThe unpleasant or bitter taste of the drug is a critical factor as the drug after disintegration into fine particles or granules in the oral mucosa is exposed to the taste buds. Hence, taste is one of the key parameter taken into account in development phase of fast dissolving drug delivery system. It is difficult to mask the bitter taste by the incorporation of sweetening agents alone readily available in the market. Therefore, in the recent years advancement in the technology has led to make improvement in such situations using combination of sweeteners with encapsulation and utilizing the technique of coating and making granules.13, 14

2.MOISTURE SENSITIVITYVarious fast dissolving tablets are moisture sensitive and are unstable to maintain the desired characteristic features of the drug under conditions of optimum humidity and controlled temperature. Therefore, several strategies are taken into consideration such as addition of additives (water soluble) to accelerate the dissolving ability and also to enhance taste. Addition of these additives imparts a serious damaging affect therefore; incorporation of suitable desiccants besides taking precautionary steps can prevent the deleterious effect of the hazards associated with the environment.15, 16

3.MOUTH FEELFast dissolving tablets must not break into granules into the mouth cavity. Therefore, particle size in the smaller range is preferred for formulation development. In addition, the property of mouth feel can be achieved by the addition of cooling and flavoring agents that could result in enhanced patient compliance.17

4.MECHANICAL STRENGTH AND DISINTEGRATION TIME Since faster and quick disintegration activity with rapid onset of action has always been demanded by the patients. Several means in the past few decades were adopted to formulate it using different techniques like freeze drying, wet mass compression and molding that result in formation of highly porous mass.18, 19 During the formulation development binder is added to provide mechanical strength and several water soluble polymers like gelatin, dextran and maltodextrin incorporated to maintain the shape. Secondly, agents like sucrose and mannitol facilitates the disintegration activity of the matrix supporting mediator.20

5.TABLET SIZE The patient compliance is also dependent on the size of the tablet which in turn related to the patient comfort in intake of dosage form. Research reported that the size of the tablet easier for the patient to swallow is 7-8 mm while the size preferred

to handle is found to be larger 8 mm. Therefore, both parameters tablet size that encompasses both easy swallowing and easy manufacturing are so far, quite problematic to accomplish.21

METHODS

FAST DISSOLVING PRODUCT MANUFACTURING TECHNIQUES

1. DIRECT COMPRESSIONDirect compression is the most preferable, demanding and simplest technique employed to manufacture a solid oral dosage form. Minimum number of steps involved, low cost of equipment utilized and commonly used excipients are the topmost features in selection of tablet manufacturing by direct compression technique.22 The technique involves a two step process in which the active (API) and excipients is mixed together and compacted using tableting machine.23

2. SUBLIMATION Sublimation technique involves the formation of pores through the use of several volatile substances like thymol, camphor and menthol. The porous network of the matrix created results in quick water uptake which is due to the wicking action, hence faster rate of disintegration achieved.24, 25

3. MOULDING It is another method to manufacture tablet in which either heat or solvent is used. The advantage of this method is better taste masking and quicker breaking up of tablet into fine particles or granules. However, these features are enhanced when porous mass of such tablets is produced using various physically modified components utilized in the procedure. The porous network created in the tablet is one of the major steps in providing faster dissolution. However, several drawbacks associated using this technique is poor mechanical strength that results in difficulty in handling. 26, 27

5. FREEZE DRYINGFreeze drying is also known as “Lyophilization”. In this process the solvent (water) is removed from a solution or suspension form of a drug along with the carrier incorporated. Tablets manufacturing by freeze drying produces tablets of high porosity and therefore, offers faster dissolution and disintegration. The medicament is released immediately as soon as it is kept in the oral cavity. The process is carried out at a temperature not high enough so as to reverse the affect produce by heat on the drug product, which will eventually improve the stability of the product. However the major drawback of this technique is high cost involve and also the product manufacture through freeze

drying is difficult to maintain the optimum feature of humidity and temperature.28

6. MELT GRANULATIONIt is a process of manufacturing tablets in which powder mass is agglomerated using a binder that melts. The technique offers the advantage that no water or organic solvents is required .Since no drying step is involved, the process is less tedious, and therefore less energy than other granulation techniques are needed. It is a versatile technique to improve the dissolution profile of drugs.29

SUPERDISINTEGRANTS USED IN FAST DISSOLVING TABLETSDisintegrants play a pivotal role in facilitating the breaking up of a tablet into fine particles or granules when exposes to the medium (water). Hence, promote the water molecules to enter into the tablet and thus, mechanism of disintegration is achieved.30 The general mechanism of tablet disintegration is as follows.31

1. Wetting down of tablet.2. The liquid to be dissolved enters into the crevices or pores.3. The added disintegrant swells due to absorption of water.4. Due to swelling, tablet disintegrates into powder particles or granules.In order to produce robust tablets with desired properties of lesser disintegration and faster dissolution time particles of cohesive nature are required. The incorporated medicament must diffuse, dissolve and so a strong tablet resists dissolution. Tablet breaking agents added in the formulation to aid in the process of tablet disruption and fragmentation when exposes to water.32 Researchers has studied the effect, concentration and activity of disintegrants and superdisintegrants on disintegration time. According to Rudinic and Schwartz, The concentration of starch suggested is 5% but this concentration can be increased by up to 15% if a drug has to been quickly disintegrated.33 In other study Davies studied the affect of hydrophobic lubricant on the activity of disintegrant added.34

MECHANISM OF DISINTEGRANT ACTIVITY:

1. WATER WICKINGWicking through crospovidone is one of the effective mechanisms of disintegration and is defined as the ability of the disintegrant to penetrate water uptake into the tablet matrix resulting in the displacement of trapped air.35 However, porous tablets impart a significant effect in the disintegration pathway. The fluid enters into the crevices of the tablet matrix by means of capillary action and disrupts the interparticulate

bond through which the tablet breaks.36

2. SWELLINGSwelling is the mechanism of tablet deaggregation in which water uptake is facilitated in to the tablet matrix that causes disintegrants to swell and breaks.37 The porosity and packing fraction also imparts a significant impact on the disintegration behavior therefore, powder with poor porosity exhibits poor disintegration time.38

3. REPULSIONAccording to the theory based on the mechanism of particle repulsion tablet disintegration is also caused by particles that do not have the ability to swell. However, the tablet deaggregation mechanism depends on the forces of repulsion that exists between the powder particles. Hence researchers concluded that wicking is thought to be the primary mechanism of tablet breakup besides repulsion.39

4. PARTICLE DEFORMATIONDisintegrants during the compression phase of tableting under deformation and particles return to their precompression shape upon wetting with water. Hence the mechanism of tablet deaggregation is achieved as number of deformed particle increases.40

5. EFFERVESCENCESTablet disintegration by effervescence involves the expulsion of carbon dioxide gas when chemical reaction between citric and tartaric acid with bicarbonates and carbonates takes place. This favors the faster rate of dissolution with an added advantage of being good mouth feel.41

6. ENZYMATIC REACTION Human body has several enzymes. These Enzymes help to break the bonds that exist between the primary powder particles. Hence, facilitates in the deaggregation mechanism of tablets.42, 43

57

INTRODUCTION

The emergence of new data on vitamins and minerals suggests that their potential benefits for the body are beyond than what is being anticipated for the past 100 years or so. The human body, besides having many vital organs, has 270 bones,1 many fuse during growth, leaving 206 separate bones in an adult2. Adult bones need constant maintenance and hence, undergo a continuous state of remodeling, which happens in a certain pattern by the two important cells osteoclasts and osteoblasts along with connective tissue blood vessels and nerves. Osteoclasts degrade the organic matrix, does the resorption of bone by removing the mineral content. Osteoblasts on the other hand, migrate to resorption site and synthesize and mineralize the new bone matrix through a process called coupling3,4. This process is based on series of metabolic reactions, and requires, besides calcium and vitamin D, a constant supply of many dietary nutrients including proteins, minerals like Mg, P, K,

Mn, Cu, Fe, Bo, Zn, and vitamins like A, K, C, and the B complex. Cortical bone has a network of capillaries, the intracortical canals links the periosteum and endosteum, it consists of transverse Volkmann canals and longitudinal Haversian canals5,6. A sufficient blood supply is essential for bone strength it transports oxygen, metabolic wastes, nutrients, minerals and oxygen required for mineralization5-7. During modeling the endothelial cells form a vascular channel for nutrient supply to enter from the growth plate region of cartilage and provide a site for new bone formation5,8. Blood vessels present at the bone remodeling site enable the coupling reaction9,10. The two principal components of bones are collagen and calcium phosphate that make up the individual bones of the human skeletal system. Information regarding the elements involved in bone formation was retrieved through studies published from 1990 to 2018 in PubMed, Medline and other authentic search engines available in the

University. The theme of this review is to highlight the individual roles of specific vitamins and minerals at the respective steps of bone formation.

DISCUSSION

Our skeletal system, in early years, is the most neglected part of the body till we reach the twilight zone. Then comes the recognition of the success story of this unsung hero in shaping, storing, protecting and producing various metabolites as well as enabling the movement of the body for work and play. Like the rest of the body, bone tissues constantly break down and regenerate. It is important to understand factors that have a great influence on bone formation to maintain a healthy skeletal system. Diet of all the factors remains utmost in this endeavor. Vitamins and minerals, the naturally occurring chemical compounds, are supreme in supporting bone modelling.

A series of events occur in the remodeling of bone. It begins with the activation followed by resorption carried out by the osteoclasts, then there is breakdown and removal of bone and eventually new bone is laid by the osteoblast cells. Later there is an inactive phase. In the process of remodeling, paracrine and endocrine factors have an effect on osteoblastic and osteoclastic activities11,12. Preosteoclasts formation is stimulated by monocytes/macrophages12. Preosteoclasts then fuse and become osteoclasts12,13. Preosteoclasts are present in abundance on the surface of periosteum, at active growth sites14,15.Runx2 is an essential transcription factor which initiates the differentiation of osteoblasts and forms preosteoblasts. Growth factors, like transforming

growth factor-beta (TGF-β) and insulin-like growth factor type 1 (IGF-1) contribute in the formation of new bone16,17. Formation and resorption of bone occurs independently.

Stimulators and Inhibitors of Bone ResorptionParathyroid hormone causes bone formation but can also resorb bone. It attaches to a receptor, PTH/PTHrP type 1 to activate signaling pathway, which includes the canonical Wnt-signaling pathway that has catabolic as well as anabolic effects18. Teriparatide is known for increasing cancellous and endocortical ossification, at sites which are actively remodeling bone. However it increases cortical porosity19. PTHrP 1 and its analog abaloparatide, binds to PTH/PTHrP 1 receptor, increases the markers of bone formation and resorpion, but not as much as teriparatide20,21.

Process of resorption is primarily inhibited by substances that decrease the bone turn over, such as denosumab, bisphosphonates, and selective estrogen receptor modulators (SERMs). Various humans and animals studies with osteopetrosis proved that reduction in resorption of bone does not always have an association with reduced bone formation if the osteoclasts remain together22-24. A protease Cathepsin K (CatK), found abundantly in osteoclasts plays a role in degrading bone’s organic matrix.

ROLE OF VITAMINS:Vitamins being crucial nutrients are essential to perform various biochemical and physiological functions. It is important to include vitamins in our diet. Vitamins play an integral role in the formation of bone be it water soluble such as B complex and vitamin C or fat soluble such as vitamins A, D, E and K.

BONE IS NOT JUST CALCIUM AND VITAMIN D- A REVIEW OF ESSENTIAL NUTRIENTS REQUIRED FOR BONE HEALTH


INTRODUCTION


DISCUSSION

















METHODS


















58

SANA LODHI, SAEEDA BAIG, DANIAL ARSHAD


Vitamin C (Ascorbic acid):

Ascorbic acid, a water-soluble vitamin, is well known for its antioxidant activity, scavenging reactive oxygen species (ROS) and reactive nitrogen species (RNS). In the development of bone and cartilage, Ascorbic acid, plays a major role, being an important cofactor for prolyl lysyl hydroxylase.25-27 It is required for the differentiation of mesenchymal-derived cell types, including adipocytes28, osteoblasts29-32 myoblasts33,34, and chondrocytes35,36. It prevents the loss of osteoblast

differentiation markers (Osterix, osteocalcin, Runx2, BMP-2) and attenuates bone loss; as well as stimulates bone formation37.The growth factor effect is regulated through stimulation of collagen matrix by Vitamin C38 which is vital for the differentiation of osteoblasts for expression of osterix39.

The deficiency of vitamin C can compromise the proliferation of chondrocytes at the growth plate, the synthesis of matrix and can reduce osteoblasts 39,40.

B VITAMINS:The B vitamins function as cofactors for the enzymatic processes that are a part of energy-releasing pathways for carbohydrates, fats and proteins. Research reveals the importance of B vitamins in bone health with a focus on B6, B12 (cobalamin), B9 (folate) as cofactors for the enzymes required for DNA metabolism and the remethylation of homocysteine41-44. VITAMIN B3 (NIACIN):Vitamin B3 (Niacin) is required in the form of two active coenzymes, nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP). The major role of NAD is concerning DNA processing, cell differentiation, and mobilizing calcium, providing substrates vital for all these processes45. The role of NAD in bone is through its action in calcium signaling. From the intracellular stores calcium is released under its influence of NAD and binding and opening to a class of calcium channels called ryanodine receptors which are present in membranes of organelles46.

In addition to calcium signaling, NAD is a precursor of cyclic Adenosine diphosphate ribose46.

VITAMIN B6 (PYRIDOXINE):The role of B6 in the formation of bone is to provide a substrate for ALP (alkaline phosphatases)47 to facilitate the coupling of bone cells, osteoclasts and osteoblasts with the help of G6PD (glucose 6-phosphate dehydrogenase)48 hence B6 deficiency causes an increase in bone cavities, weakens bone, reduces trabecular number and thickness and decreases new bone formation49.

VITAMIN B9 FOLATE:Vitamin B9 folate is involved in the methylation of DNA, RNA, proteins and phospholipids providing methyl group in the nucleotide synthesis. Folic acid is also required in the metabolism of homocysteine hence, deficiency leads to increased serum levels of homocysteine resulting in hyperhomocysteinemia47 which may promote inflammatory processes via oxidative stress50. Also the accumulated amount of homocysteine51 binds to the collagen and deposits in the bone which activates osteoclastic processes decreasing bone strength and compromising osteoblastic activity52. Overall altering the biochemical and anatomical characteristics of bone.

VITAMIN B12 COBALAMIN:Cyanocobalamin (B12) is linked to the action of two enzymes, l-methylmalonyl-coenzyme A (CoA) mutase and methiononine synthase53. B12 is directly involved in proliferation of osteoblasts and activity of alkaline phosphatase54. The homocysteine to methionine metabolism described above involves methionine synthase which is a Vitamin B12 dependent enzyme. Thus to prevent osteoporosis and ensure proper bone health supplementation of B12 in addition to Folic acid is crucial.51

VITAMIN K:Vitamin K is essential for bone strength and it regulates bone remodeling. During the process of mineralization in bone formation synthesis of osteocalcin is Vitamin K dependent. It is hypotheses that vitamin K introduces calcium binding sites during mineralsation on the matrix vesicle. Matrix vesicle (MVs) is different from the plasma membrane possessing a distinctive composition of lipid and protein which helps in the facilitation of initialization of process of mineralization at the matrix front hence, calcium crystallizes here and bone structure is laid on. The function of vitamin K is to carboxylate Glutamate residues, introducing calcium binding sites during the posttranslational modification. Vitamin K along calcium and vitamin D increases bone health. Since, bioavailablity of vitamin K is better hence; its affects are long lasting, imparting greater bone strength55.

VITAMIN A:Most of the biological actions of vitamin A are controlled by all-trans-retinoic-acid. The bone resorptive effect is dependent on osteoclastogeneic cytokine RANKL56. Vitamin A increases mRNA and consequently expression of RANKL protein. The function of vitamin A is to bind to

osteoprotegrin (OPG), inhibiter of RANKL and consequently increase the expression of RANK/RANKL interaction between osteoblastic and osteoclastic cells. Toxicity of vitamin A may lead to an increase in osteoclastic activity resulting in bone fragility.

ROLE OF MINERALS:PHOSPHORUS:Phosphorus regulates proteins and produces energy by phosphorylation. In bones phosphorus is present in the form of Hydroxyapetite in combination with calcium and hydroxyl ions, forming a crystalline structure imparting strength to the skeleton. In order to build and maintain a strong bony structure Ca/P ratio between 1.67 and 1.5 is required. In case of calcium deficiency the hydroxyapatite has a structure solely occupied by phosphate or hydrogen phosphate, HPO4

2–, anions and this can result in toxicity.55

MAGNESIUM:Magnesium is required for the strength and firmness of bones. Magnesium stimulates the production of calcitonin from the thyroid gland which helps to regulate levels of calcium and phosphate in bones and blood. It is required to convert vitamin D into its active form. Magnesium deficiency can result in resistance of vitamin D.57 Alkaline phosphatases require magnesium for the formation of calcium crystals, hence low levels of magnesium will form abnormally shaped crystals. Bones act as a reservoir of magnesium. Calcium and magnesium work synergistically, so deficiency of even one of them will affect the metabolism of the other. If one is taking calcium but is deficient on magnesium then it will result in deposition of calcium in soft tissues.58

SILICA: Silica supplements tend to increase bone collagen by cross linking collagen strands, hence, strengthening connective tissue matrix. It has a direct affect on the rate of mineralization, especially when the levels of calcium are decreased in the body. Silica traces are seen at active sites of bone mineralization. It binds with Calcium, and initiates the process of calcification to maintain strong flexible bones.59

ZINC:Zinc is required to form a matrix of collagen proteins on which calcium phosphorus compound is laid which is required for mineralization of bone. Zinc is required to produce enzymes that help in diminishing and recycling residues of bone proteins. Zinc is present at bone repair sites, hence it helps in absorption of Calcium and bone healing59.

COPPER:Copper being a cofactor for many enzymes, such as Lysyl oxidase, by its activity in connective tissues, forms collagen and helps in giving mechanical strength to the bone The function of this enzyme is to introduce cross linking active sites in collagen and elastin during post translational modification by oxidation at some sites of the lysine and hydroxylysine amino acids60.

POTASSIUM: The protein rich foods on metabolism can lead to excessive production of endogenous acid which is mobilized by base from the skeleton and hence can be a contributor in decreasing in bone mass especially during the advancing age. Potassium bicarbonate has been found at low dose can help in neutralizing the endogenous acid, improving the balance between calcium/phosphorus, reducing osteoclastic activity and hence increasing osteoblasticity.61

STRONTIUM:Strontium has a high affinity for bone and is thought

to play a critical role in bone health. It tends to migrate to the sites where active remodeling is taking place and promotes mineralization of the bones and teeth. There are about 320 mg of strontium in the body, with 99% of this located in the bones and teeth. Strontium is capable of replacing a small proportion of calcium in the calcified crystals of bone and teeth. As it appears, strontium adds strength to these tissues, making them more resistant to breakdown. Strontium also appears to draw extra calcium into the bone.62

FLUORIDE:A trace element which has an effect on bone mineral, bone cells and bone architecture. Fluoride is substituted with the hydroxyl group in hydroxyapatite, forming fluorapatite. Fluoride causes retardation of mineralization and the mineral produced is then less prone to dissolution altered63-65. Toxicity of fluoride can inhibit the synthesis of type I collagen and decreases the cross linking of collagen. It has an influence on the proteoglycan structure66 and matrix metallo-proteinases67.

By researches it has been proved that an increase in the formation of fluoroapatite weakened the protein-hydroxyapatite interfaces

CONCLUSION

The major contributors of bone remodelling are vitamins and minerals discussed above. These predominantly help in the formation of collagen matrix on which bone is laid. Lack of awareness in Pakistan is a leading cause of Osteoporosis and other acquired and congenital bone diseases. Poor nutrition, sedentary lifestyles, low socioeconomic status together has an effect on bone health. The International Osteoporosis Foundation, in its Asia-Pacific Audit, now warns that by 2050, 87.2m people will be over 50 years of age, and vulnerable to osteoporosis.

REFERENCES

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