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Vitamin D And Its Role In Osteoporosis Biology

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    Osteoporosis is a bone disease characterized by low bone mass and impairment of bone tissue ensuing in compromised bone strength and addition in hazard of break, peculiarly of the hip, spinal column and carpus. In grownups, a normal procedure called reabsorption takes topographic point where there is a day-to-day remotion of little sums of bone mineral, which must be balanced by an equal deposition of new mineral if bone strength is to be preserved. When this equilibrium tips toward inordinate reabsorption, our castanetss weaken ( osteopenia ) and over clip can go brickle and prone to break ( osteoporosis ) ( Sipos, Pietschmann, Rauner, Kerschan-Schindl, & A ; Patsch, 2009 ) . This continual reabsorption and redeposition of bone mineral, or bone remodeling, is closely tied to the pathophysiology of osteoporosis. Osteoporosis can be classified as primary and secondary. Primary osteoporosis is defined as the loss of bone mass related to the ageing procedure, including estrogen lack due to menopause and secondary osteoporosis is attributed to concomitant diseases such as celiac disease, haemophilia, nephritic disease or medicines such as glucocorticoids, decoagulants, chemotherapeutic drugs, etc ( Sipos et al. , 2009 ) .

    Epidemiology of Osteoporosis

    As the population ages, Osteoporosis continues to be a major public wellness issue. Currently it is estimated that over 200 million people worldwide suffer from this disease. Today, there are about 2 million Canadians ( one in four adult females and one in eight work forces over the age of 50 ) who suffer from Osteoporosis ( Rosen & A ; Drezner, 2010 ) . From a fiscal point of view, the cost of handling Osteoporosis is estimated to be $ 1.9 billion each twelvemonth in Canada entirely where long term, infirmary and chronic attention history for the bulk of these costs ( Osteoporosis Canada, 2011 ) . Given the increasing proportion of older people in the population, these costs will probably lift.

    Pathophysiology of Osteoporosis

    The long castanetss ( e.g. thighbone, humerus ) are cannular in form, with a strong outer shell- the “ cortical bed ” , environing a softer, spongier nucleus called “ trabeculate ” bone ( Kanis et al. , 2002 ) . The combination of these two types makes these castanetss strong and light, but flexible plenty to absorb the emphasis from high impact exercisings without interrupting. The vertebrae are likewise constructed, with a thick cortical bed environing sheets of trabeculate bone. The balance between bone reabsorption and bone deposition is determined by the activities of two rule cell types, “ osteoclasts ” and “ bone-forming cells ” . Osteoclasts contain extremely active ion channels in the cell membrane that pump protons into the extracellular infinite, therefore take downing the pH in their ain microenvironment, and finally dissolves the bone mineral ( Kanis et al. , 2002 ) . Osteoblasts nevertheless are able to put down new bone mineral. The balance between the activities of these two cell types governs whether bone is made, maintained, or lost. Typically, in the bone reconstructing rhythm, osteoclasts are activated foremost, taking to cram reabsorption followed by a brief “ reversal ” stage, during which the reabsorption “ cavity ” is occupied by bone-forming cells precursors. Bone formation, so begins as progressive moving ridges of bone-forming cells signifier and lay down fresh bone matrix ( Bartl & A ; Bartl, 2011 ) . Hormones play the function of being the most important modulators of bone formation. It is good established that estrogen, parathyroid endocrine, and testosterone are indispensable for optimum bone development and care ( Bartl & A ; Bartl, 2011 ) . Taking these endocrines in factor along with the osteoblasts/osteoclasts equilibrium, if the net bone loss is much more important than net bone addition, osteoporosis develops.

    Diagnosing Osteoporosis

    Diagnosing osteoporosis remains a serious challenge because of the deficiency of symptoms in the absence of breaks, which has resulted in suboptimal degree of diagnosing, intervention and unnecessarily high rates of breaks. Medical history that is positive for hazard factors should motivate farther probes to name osteoporosis by mensurating bone mineral denseness utilizing dual-energy x-ray absorptiometry ( DXA ) . Recommendations from the 2010 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis in Canada provinces that the recommended elements in the History and Physical Examination should place future breaks and autumn hazards such as anterior breakability breaks, parental hip break, glucocorticoid usage, current smoke, high intoxicant consumption, arthritic arthritis, and inquire about falls in the old 12 months, pace and balance, accurate tallness and weight measurings ( Bartl & A ; Bartl, 2011 ) . Other hazard factors that have been associated with osteoporosis include: breast-fed babies, older grownups ( & gt ; 65 ) , corpulent, limited Sun exposure, dark-skin, fat malabsorption issues, Caucasic race, big history of breaks, and hapless seeing.

    Treatment and Management of Osteoporosis

    Traditionally, the pillar of the intervention of Osteoporosis includes non-pharmacological and pharmacological therapies. Non-pharmacological therapy includes 1200mg of elemental Ca and 800IU of vitamin D daily with lifestyle alterations that include weight loss, smoking surcease, and reding on autumn bar and turning away of heavy intoxicant ( Delmas, 2002 ) . In add-on to non-pharmacological therapy, pharmacological intercessions such as bisphosphonates are recommended for those with established osteoporosis ( T a‰¤ -2.5 ) or a breakability break ( hip or vertebral ) ( Delmas, 2002 ) . Recent literature points to the fact that combined therapy utilizing bisphosphonates, Ca and vitamin D is the most effectual intervention for osteoporosis instead than a individual therapy ( Bartl & A ; Bartl, 2011 ) .

    Vitamin D, its lack and the nexus to Osteoporosis

    There are two chief signifiers of the fat-soluble vitamin D: Vitamin D3 or vitamin D, which is synthesized in the tegument following exposure to sunlight or ultraviolet light and from nutritionary beginnings like fatty fish, and vitamin D2, vitamin D, which can be obtained from enlightening workss or other nutrients ( Sipos et al. , 2009 ) . Vitamin D3 is hydroxylated in the liver into 25-hydroxyvitamin D3 ( 25 ( OH ) D ) and finally in the kidneys into 1, 25 dihydroxyvitamin D3 ( 1, 25 ( OH ) 2D ) , which remains as the active metabolite that stimulates calcium soaking up into the intestine ( Sipos et al. , 2009 ) . This active metabolite, 1, 25 ( OH ) 2D enters the cells and binds to a vitamin D receptor and allows Ca to come in the cells through membrane proteins. The 1, 25 ( OH ) 2D finally has its consequence on marks like bone, bowel, and kidney and stimulates calcium conveyance from these variety meats to the blood. However, the production of 1, 25 ( OH ) 2D is stimulated by parathyroid endocrine ( PTH ) and direct and indirect negative feedback via Ca exist to modulate the production of this metabolite.

    Figure 1: Structure of Vitamin D and its enumeration system ( DeLuca, 2004 ) .

    Vitamin D aids the soaking up of Ca from the enteric piece of land by exciting the synthesis of calcium-binding protein in the enteric mucose membrane. It besides aids the reabsorption of phosphate in the nephritic tubing. Vitamin D mobilizes phosphate from the bone to keep serum phosphate degrees, and stimulates the active phosphate conveyance.

    Figure 2: Conventional diagram of the different maps of vitamin D. Photo recognition from medscape.com

    The lack of this endocrine creates a lacking deposition of hydroxyapatite in the castanetss. This is due to unequal soaking up of Ca from the enteric piece of land, and from the keeping of P in the kidney. As with many other organ systems, enteric Ca soaking up diminutions with aging, and this is one pathological factor that has been identified as a cause of osteoporosis in the aged ( Lau & A ; Baylink, 1999 ) . This abnormalcy, so leads to secondary hyperparathyroidism, which is characterized by high serum parathyroid endocrine ( PTH ) and an addition in bone reabsorption. In population-based surveies, there is a gradual addition in serum PTH from about 20 old ages of age onward and the cause of the addition in PTH is thought to be partially due to impaired enteric Ca soaking up that is associated with aging, a cause that is non wholly clear but at least in some cases is related to some signifier of vitamin D lack ( Lau & A ; Baylink, 1999 ) . There are three types of vitamin D lack: ( 1 ) primary vitamin D lack, which is due to a lack of vitamin D, the parent compound ; ( 2 ) a lack of 1,25 ( OH ) ( 2 ) D ( 3 ) ensuing from decreased nephritic production ; and ( 3 ) opposition to 1,25 ( OH ) ( 2 ) D ( 3 ) action owing to decreased reactivity in mark tissues ( Lau & A ; Baylink, 1999 ) . The cause for the opposition to 1, 25 ( OH ) ( 2 ) D ( 3 ) could be related to the determination that the vitamin D receptor degree in the bowel tends to diminish with age. All three types of lacks can happen with aging, and each has been implicated as a possible cause of enteric Ca malabsorption, secondary hyperparathyroidism, and osteoporosis ( Lau & A ; Baylink, 1999 ) . To combat, there are two signifiers of vitamin D replacing therapies: field vitamin D therapy and active vitamin D parallel ( or D-hormone ) therapy. Primary vitamin D lack can be corrected by vitamin addendums of 1000 U a twenty-four hours of field vitamin D whereas 1,25 ( OH ) ( 2 ) D ( 3 ) deficiency/resistance requires active vitamin D parallel therapy to rectify the high serum PTH and the Ca malabsorption ( Lau & A ; Baylink, 1999 ) .

    Native Vitamin D versus Vitamin D Analogues

    Excessive supplementation of vitamin D can do hypercalcaemia, which can take to vascular and tissue calcification that can damage the bosom, blood vass and the kidneys. As a consequence, recent surveies have considered man-made vitamin D parallels such as alfacalcidol and calcitriol in order to avoid the harmful effects of inordinate supplementation with native vitamin D. In vitamin D sufficient patients, native vitamin D does non supply any benefits. In add-on, in patients with vitamin D endocrine lack, or vitamin D endocrine receptor shortages in measure and quality, they are found to be immune to native vitamin D. Unlike native vitamin D that is chiefly found in the serum, vitamin D parallels are a prodrug of native vitamin D and increase in concentration on the mark variety meats such as castanetss for both vitamin D depleted and full patients. As a consequence they bypass the kidney ‘s negative feedback cringle and consequence in a higher concentration without doing hypercalcaemia and hyperparathyroidism ( Kanis et al. , 2002 ) . However, there is by and large a suboptimal grasp by both doctors and patients of the importance of vitamin D for care of bone wellness as reflected in the low figure of patients who reported on a regular basis taking these addendums ( Chan, Scott, & A ; Sen, 2010 ) . Recently in 2009, in an online study survey conducted at Spaulding Rehabilitation Hospital in Boston, USA, merely 54 % of practicians ( doctors, physician helpers and nurse practioners ) were ordering vitamin D for the intervention of osteoporosis ( Morse et al. , 2009 ) .

    Capstone Objective and PICO Question

    The deficiency of the usage of vitamin D could potentially be due to a deficiency of apprehension of how vitamin D maps and when it is utile. This paper will concentrate on 5 surveies that were late published that aid to understand the difference between native vitamin D and vitamin D parallels. Specifically, in the scene of patients with osteoporosis, does the supplementation of Vitamin D analogues with bisphosphonates help to cut down the incidence of breaks more than native Vitamin D? A deeper apprehension of when to utilize what sort of vitamin D should increase its use to let for its benefits for the patients enduring from this unwellness.

    Methods

    2.1 Strategy for Accessing Evidence Based Medicine:

    I conducted a systematic reappraisal of all English articles utilizing MEDLINE ( Ovid, PubMed ) from January 1980 to March 2011. I used Medical Subject Heading ( MeSH ) footings which included tests ( randomized controlled test, controlled clinical test, random allotment, dual blind method, single-blind method or uncontrolled tests ) , meta analysis, vitamin D ( vitamin D, vitamin D, 25-hydroxyvitamin D ) , vitamin D parallels ( alfacalcidol, calcitriol ) , osteoporosis ( primary osteoporosis, secondary osteoporosis ) fractures ( hips breaks, femoral cervix breaks, femoral breaks, humeral breaks, radius breaks, or tibial breaks ) , worlds, elderly, falls and bone mineral denseness.

    Critical Appraisal

    3.1 Justification of the documents:

    The undermentioned documents include 2 meta-analyses and 3 randomized controlled tests. I decided to include meta-analyses because they provide a wealth of information relating to my PICO inquiry. Since they study the derivation and statistical testing of overall factors / consequence size parametric quantities in related surveies, it normally carries a higher statistical power to observe an consequence. The two meta-analyses include merely methodologically sound surveies, giving us a best grounds meta-analysis since it combines several surveies and will accordingly be less influenced by local findings than individual surveies will be. The 3 randomized controlled tests ( RCT ) included were outside the surveies incorporated in the meta-analysis and besides provided good grounds to reply our PICO inquiry. Although these are individual surveies, the RCTs are considered by most to be the most dependable signifier of scientific grounds in the hierarchy of grounds that influences healthcare policy and pattern because they can cut down false causality and prejudice.

    3.2 Evidence-based Medicine

    Paper 1: ” Differential Effects of D-Hormone Analogs and Native Vitamin D on the Hazard of Falls: A Comparative Meta-Analysis ” by Richy et al. , 2007.

    Summary- The purpose of this paper was to compare the antifall efficaciousness of native vitamin D to its hydroxylated parallels alfacalcidol and calcitriol utilizing 11 randomised and double-blind and 3 randomised surveies ( 21, 268 topics ) from January 1995- May 2007.

    Results- The consequences from this survey are valid for our clinical inquiry since this survey was interested in understanding the function of native vitamin D versus vitamin D analogues in the bar of falls. In add-on, all the patients that started the tests were decently analyzed and accounted for at the terminal of the tests every bit good, with the per centum drop-out rates calculated. For 11 tests, the patients and their clinicians were kept blind with respects to whether they were being treated with vitamin D, vitamin D parallel or a placebo. The population of people included in the 14 tests were similar in age ( average age: 78.3 A±4.8 ) and included both work forces and adult females and the average continuance was 12 months. Using the information, the comparative hazard ( RR ) for falling when allocated to active intervention was 0.94 ( 95 % assurance interval ( CI ) 0.90-0.99 ) compared to placebo. Vitamin D parallels did supply a statistically important lower degree of hazard ( RR=0.79, CI 0.64-0.96 ) when compared to native vitamin D ( RR=0.95, CI 0.87-1.01 ) with the intergroup difference P=0.049. The figure needed to handle ( NNT ) , which is a step of the figure of patients who need to be treated in order to forestall one autumn was calculated to be 12 for vitamin D parallel and 52 for native vitamin D.

    As with any survey, there are restrictions. The appraisal of falls may be biased on mean given that callback prejudice is frequent among aged work forces and adult females. In add-ons, the consequences from this survey usage population that is non needfully affected with osteoporosis, which makes it somewhat hard to work these consequences and use them to our population that has osteoporosis. However, given the prevalence of this unwellness and the age of topics, it is possible that a important portion of the population that was studied by this group could hold osteoporosis. In our instance, vitamin D parallel intervention from this survey can be rather executable for our population with osteoporosis every bit good. In add-on, there are no possible injuries from this therapy that outweigh the benefits. The likely high quality of vitamin D parallels compared to native vitamin D relies on the determination that the metabolic tract of vitamin D endocrine analogues bypasses the nephritic feedback ordinance, ensuing in higher concentration of D-hormone at the receptors of mark variety meats ( Sipos et al. , 2009 ) .

    Paper 2: “ Vitamin D Analogues versus Native Vitamin D in Preventing Bone Loss and Osteoporosis-Related Fractures: A Comparative Meta-analysis ” by Richy et al. , 2005.

    Summary- The purpose of this survey was compare the consequence of native vitamin D to its hydroxylated parallels alfacalcidol and calcitriol in continuing bone mineral denseness ( BMD ) in both primary and corticosteroid-induced osteoporosis utilizing 32 randomized, controlled, double-blind tests from January 1985- January 2003.

    Results- In this survey, clinical tests were considered eligible if topics were ( 1 ) pre- or station menopausal adult females, work forces aged & gt ; 50 old ages or patients necessitating corticoids daily ( 2 ) randomized to take native versus vitamin D parallel ( 3 ) and double-blinded with a minimum survey continuance of 6 months with BMD results assessed utilizing double X-ray absorptiometry ( DXA ) . Study heterogeneousness was kept in head to guarantee that all groups in the clinical tests were similar to each other and sensitivity analyses were performed by analysing the impact of the undermentioned covariant on planetary estimations: age, sex ratio, compound, dosage, survey design, survey continuance, twelvemonth of publication, impact factor of diary and the dropout rates. Therefore, aside from the intercession, all groups were treated every bit. The survey demonstrated that the two vitamin D parallels, alfacalcidol and calcitriol appeared to exercise a higher preventive consequence on bone loss and break rates than compared to native vitamin D and placebo. It was found at a average 24 month continuance that alfacalcidol and calcitriol versus placebo had a important preventive consequence on hip and lumbar bone loss with an consequence size ( ES ) of 0.36 ( P & lt ; 0.0001 ) compared to ES= 0.17 ( P & lt ; 0.0005 ) for native vitamin D versus placebo. Additionally, when comparing the adjusted planetary comparative hazards for breaks, alfacalcidol and calcitriol provided a more pronounced preventive efficaciousness against breaks with a rate difference ( RD ) of 10 % ( CI= -2 to 17 ) compared to native vitamin D with an RD of 2 % ( CI=1-2 ) . In patients treated with corticoids, placebo-comparison surveies showed that vitamin-D parallels and native had similar effects on BMD ( ES 0.38 V 0.41, p=0.88 ) . Effectss were non significantly different with respect to spinal BMD, and neither D parallels nor native vitamin D significantly prevented breaks. However, in tete-a-tete surveies comparing vitamin-D parallels and native vitamin D in this population, the parallels were significantly better at continuing femoral-neck BMD and at forestalling spinal breaks, prefering D-analogues for femoral cervix BMD: ES=0.31 ( P & lt ; 0.02 ) and spinal breaks RD=15 % ( CI= 6.5-25 ) . Therefore, this survey established the high quality of D-analogues in forestalling bone loss and breaks in primary, post-menopausal osteoporosis, but seems to be ill-defined for corticoid induced osteoporosis.

    Paper 3: “ Superiority of a Combined Treatment of Alendronate and Alfacalcidol Compared to the Combination of Alendronate and Plain Vitamin D or Alfacalcidol Entirely in Established Post-menopausal or Male Osteoporosis ” by Ringe, J.D. et al. , 2007.

    Summary- The intent of this unfastened randomized controlled test was to compare the efficaciousness and safety of a intervention with either alfacalcidol entirely ( group A ) or alendronate with native vitamin D ( group B ) in patients with osteoporosis or vitamin D parallel ( alfacalcidol ) and a bisphosphonate ( Fosamax ) ( group C ) combined.

    Results- In this 2- twelvemonth survey, 90 patients were indiscriminately organized utilizing the inclusion standards of ( 1 ) established postmenopausal and male osteoporosis ( 2 ) No secondary osteoporosis ( 3 ) BMD L2-L4 & lt ; 3.0 T mark ( 4 ) BMD entire hip & lt ; 2.5 T mark ( 5 ) One or more prevailing vertebral break ( 5 ) No bisphosphonate, fluoride, or PTH intervention in the last 6 months. BMD was measured utilizing DXA at the beginning, and after 12 and 24 months. ES measuring for the group C versus group A was 0.9322 with a CI of 0.7740 ( P & lt ; 0.0001 ) and versus group B was 0.8511, CI= 0.6959 ( P & lt ; 0.0001 ) . This big high quality ( ES & gt ; 0.70 ) of the combination therapy of alfacalcidol and Fosamax versus both group A and B was besides resonating when the figure of patients with new breaks ( vertebral and non-vertebral ) was examined after 24 months. ES of group C versus group A was 0.6167, CI=0.5253 ( P & lt ; 0.02 ) and versus group B was 0.6333, CI=0.5379 ( P & lt ; 0.01 ) . The consequences from this survey are relevant to our survey population because they include patients with osteoporosis and besides place that a combination therapy of Fosamax and alfacalcidol is much more notable than monotherapy entirely. There are nevertheless, important restrictions to this survey every bit good. Several surveies have concluded that the consequences of unblinded RCTs tend to be biased toward good effects merely and it possible that this survey could endure from this every bit good as perceiver prejudice.

    Paper 4: “ Effectss of Combined Treatment with Alendronate and Alfacalcidol on Bone Mineral Density and Bone Turnover in Postmenopausal Osteoporosis: A two-years, randomized, multiarm, controlled test ” by One, K. et al. , 2007.

    Summary- The purpose of this prospective, randomized, single-blind, controlled test of 24 months ‘ continuance survey was to measure 197 postmenopausal adult females with osteoporosis to compare the efficaciousness of Alendronate + Alfacalcidol + Ca ( group A ) , Alendronate + Calcium ( group B ) , Alfacalcidol + Ca ( group C ) , or Calcium entirely ( group D ) , on bone mineral denseness and bone metamorphosis markers. BMD was measured at the lumbar spinal column ( L2-L4 ) and the thighbone cervix utilizing double energy x-ray absorptiometry ( LUNAR DPX ) at baseline and after 12 and 24 months. The 5 % degree of statistical significance has been used for all appraisals.

    Results- Subjects were randomized to groups A, B, C and D. At 2-years, and at the lumbar degree, the highest important addition in bone mass was seen for group A +8.4 % , followed by group B +6.4 % , and group C +2.3 % , while a important lessening was seen among topics from group D -2.5 % . A similar form was observed at the femoral cervix degree, with additions runing from +5.3 % for group A, +3.8 % for group B, +1.2 % ( NS ) for group C, and -6.4 % for group D. Data from this randomized controlled test suggested a higher efficaciousness in increasing bone mineral denseness and a similar tolerance of combined therapy with Alendronate and Alfacalcidol compared to Alfacalcidol entirely, and to Alendronate as a consistent tendency. Importantly, the combined therapy resulted in lower rates of hypercalcinuria, hypercalcaemia, and hypocalcaemia compared to monotherapies. However, restrictions of this survey include conformity. It was ill recorded, although this parametric quantity is recognized as a major determiner of intervention efficaciousness. Nevertheless, farther big, double-blind, dose-ranging surveies in postmenopausal osteoporosis and topics with increased hazard of falls are still required to corroborate the interactive efficaciousness of Alendronate in combination with Alfacalcidol in the decrease of falls and vertebral, non-vertebral breaks.

    Paper 5: “ Prevention and intervention of glucocorticoid-induced osteoporosis with

    active vitamin D3 parallels: a reappraisal with meta-analysis of randomised

    controlled tests including organ organ transplant surveies ” by de Nijs, R. N. J. et al. , 2004.

    Summary- The purpose of this reappraisal with meta-analysis was to find if there is a principle to utilize activated signifiers of vitamin D3 to handle or forestall glucocorticoid-induced osteoporosis, and to compare the ei¬ˆect of active vitamin D3 metabolites with native vitamin D and/or Ca, placebo, and no intervention.

    Results- The assignment of the patients to the different groups was randomized, although they were non needfully blinded. Selection standards and group heterogeneousness was kept in history before the start of the test to guarantee that the groups did non differ much. Refering the consequence on bone mineral denseness, the pooled consequence size of active vitamin D3 parallels compared with no intervention, placebo, plain vitamin D3 and/or Ca was 0.35 ( 95 % assurance interval ( CI ) 0.18, 0.52 ) . Compared with bisphosphonates, the pooled consequence size was -1.03 ( 95 % CI -1.71, -0.36 ) . However, the pooled estimation of the comparative hazard for vertebral breaks of active vitamin D3 parallels compared with no intervention, placebo, plain vitamin D3 and/or Ca was 0.56 ( 95 % CI 0.34, 0.92 ) and compared with bisphosphonates it was 1.20 ( 95 % CI 0.32, 4.55 ) . Active vitamin D3 analogues diminish the hazard of vertebral breaks and continue bone during glucocorticoid therapy more efficaciously than no intervention, placebo, plain vitamin D3 and/or Ca, but bisphosphonates are more effectual in continuing bone mineral denseness. In add-on, there do non look to be any documented instances of possible injury with vitamin D parallel therapy that would outweigh its benefits. In drumhead, this survey indicated that active vitamin D3 parallels are ei¬ˆective in continuing bone and reduces the hazard of vertebral breaks during intervention with GCs.

    Decision

    In decision, our PICO inquiry of whether vitamin D parallels in combination with bisphosphonates were superior to native vitamin D was addressed. Literature eludes that vitamin D parallels are better than native vitamin D intervention regardless of whether in combination with bisphosphonates or non. The documents that were selected were bias free and most included some signifier of inclusion standards. Our population is similar in footings of age from the 1s studied in these documents that the consequences would be extremely applicable. Of class, there are still legion differences such as clip, civilization, and phase of unwellness that differ from one survey to the following which can impact the consequences and those differences must still be kept in head. Overall, this survey has been able to compare different modes of break hazard decrease that would be extremely applicable in our population.

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