Impact of Vitamin D Therapy in treating X-linked hypophosphatemic rickets Kate Barratt Research Proposal For the degree of Masters by Research

Impact of Vitamin D Therapy in treating
X-linked hypophosphatemic rickets
Kate Barratt
Research Proposal
For the degree of Masters by Research (Medical Science)
Supervisors
Associate Professor Paul Anderson
Professor Gerald Atkins
Professor Howard Morris

OUTLINE:
X-Linked HypohposphatemicHypophosphatemic (XLH) Rickets is a rare hereditary disorder that was commonly referred to as “Vitamin D Resistant Rickets.”that is difficult to treat without significant side-effects. XLH, is caused by a mutation on in the osteocyte genethe, phosphate-regulating endopeptidase homolog, X-linked (PHEX), which gene, and the pathophysiology of this disease presents soon after birth. This PHEX mutation causes the impaired cleavage and accumulation of prevents the breakdown of Fibroblast Growth Factor 23 (FGF23) and thus the effects of excessive FGF23 are seen. Elevated FGF23 levels in XLH causes excessive renal excretion of pPhosphate leading to hypophosphatemia, and low circulating active vitamin D (1,25(OH)2D) levels due to both inhibited synthesis and excessive catabolism of vitamin D. It has been long thought that disturbed renal metabolism of vitamin D is major contributor to the development of wasting and hyphosphaemia,undermineralised bone, or rickets elevated PTH and CYP24a1, low circulating vitamin D, bone pain, spontaneous fractures, hearing loss, dental abscess, and osteomalacia develop in the first few years of life. However, recent evidence suggest that Vitamin D and phosphate supplementation are commonly used to attempt to normalise serum biochemistry and the rachitic bone phenotype. More recently FGF23 antibodies and vitamin D analogues have been used in isolation, or in conjunction, with vitamin supplementation to improve outcomes. All of these current therapies are inefficient at treating this disease without causing severe side effects such as hypercalcaemia and nephrocalcinosis.Our team is researching the effects of elevated FGF23 on the HYP skeleton and possible alternatives for therapies. I will be concentrating on the use of dietary vitamin supplementation, infusion of inactive vitamin D, and inhibition of the vitamin D catabolising enzyme, CYP24a1.The murine homolog for XLH, HYP, will be used for the purposes of in vitro analyses. (a) local metabolism of 1,25(OH)2D in bone has an independent and critical role for bone mineralisation (b) that the inhibition of vitamin D catabolism in disorders of rickets due to FGF23 excess, induces the near-complete healing of rickets without the need to lower FGF23 levels nor rescue the hypophosphatemia. These data, and the importance of finding effective treatments for XLH provide great importance for investigating the following hypothesis and aims:Hypothesis: Raising active vitamin D (1,25D) levels within the bone and/or the intestine (via preventing catabolism) prevents rickets in the Hyp mouse model (the mouse homolog for the disorder of XLH) by increasing mineralisation.Aim 1: To determine whether raising circulating 25-hydroxyvitamin D (25D) levels heal the bone in Hyp mice.Aim 2: To determine whether raising osteocyte levels of active vitamin D (1,25(OH)2D) heals the bone of Hyp mice.LITERATURE REVIEW:
416623574295Figure 1: Bone deformities in a severe case of XLH0Figure 1: Bone deformities in a severe case of XLHPrevalence and impact of X-linked Hypophosphatemic Rickets: X-Linked Hypophosphatemia (XLH) is a rare genetic disorder, affecting 1 in 20,000 individuals ADDIN EN.CITE <EndNote><Cite><Author>Azam</Author><Year>2003</Year><RecNum>4275</RecNum><DisplayText>(Azam et al. 2003)</DisplayText><record><rec-number>4275</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599893″>4275</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Azam, N.</author><author>Zhang, M. Y.</author><author>Wang, X.</author><author>Tenenhouse, H. S.</author><author>Portale, A. A.</author></authors></contributors><titles><title>Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title><abbr-1>Endocrinology</abbr-1></periodical><pages>3463-8</pages><volume>144</volume><number>8</number><dates><year>2003</year></dates><label>22747512</label><urls></urls></record></Cite></EndNote>(Azam et al. 2003). The disease is characterised by the excessive renal excretion of serum phosphate leading to hypophosphatemia. Hypophosphatemia is generally considered to result in reduced hydroxyapatite (bone mineral) formation resulting in under-mineralisation of the skeleton or rickets (Figure 1). XLH usually presents in late infancy as growth retardation, skeletal deformities and rickets become apparent. XLH children display a delay in walking, bowed legs, craniostenosis, dental abscesses, entesopathy, fractures, and bone pain PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWtpdGllPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWtpdGllPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48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ADDIN EN.CITE.DATA (Linglart et al. 2014; Makitie et al. 2003). The principal symptoms of XLH in adults are bone pain, joint pain, and stiffness. As patients age, long-term weight bearing on misaligned joints often results in osteoarthritis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Che et al. 2016). While treatment with oral phosphate and active vitamin D compounds, such as 1,25(OH)2D, are a common therapy for XLH, treatment from infancy results in the best outcomes for children suffering with XLH ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). However, treatment of XLH patients frequently results either in severe side effects such as hypercalcaemia, or has no positive effects on bone health ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). While recent developments have provided new therapeutic options, numerous side effects have been reported ADDIN EN.CITE <EndNote><Cite><Author>Carpenter</Author><Year>2011</Year><RecNum>98</RecNum><DisplayText>(Carpenter et al. 2011)</DisplayText><record><rec-number>98</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1536560091″>98</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Carpenter, T. O.</author><author>Imel, E. A.</author><author>Holm, I. A.</author><author>Jan de Beur, S. M.</author><author>Insogna, K. L.</author></authors></contributors><auth-address>Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520-8064, USA. [email protected]</auth-address><titles><title>A clinician&apos;s guide to X-linked hypophosphatemia</title><secondary-title>J Bone Miner Res</secondary-title></titles><periodical><full-title>J Bone Miner Res</full-title></periodical><pages>1381-8</pages><volume>26</volume><number>7</number><edition>2011/05/04</edition><keywords><keyword>*Familial Hypophosphatemic Rickets/diagnostic</keyword><keyword>imaging/pathology/physiopathology/therapy</keyword><keyword>*Genetic Diseases, X-Linked</keyword><keyword>Humans</keyword><keyword>Practice Guidelines as Topic</keyword><keyword>Radiography</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1523-4681 (Electronic) 0884-0431 (Linking)</isbn><accession-num>21538511</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/21538511</url></related-urls></urls><custom2>PMC3157040</custom2><electronic-resource-num>10.1002/jbmr.340</electronic-resource-num></record></Cite></EndNote>(Carpenter et al. 2011). Thus, further efforts are required to establish effective therapies which heal the under-mineralised bone disorder without causing significant side effects.
25761952510790Figure 2: XLH Pathophysiology00Figure 2: XLH PathophysiologyThe cause of XLH: In XLH, a loss-of-function mutation in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene results in excessive levels of the Fibroblast Growth Factor 23 (FGF23) protein PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWlmaGVpdC1OZXN0bGVyPC9BdXRob3I+PFllYXI+MjAx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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWlmaGVpdC1OZXN0bGVyPC9BdXRob3I+PFllYXI+MjAx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ADDIN EN.CITE.DATA (Leifheit-Nestler et al. 2017). Fibroblast Growth Factor 23 (FGF23) is a bone derived hormone that was relatively recently discovered in 2000. FGF23 is mainly produced in two bone cell types, osteoblasts and osteocytes, and is normally produced in response to high levels of circulating phosphorus and active vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) ADDIN EN.CITE <EndNote><Cite><Author>Erben</Author><Year>2017</Year><RecNum>8</RecNum><DisplayText>(Erben 2017)</DisplayText><record><rec-number>8</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519791986″>8</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Erben, R. G.</author></authors></contributors><auth-address>1 Department of Biomedical Sciences, Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine, Vienna, Austria.</auth-address><titles><title>Pleiotropic Actions of FGF23</title><secondary-title>Toxicol Pathol</secondary-title></titles><periodical><full-title>Toxicol Pathol</full-title></periodical><pages>904-910</pages><volume>45</volume><number>7</number><keywords><keyword>bone</keyword><keyword>bone mineralization</keyword><keyword>cardiovascular system</keyword><keyword>endocrine system</keyword><keyword>mineral metabolism</keyword><keyword>renal</keyword><keyword>transgenic animals</keyword></keywords><dates><year>2017</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1533-1601 (Electronic) 0192-6233 (Linking)</isbn><accession-num>29096595</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/29096595</url></related-urls></urls><electronic-resource-num>10.1177/0192623317737469</electronic-resource-num></record></Cite></EndNote>(Erben 2017). In a feedback mechanism, FGF23 is responsible for the promoting the excretion of phosphorus as well as reducing 1,25(OH)2D levels (Figure 2) ADDIN EN.CITE <EndNote><Cite><Author>Portale</Author><Year>2012</Year><RecNum>66</RecNum><DisplayText>(Portale, Perwad &amp; Miller 2012)</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032235″>66</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Portale, Anthony A.</author><author>Perwad, Farzana</author><author>Miller, Walter L.</author></authors></contributors><titles><title>Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action</title><secondary-title>Pediatric Bone</secondary-title></titles><pages>679-698</pages><dates><year>2012</year></dates><isbn>9780123820402</isbn><urls></urls><electronic-resource-num>10.1016/b978-0-12-382040-2.10025-5</electronic-resource-num></record></Cite></EndNote>(Portale, Perwad & Miller 2012). . In XLH, elevated FGF23 levels prevent the renal proximal tubular phosphate reabsorption, by reducing Sodium-Phosphate transporters (NaPi2a and NaPi2c) as well as inhibits the intestinal sodium-phosphate transporter (NaPi2b), resulting in inappropriately high phosphate wasting PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
TnVtPjU4PC9SZWNOdW0+PERpc3BsYXlUZXh0PihLaWRvIGV0IGFsLiAyMDEzKTwvRGlzcGxheVRl
eHQ+PHJlY29yZD48cmVjLW51bWJlcj41ODwvcmVjLW51bWJlcj48Zm9yZWlnbi1rZXlzPjxrZXkg
YXBwPSJFTiIgZGItaWQ9Inhmd2Z4czl2MnpycGU5ZXIyYTlwd2Q5Znh2NXoydjkyd2U1ZCIgdGlt
ZXN0YW1wPSIxNTMzMDMyMTAzIj41ODwva2V5PjxrZXkgYXBwPSJFTldlYiIgZGItaWQ9IiI+MDwv
a2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9y
ZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+S2lkbywgUy48L2F1dGhvcj48
YXV0aG9yPkthbmVrbywgSS48L2F1dGhvcj48YXV0aG9yPlRhdHN1bWksIFMuPC9hdXRob3I+PGF1
dGhvcj5TZWdhd2EsIEguPC9hdXRob3I+PGF1dGhvcj5NaXlhbW90bywgSy48L2F1dGhvcj48L2F1
dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5EZXBhcnRtZW50IG9mIE1vbGVjdWxh
ciBOdXRyaXRpb24sIFVuaXZlcnNpdHkgb2YgVG9rdXNoaW1hIEdyYWR1YXRlIFNjaG9vbCwgMy0x
OC0xNSBLdXJhbW90by1jaG8sIFRva3VzaGltYSwgSmFwYW4uPC9hdXRoLWFkZHJlc3M+PHRpdGxl
cz48dGl0bGU+Vml0YW1pbiBEIGFuZCB0eXBlIElJIHNvZGl1bS1kZXBlbmRlbnQgcGhvc3BoYXRl
IGNvdHJhbnNwb3J0ZXJzPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPkNvbnRyaWIgTmVwaHJvbDwv
c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPkNvbnRyaWIg
TmVwaHJvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjg2LTk3PC9wYWdlcz48dm9s
dW1lPjE4MDwvdm9sdW1lPjxlZGl0aW9uPjIwMTMvMDUvMDk8L2VkaXRpb24+PGtleXdvcmRzPjxr
ZXl3b3JkPkFic29ycHRpb248L2tleXdvcmQ+PGtleXdvcmQ+QW5pbWFsczwva2V5d29yZD48a2V5
d29yZD5DYWxjaXRyaW9sL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bSwgRGll
dGFyeS90aGVyYXBldXRpYyB1c2U8L2tleXdvcmQ+PGtleXdvcmQ+Q2hyb25pYyBLaWRuZXkgRGlz
ZWFzZS1NaW5lcmFsIGFuZCBCb25lIERpc29yZGVyL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdv
cmQ+RmFtaWxpYWwgSHlwb3Bob3NwaGF0ZW1pYyBSaWNrZXRzL2RpZXQgdGhlcmFweS9tZXRhYm9s
aXNtPC9rZXl3b3JkPjxrZXl3b3JkPkZpYnJvYmxhc3QgR3Jvd3RoIEZhY3RvcnMvcGh5c2lvbG9n
eTwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVndWxhdGlvbjwva2V5d29yZD48
a2V5d29yZD5HbHVjdXJvbmlkYXNlL3BoeXNpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+SHVtYW5z
PC9rZXl3b3JkPjxrZXl3b3JkPkh5cG9waG9zcGhhdGVtaWEvcGh5c2lvcGF0aG9sb2d5PC9rZXl3
b3JkPjxrZXl3b3JkPkludGVzdGluYWwgQWJzb3JwdGlvbjwva2V5d29yZD48a2V5d29yZD5LaWRu
ZXkgVHVidWxlcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtl
eXdvcmQ+TWljZSwgS25vY2tvdXQ8L2tleXdvcmQ+PGtleXdvcmQ+UGFyYXRoeXJvaWQgSG9ybW9u
ZS9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlBob3NwaGF0ZXMvKm1ldGFib2xpc208L2tl
eXdvcmQ+PGtleXdvcmQ+UGhvc3Bob3J1cywgRGlldGFyeS9waGFybWFjb2tpbmV0aWNzPC9rZXl3
b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgQ2FsY2l0cmlvbC9kZWZpY2llbmN5L3BoeXNpb2xvZ3k8
L2tleXdvcmQ+PGtleXdvcmQ+U29kaXVtLyptZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPlNv
ZGl1bS1QaG9zcGhhdGUgQ290cmFuc3BvcnRlciBQcm90ZWlucywgVHlwZSBJSS8qbWV0YWJvbGlz
bTwva2V5d29yZD48a2V5d29yZD5WaXRhbWluIEQvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3
b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48L2RhdGVzPjxpc2JuPjE2NjItMjc4MiAoRWxl
Y3Ryb25pYykmI3hEOzAzMDItNTE0NCAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjM2
NTI1NTI8L2FjY2Vzc2lvbi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3
Lm5jYmkubmxtLm5paC5nb3YvcHVibWVkLzIzNjUyNTUyPC91cmw+PC9yZWxhdGVkLXVybHM+PC91
cmxzPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMTU5LzAwMDM0Njc4NjwvZWxlY3Ryb25p
Yy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE.DATA (Kido et al. 2013). Excess FGF23 levels also acts to markedly reduce 1,25(OH)2D levels both by supressing the hydroxylase 25-hydroxyvitamin D 1?-hydroxylase enzyme, CYP27B1, which is responsible for the conversion of inactive vitamin D (25(OH)D) to 1,25(OH)2D, and by inducing the 25-hydroxyvitamin D 24-hydroxylase enzymevitamin D catabolizing enzyme, CYP24A1, which acts to both convertt 1,25(OH)2D, and as well as 25(OH)D, to inactive metabolites PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Liu et al. 2016a).

In addition to XLH, several other disorders in the regulation of FGF23 result in hypophosphatemia and hypovitaminosis D with similar effects on poor bone mineralisation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PaGF0YTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
Y051bT43OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oT2hhdGEgZXQgYWwuIDIwMTQpPC9EaXNwbGF5
VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjc5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtleXM+PGtl
eSBhcHA9IkVOIiBkYi1pZD0ieGZ3ZnhzOXYyenJwZTllcjJhOXB3ZDlmeHY1ejJ2OTJ3ZTVkIiB0
aW1lc3RhbXA9IjE1MzMwMzI0NDAiPjc5PC9rZXk+PGtleSBhcHA9IkVOV2ViIiBkYi1pZD0iIj4w
PC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8
L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5PaGF0YSwgWS48L2F1dGhv
cj48YXV0aG9yPllhbWF6YWtpLCBNLjwvYXV0aG9yPjxhdXRob3I+S2F3YWksIE0uPC9hdXRob3I+
PGF1dGhvcj5Uc3VnYXdhLCBOLjwvYXV0aG9yPjxhdXRob3I+VGFjaGlrYXdhLCBLLjwvYXV0aG9y
PjxhdXRob3I+S29pbnVtYSwgVC48L2F1dGhvcj48YXV0aG9yPk1peWFnYXdhLCBLLjwvYXV0aG9y
PjxhdXRob3I+S2ltb3RvLCBBLjwvYXV0aG9yPjxhdXRob3I+TmFrYXlhbWEsIE0uPC9hdXRob3I+
PGF1dGhvcj5OYW1iYSwgTi48L2F1dGhvcj48YXV0aG9yPllhbWFtb3RvLCBILjwvYXV0aG9yPjxh
dXRob3I+T2thbm8sIFQuPC9hdXRob3I+PGF1dGhvcj5Pem9ubywgSy48L2F1dGhvcj48YXV0aG9y
Pk1pY2hpZ2FtaSwgVC48L2F1dGhvcj48L2F1dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRk
cmVzcz5EZXBhcnRtZW50IG9mIEJvbmUgYW5kIE1pbmVyYWwgUmVzZWFyY2gsIE9zYWthIE1lZGlj
YWwgQ2VudGVyIGFuZCBSZXNlYXJjaCBJbnN0aXR1dGUgZm9yIE1hdGVybmFsIGFuZCBDaGlsZCBI
ZWFsdGgsIEl6dW1pLCBKYXBhbjsgRGVwYXJ0bWVudCBvZiBQZWRpYXRyaWNzLCBPc2FrYSBVbml2
ZXJzaXR5IEdyYWR1YXRlIFNjaG9vbCBvZiBNZWRpY2luZSwgU3VpdGEsIEphcGFuLjwvYXV0aC1h
ZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkVsZXZhdGVkIGZpYnJvYmxhc3QgZ3Jvd3RoIGZhY3RvciAy
MyBleGVydHMgaXRzIGVmZmVjdHMgb24gcGxhY2VudGEgYW5kIHJlZ3VsYXRlcyB2aXRhbWluIEQg
bWV0YWJvbGlzbSBpbiBwcmVnbmFuY3kgb2YgSHlwIG1pY2U8L3RpdGxlPjxzZWNvbmRhcnktdGl0
bGU+SiBCb25lIE1pbmVyIFJlczwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2Fs
PjxmdWxsLXRpdGxlPkogQm9uZSBNaW5lciBSZXM8L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxw
YWdlcz4xNjI3LTM4PC9wYWdlcz48dm9sdW1lPjI5PC92b2x1bWU+PG51bWJlcj43PC9udW1iZXI+
PGVkaXRpb24+MjAxNC8wMS8yOTwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+MjUtSHlkcm94
eXZpdGFtaW4gRDMgMS1hbHBoYS1IeWRyb3h5bGFzZS9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3
b3JkPjxrZXl3b3JkPkFuaW1hbHM8L2tleXdvcmQ+PGtleXdvcmQ+QW50aWJvZGllcywgTmV1dHJh
bGl6aW5nL3BoYXJtYWNvbG9neTwva2V5d29yZD48a2V5d29yZD5DYWxjaXVtL2Jsb29kPC9rZXl3
b3JkPjxrZXl3b3JkPkVhcmx5IEdyb3d0aCBSZXNwb25zZSBQcm90ZWluIDEvbWV0YWJvbGlzbTwv
a2V5d29yZD48a2V5d29yZD5GYW1pbGlhbCBIeXBvcGhvc3BoYXRlbWljIFJpY2tldHMvKmJsb29k
L2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPkZlbWFsZTwva2V5d29yZD48a2V5d29yZD5GZXR1
cy9kcnVnIGVmZmVjdHMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5GaWJyb2JsYXN0IEdy
b3d0aCBGYWN0b3JzLypibG9vZDwva2V5d29yZD48a2V5d29yZD5HZW5lIEV4cHJlc3Npb24gUmVn
dWxhdGlvbiwgRGV2ZWxvcG1lbnRhbC9kcnVnIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+R2x1
Y3Vyb25pZGFzZS9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3b3JkPjxrZXl3b3JkPkh1bWFuczwv
a2V5d29yZD48a2V5d29yZD5LaWRuZXkvZW1icnlvbG9neS9tZXRhYm9saXNtPC9rZXl3b3JkPjxr
ZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+TWF0ZXJuYWwtRmV0YWwgRXhjaGFuZ2UvZHJ1
ZyBlZmZlY3RzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPk1pY2U8L2tleXdvcmQ+PGtleXdv
cmQ+TWluZXJhbHMvbWV0YWJvbGlzbTwva2V5d29yZD48a2V5d29yZD5PcmdhbiBDdWx0dXJlIFRl
Y2huaXF1ZXM8L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3BoYXRlcy9ibG9vZDwva2V5d29yZD48a2V5
d29yZD5QbGFjZW50YS9kcnVnIGVmZmVjdHMvKm1ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+
UHJlZ25hbmN5PC9rZXl3b3JkPjxrZXl3b3JkPlJlY2VwdG9ycywgRmlicm9ibGFzdCBHcm93dGgg
RmFjdG9yL2dlbmV0aWNzL21ldGFib2xpc208L2tleXdvcmQ+PGtleXdvcmQ+UmVjb21iaW5hbnQg
UHJvdGVpbnMvcGhhcm1hY29sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPlNpZ25hbCBUcmFuc2R1Y3Rp
b24vZHJ1ZyBlZmZlY3RzL2dlbmV0aWNzPC9rZXl3b3JkPjxrZXl3b3JkPlRpbWUgRmFjdG9yczwv
a2V5d29yZD48a2V5d29yZD5WaXRhbWluIEQvYmxvb2QvKm1ldGFib2xpc208L2tleXdvcmQ+PGtl
eXdvcmQ+Vml0YW1pbiBEMyAyNC1IeWRyb3h5bGFzZS9nZW5ldGljcy9tZXRhYm9saXNtPC9rZXl3
b3JkPjxrZXl3b3JkPkZnZjIzPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgYW5pbWFsIG1vZGVs
czwva2V5d29yZD48a2V5d29yZD5Pc3Rlb21hbGFjaWEgYW5kIHJpY2tldHM8L2tleXdvcmQ+PGtl
eXdvcmQ+U3lzdGVtcyBiaW9sb2d5LWJvbmUgaW50ZXJhY3RvcnM8L2tleXdvcmQ+PGtleXdvcmQ+
Vml0YW1pbiBkPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PHB1
Yi1kYXRlcz48ZGF0ZT5KdWw8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48aXNibj4xNTIzLTQ2
ODEgKEVsZWN0cm9uaWMpJiN4RDswODg0LTA0MzEgKExpbmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24t
bnVtPjI0NDcwMTAzPC9hY2Nlc3Npb24tbnVtPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRw
czovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yNDQ3MDEwMzwvdXJsPjwvcmVsYXRlZC11
cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTAwMi9qYm1yLjIxODY8L2Vs
ZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjwvcmVjb3JkPjwvQ2l0ZT48L0VuZE5vdGU+
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PaGF0YTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl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 EN.CITE.DATA (Ohata et al. 2014). Converse to effects of FGF23 excess disorders, if FGF23 is ablated, hyperphosphatemia and hypophosphaturia result PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaXRhcmE8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS
ZWNOdW0+NTk8L1JlY051bT48RGlzcGxheVRleHQ+KFNpdGFyYSBldCBhbC4gMjAwNik8L0Rpc3Bs
YXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1iZXI+NTk8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48
a2V5IGFwcD0iRU4iIGRiLWlkPSJ4ZndmeHM5djJ6cnBlOWVyMmE5cHdkOWZ4djV6MnY5MndlNWQi
IHRpbWVzdGFtcD0iMTUzMzAzMjE5NCI+NTk8L2tleT48a2V5IGFwcD0iRU5XZWIiIGRiLWlkPSIi
PjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x
NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlNpdGFyYSwgRC48L2F1
dGhvcj48YXV0aG9yPlJhenphcXVlLCBNLiBTLjwvYXV0aG9yPjxhdXRob3I+U3QtQXJuYXVkLCBS
LjwvYXV0aG9yPjxhdXRob3I+SHVhbmcsIFcuPC9hdXRob3I+PGF1dGhvcj5UYWd1Y2hpLCBULjwv
YXV0aG9yPjxhdXRob3I+RXJiZW4sIFIuIEcuPC9hdXRob3I+PGF1dGhvcj5MYW5za2UsIEIuPC9h
dXRob3I+PC9hdXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBv
ZiBEZXZlbG9wbWVudGFsIEJpb2xvZ3ksIEhhcnZhcmQgU2Nob29sIG9mIERlbnRhbCBNZWRpY2lu
ZSwgUkVCIDMwMywgMTg4IExvbmd3b29kIEF2ZS4sIEJvc3RvbiwgTUEgMDIxMTUsIFVTQSwgYW5k
IFRoZSBHZW5ldGljcyBVbml0LCBTaHJpbmVycyBIb3NwaXRhbCwgTW9udHJlYWwsIFF1ZWJlYywg
Q2FuYWRhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkdlbmV0aWMgYWJsYXRpb24gb2Yg
dml0YW1pbiBEIGFjdGl2YXRpb24gcGF0aHdheSByZXZlcnNlcyBiaW9jaGVtaWNhbCBhbmQgc2tl
bGV0YWwgYW5vbWFsaWVzIGluIEZnZi0yMy1udWxsIGFuaW1hbHM8L3RpdGxlPjxzZWNvbmRhcnkt
dGl0bGU+QW0gSiBQYXRob2w8L3NlY29uZGFyeS10aXRsZT48L3RpdGxlcz48cGVyaW9kaWNhbD48
ZnVsbC10aXRsZT5BbSBKIFBhdGhvbDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIx
NjEtNzA8L3BhZ2VzPjx2b2x1bWU+MTY5PC92b2x1bWU+PG51bWJlcj42PC9udW1iZXI+PGVkaXRp
b24+MjAwNi8xMi8wNzwvZWRpdGlvbj48a2V5d29yZHM+PGtleXdvcmQ+QW5pbWFsczwva2V5d29y
ZD48a2V5d29yZD5Cb25lIERlbnNpdHkvZ2VuZXRpY3M8L2tleXdvcmQ+PGtleXdvcmQ+Qm9uZSBh
bmQgQm9uZXMvKmFibm9ybWFsaXRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2lmaWNhdGlvbiwg
UGh5c2lvbG9naWM8L2tleXdvcmQ+PGtleXdvcmQ+Q2FsY2l1bS9ibG9vZC91cmluZTwva2V5d29y
ZD48a2V5d29yZD5GaWJyb2JsYXN0IEdyb3d0aCBGYWN0b3JzLypnZW5ldGljcy9tZXRhYm9saXNt
PC9rZXl3b3JkPjxrZXl3b3JkPkdlbmUgRXhwcmVzc2lvbjwva2V5d29yZD48a2V5d29yZD5IaW5k
bGltYi9kaWFnbm9zdGljIGltYWdpbmc8L2tleXdvcmQ+PGtleXdvcmQ+S2lkbmV5L21ldGFib2xp
c208L2tleXdvcmQ+PGtleXdvcmQ+TWljZTwva2V5d29yZD48a2V5d29yZD5NaWNlLCBNdXRhbnQg
U3RyYWluczwva2V5d29yZD48a2V5d29yZD5NaXhlZCBGdW5jdGlvbiBPeHlnZW5hc2VzL2dlbmV0
aWNzPC9rZXl3b3JkPjxrZXl3b3JkPk1vZGVscywgQW5pbWFsPC9rZXl3b3JkPjxrZXl3b3JkPlBh
cmF0aHlyb2lkIEhvcm1vbmUvYmxvb2QvdXJpbmU8L2tleXdvcmQ+PGtleXdvcmQ+UGhvc3BoYXRl
cy9ibG9vZC91cmluZTwva2V5d29yZD48a2V5d29yZD5SYWRpb2dyYXBoeTwva2V5d29yZD48a2V5
d29yZD5TaWduYWwgVHJhbnNkdWN0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlNvZGl1bS1QaG9zcGhh
dGUgQ290cmFuc3BvcnRlciBQcm90ZWlucywgVHlwZSBJSWEvbWV0YWJvbGlzbTwva2V5d29yZD48
a2V5d29yZD5WaXRhbWluIEQvZ2VuZXRpY3MvKm1ldGFib2xpc208L2tleXdvcmQ+PC9rZXl3b3Jk
cz48ZGF0ZXM+PHllYXI+MjAwNjwveWVhcj48cHViLWRhdGVzPjxkYXRlPkRlYzwvZGF0ZT48L3B1
Yi1kYXRlcz48L2RhdGVzPjxpc2JuPjAwMDItOTQ0MCAoUHJpbnQpJiN4RDswMDAyLTk0NDAgKExp
bmtpbmcpPC9pc2JuPjxhY2Nlc3Npb24tbnVtPjE3MTQ4Njc4PC9hY2Nlc3Npb24tbnVtPjx1cmxz
PjxyZWxhdGVkLXVybHM+PHVybD5odHRwczovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8x
NzE0ODY3ODwvdXJsPjwvcmVsYXRlZC11cmxzPjwvdXJscz48Y3VzdG9tMj5QTUMxNzYyNDg5PC9j
dXN0b20yPjxlbGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4yMzUzL2FqcGF0aC4yMDA2LjA2MDMy
OTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaXRhcmE8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS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=
ADDIN EN.CITE.DATA (Sitara et al. 2006). The role of phosphate in XLH: Phosphate, whilst less tightly regulated than calcium, plays a critical role in bone homeostasis including directly contributing to chondrocyte maturation and skeletal mineralisation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LbzwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJlY051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ADDIN EN.CITE.DATA (Ko et al. 2016). The main regulator of serum pPhosphate levels isis easily effected by levels of FGF23. However, , Parathyroid Hormone (PTH), and active vitamin D (1,25(OH)2D3 contribute to the regulating of phosphate levels as well). As discussed, in XLH, elevated FGF23 levels prevent the renal proximal tubular phosphate reabsorption, by reducing Sodium-Phosphate transporters (NaPi2a and NaPi2c) as well as inhibits the intestinal sodium-phosphate transporter (NaPi2b). When supplemented with phosphate alone, XLH patients show a partial improvement in the rachitic phenotype, but no improvement in endosteal bone mineralisation ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><DisplayText>(Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Marie, Travers & Glorieux 1981). This effect of phosphate is considered to directly effect of chondrocyte differentiation and apoptosis…….(REFs). Consistent with the effect of phosphate on the growth plate, pPhosphate supplementation also only works in the children where the activity of growth plate is significant young. N, with no benefits of phosphate were observed seen inin adult patients with osteomalacia (the adult form of rickets) ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><DisplayText>(Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Marie, Travers & Glorieux 1981). 3364302110478Figure 3: The mechanism of coordinated bone mineralisation in osteocytes.Figure 3: The mechanism of coordinated bone mineralisation in osteocytes.Phosphate plays a critical role in the mineralisation of the skeleton. The formation of hydroxyapatite (HAP) in the skeleton requires combination of inorganic Phosphate (Pi) with calcium (Ca) (Figure 3). The presentation of inorganic phosphate for combination with calcium is not dependent on serum phosphate levels, but rather by the co-ordinated production by osteoblasts. This process is governed by at least three cell membrane associated proteins Ectonucleotide Pyrophosphatase/Phosphodiesterase 1 (NPP1), 3376295435610Figure 3: The mechanism of coordinated bone mineralisation in osteocytes.Figure 3: The mechanism of coordinated bone mineralisation in osteocytes.Progressive Ankylosis Protein (ANK) and Tissue Non-specific Alkaline Phosphatase (TNAP). Conversion of pyrophosphate (PPi) to Pi by TNAP is common to mineralising osteoblasts. A high PPi to Pi ratio has been shown to be inhibitory for HAP formation. In the mouse model of XLH (Hyp mice), excessive FGF23 contributes to PPi accumulation, by reducing TNAP expression and decreasing the conversion to Pi (REF). These data partly explain why elevating serum phosphate levels does not contribute to improving bone minersalisation in XLH. Furthermore, the key to improving bone mineralsition in XLH may lie in reducing PPi:Pi ratio through regulation of one or more osteoblastic genes in the bone mineralisation pathway. 336359512700Figure 4: Basic principles of vitamin D synthesis and catabolism.Figure 4: Basic principles of vitamin D synthesis and catabolism.In healthy patients, hypophosphatemia stimulates the synthesis of 1,25(OH)D3, and hyperphosphatemia down regulates the synthesis of 1,25(OH)D3 ADDIN EN.CITE <EndNote><Cite><Author>Portale</Author><Year>2012</Year><RecNum>66</RecNum><DisplayText>(Portale, Perwad &amp; Miller 2012)</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032235″>66</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Portale, Anthony A.</author><author>Perwad, Farzana</author><author>Miller, Walter L.</author></authors></contributors><titles><title>Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action</title><secondary-title>Pediatric Bone</secondary-title></titles><pages>679-698</pages><dates><year>2012</year></dates><isbn>9780123820402</isbn><urls></urls><electronic-resource-num>10.1016/b978-0-12-382040-2.10025-5</electronic-resource-num></record></Cite></EndNote>(Portale, Perwad & Miller 2012). In XLH patients, hypophosphatemia results in a drop in 1,25(OH)D3, not an increase ADDIN EN.CITE <EndNote><Cite><Author>Portale</Author><Year>2012</Year><RecNum>66</RecNum><DisplayText>(Portale, Perwad &amp; Miller 2012)</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032235″>66</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Portale, Anthony A.</author><author>Perwad, Farzana</author><author>Miller, Walter L.</author></authors></contributors><titles><title>Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action</title><secondary-title>Pediatric Bone</secondary-title></titles><pages>679-698</pages><dates><year>2012</year></dates><isbn>9780123820402</isbn><urls></urls><electronic-resource-num>10.1016/b978-0-12-382040-2.10025-5</electronic-resource-num></record></Cite></EndNote>(Portale, Perwad & Miller 2012). To make matters worse, CYP24A1 levels increase and therefore a high rate of catabolism ensues ADDIN EN.CITE <EndNote><Cite><Author>Portale</Author><Year>2012</Year><RecNum>66</RecNum><DisplayText>(Portale, Perwad &amp; Miller 2012)</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032235″>66</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Book Section”>5</ref-type><contributors><authors><author>Portale, Anthony A.</author><author>Perwad, Farzana</author><author>Miller, Walter L.</author></authors></contributors><titles><title>Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action</title><secondary-title>Pediatric Bone</secondary-title></titles><pages>679-698</pages><dates><year>2012</year></dates><isbn>9780123820402</isbn><urls></urls><electronic-resource-num>10.1016/b978-0-12-382040-2.10025-5</electronic-resource-num></record></Cite></EndNote>(Portale, Perwad & Miller 2012). Less vitamin D in, and increased vitamin D catabolised, results in reduced bone mineral levels. Some speculation around why this happens was published in 1980. Meyer et al. suggested that the low phosphate levels trigger an increase in serum calcium levels, and therefore a reduction in PTH levels. The drop in PTH may explain the low 1,25(OH)D3 levels. When supplemented with phosphate alone, XLH patients show a partial improvement in the rachitic phenotype, but no improvement in endosteal bone mineralisation ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><DisplayText>(Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Marie, Travers & Glorieux 1981). Phosphate supplementation also only works in the young, with no benefits seen in patients with osteomalacia (the adult form of rickets) ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><DisplayText>(Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Marie, Travers & Glorieux 1981). Role of Vitamin D therapy and in XLH: The vitamin D endocrine system is responsible for the maintenance of calcium homoeostasis and skeletal growth ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>81</RecNum><DisplayText>(Rowling, Matthew J et al. 2007)</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″>81</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, Matthew J</author><author>Gliniak, Christy</author><author>Welsh, JoEllen</author><author>Fleet, James C</author></authors></contributors><titles><title>High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice</title><secondary-title>The Journal of nutrition</secondary-title></titles><periodical><full-title>The Journal of nutrition</full-title></periodical><pages>2608-2615</pages><volume>137</volume><number>12</number><dates><year>2007</year></dates><isbn>0022-3166</isbn><urls><related-urls><url>https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4</url></related-urls></urls></record></Cite></EndNote>(Rowling, Matthew J et al. 2007). Optimal bone health is achieved when adequate vitamin vitamin D is metabolised and mediated properly through genes in the intestine, kidney, and bone ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>81</RecNum><DisplayText>(Rowling, Matthew J et al. 2007)</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″>81</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, Matthew J</author><author>Gliniak, Christy</author><author>Welsh, JoEllen</author><author>Fleet, James C</author></authors></contributors><titles><title>High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice</title><secondary-title>The Journal of nutrition</secondary-title></titles><periodical><full-title>The Journal of nutrition</full-title></periodical><pages>2608-2615</pages><volume>137</volume><number>12</number><dates><year>2007</year></dates><isbn>0022-3166</isbn><urls><related-urls><url>https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4</url></related-urls></urls></record></Cite></EndNote>(Rowling, Matthew J et al. 2007). While vVitamin D can be obtained through diet and supplements, the predominant source for vitamin D is via or through the skin upon exposure to U V radiation from the sun. These forms of vitamin D are parent calciferols D2 and D3. Metabolism of these calciferolsVitamin D3, formed in the skin, is metabolised further occurs in the liver to form 25-hydroxyvitamin D (25(OH)D), mediated primarily by the hepatic enzymes CYP2R1 and CYP27A1 (Figure 4) (REF). 25(OH)D is the major circulating metabolite of vitamin D and while it is itself This new form of vitamin is 25(OH)D3. It has low affinity for the vitamin D receptor (unlikely to compete with active vitamin D), and is considered inactive, . the circulating levels of 25(OH)D is used clinically to determine a person’s vitamin D status (REF). For vitamin D to exert its activity, 25(OH)D3 is required to be further metabolised to 1,25(OH)2D catalysed by the renal cytochrome enzyme CYP27B1 enzymewhere hydroxylation results in calcitriol (active vitamin D). Active vitamin D, 1,25(OH)2D3, iOnce synthesised, active vitamin D can acts upon many tissues several via the binding the vitamin D receptor (VDR) and modulates various systems tissues PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3dsaW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
UmVjTnVtPjgxPC9SZWNOdW0+PERpc3BsYXlUZXh0PihSb2l6ZW4gZXQgYWwuIDIwMTg7IFJvd2xp
bmcsIE1hdHRoZXcgSiBldCBhbC4gMjAwNyk8L0Rpc3BsYXlUZXh0PjxyZWNvcmQ+PHJlYy1udW1i
ZXI+ODE8L3JlYy1udW1iZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ4Zndm
eHM5djJ6cnBlOWVyMmE5cHdkOWZ4djV6MnY5MndlNWQiIHRpbWVzdGFtcD0iMTUzMzExMzcyOCI+
ODE8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0iSm91cm5hbCBBcnRpY2xlIj4x
NzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0aG9yPlJvd2xpbmcsIE1hdHRo
ZXcgSjwvYXV0aG9yPjxhdXRob3I+R2xpbmlhaywgQ2hyaXN0eTwvYXV0aG9yPjxhdXRob3I+V2Vs
c2gsIEpvRWxsZW48L2F1dGhvcj48YXV0aG9yPkZsZWV0LCBKYW1lcyBDPC9hdXRob3I+PC9hdXRo
b3JzPjwvY29udHJpYnV0b3JzPjx0aXRsZXM+PHRpdGxlPkhpZ2ggZGlldGFyeSB2aXRhbWluIEQg
cHJldmVudHMgaHlwb2NhbGNlbWlhIGFuZCBvc3Rlb21hbGFjaWEgaW4gQ1lQMjdCMSBrbm9ja291
dCBtaWNlPC90aXRsZT48c2Vjb25kYXJ5LXRpdGxlPlRoZSBKb3VybmFsIG9mIG51dHJpdGlvbjwv
c2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlRoZSBKb3Vy
bmFsIG9mIG51dHJpdGlvbjwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjI2MDgtMjYx
NTwvcGFnZXM+PHZvbHVtZT4xMzc8L3ZvbHVtZT48bnVtYmVyPjEyPC9udW1iZXI+PGRhdGVzPjx5
ZWFyPjIwMDc8L3llYXI+PC9kYXRlcz48aXNibj4wMDIyLTMxNjY8L2lzYm4+PHVybHM+PHJlbGF0
ZWQtdXJscz48dXJsPmh0dHBzOi8vd2F0ZXJtYXJrLnNpbHZlcmNoYWlyLmNvbS8yNjA4LnBkZj90
b2tlbj1BUUVDQUhpMjA4QkU0OU9vYW45a2toV19FcmN5N0RtM1pMXzlDZjNxZktBYzQ4NXlzZ0FB
QWNBd2dnRzhCZ2txaGtpRzl3MEJCd2FnZ2dHdE1JSUJxUUlCQURDQ0FhSUdDU3FHU0liM0RRRUhB
VEFlQmdsZ2hrZ0JaUU1FQVM0d0VRUU1wbURfS213UmQ0c0d2RmdqQWdFUWdJSUJjNmRuVXhvQ1pM
MVlhQlpka2MydWNJNVgxLVJRZlh2UFpXS1EwMk9WY1JaWnZPRmpsMUZ6OVNDYTM4YmI3ZDBkNVZj
bGpkMXExVms4bGExTWxuTTdQTVVOT3l6SVJ4NDVPUUVCOFRvb3NrUk8xMnRjeklMMGdzYUFCcnRR
cHBRa2owV1pRdWEwM19SeklBbVVic0RXRV9jZGxib3RRQmo3aUFJU1lxcjBjMXM3SlQ4eFB6N0kz
dFJmNmkyUU5McEkxMDZHSEJXX1ZKR3ZlVXNnbzFVRHIzWnZsVngwZXNUSTU4N2hQelphUllzR2FZ
STZOUFpJNVJxZ2pRb0NNYUlhSU9mTGREMndCN3IwOTRETWdTT3JRTHRhR0QzSFVvQmJzYUpCZ09Y
X1VxN1dBM200bGVPQUdwMmdzdldIaDh6WHlXSDRiekpaUDZSY2JfWTFtNFQ0cFJPX2pSckZORE9u
Z3ZwUC1SRVc2M014NTVfY2ozdnpEWVhjOEo3RXJ6aS1OTWg0N2tFMm41M21uZXM0aERNaW4zVHBQ
cWcwTFY5Zjk1OGFLVHZjVkhkRDFpaC1raWNnU1lhMTJhRFZsS2ZqYjNocFA5MHAxM2VaZkpoM2R2
RURTOE9tRWdCYUxIdTlUYm9wQmlFTEsybnJFbS00PC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxz
PjwvcmVjb3JkPjwvQ2l0ZT48Q2l0ZT48QXV0aG9yPlJvaXplbjwvQXV0aG9yPjxZZWFyPjIwMTg8
L1llYXI+PFJlY051bT45MTwvUmVjTnVtPjxyZWNvcmQ+PHJlYy1udW1iZXI+OTE8L3JlYy1udW1i
ZXI+PGZvcmVpZ24ta2V5cz48a2V5IGFwcD0iRU4iIGRiLWlkPSJ4ZndmeHM5djJ6cnBlOWVyMmE5
cHdkOWZ4djV6MnY5MndlNWQiIHRpbWVzdGFtcD0iMTUzNDIyNTMzMyI+OTE8L2tleT48a2V5IGFw
cD0iRU5XZWIiIGRiLWlkPSIiPjA8L2tleT48L2ZvcmVpZ24ta2V5cz48cmVmLXR5cGUgbmFtZT0i
Sm91cm5hbCBBcnRpY2xlIj4xNzwvcmVmLXR5cGU+PGNvbnRyaWJ1dG9ycz48YXV0aG9ycz48YXV0
aG9yPlJvaXplbiwgSi4gRC48L2F1dGhvcj48YXV0aG9yPkxpLCBELjwvYXV0aG9yPjxhdXRob3I+
TyZhcG9zO0xlYXIsIEwuPC9hdXRob3I+PGF1dGhvcj5KYXZhaWQsIE0uIEsuPC9hdXRob3I+PGF1
dGhvcj5TaGF3LCBOLiBKLjwvYXV0aG9yPjxhdXRob3I+RWJlbGluZywgUC4gUi48L2F1dGhvcj48
YXV0aG9yPk5ndXllbiwgSC4gSC48L2F1dGhvcj48YXV0aG9yPlJvZGRhLCBDLiBQLjwvYXV0aG9y
PjxhdXRob3I+VGh1bW1lbCwgSy4gRS48L2F1dGhvcj48YXV0aG9yPlRoYWNoZXIsIFQuIEQuPC9h
dXRob3I+PGF1dGhvcj5IYWtvbmFyc29uLCBILjwvYXV0aG9yPjxhdXRob3I+TGV2aW5lLCBNLiBB
LjwvYXV0aG9yPjwvYXV0aG9ycz48L2NvbnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRpdmlzaW9u
IG9mIEVuZG9jcmlub2xvZ3kgYW5kIERpYWJldGVzIGFuZC4mI3hEO0NlbnRlciBmb3IgQXBwbGll
ZCBHZW5vbWljcywgVGhlIENoaWxkcmVuJmFwb3M7cyBIb3NwaXRhbCBvZiBQaGlsYWRlbHBoaWEg
KENIT1ApLCBVbml2ZXJzaXR5IG9mIFBlbm5zeWx2YW5pYSBQZXJlbG1hbiBTY2hvb2wgb2YgTWVk
aWNpbmUsIFBoaWxhZGVscGhpYSwgUGVubnN5bHZhbmlhLCBVU0EuJiN4RDtOdWZmaWVsZCBEZXBh
cnRtZW50IG9mIE9ydGhvcGFlZGljcywgUmhldW1hdG9sb2d5IGFuZCBNdXNjdWxvc2tlbGV0YWwg
U2NpZW5jZXMsIFVuaXZlcnNpdHkgb2YgT3hmb3JkLCBPeGZvcmQsIFVuaXRlZCBLaW5nZG9tLiYj
eEQ7RGVwYXJ0bWVudCBvZiBFbmRvY3Jpbm9sb2d5IGFuZCBEaWFiZXRlcywgQmlybWluZ2hhbSBD
aGlsZHJlbiZhcG9zO3MgSG9zcGl0YWwgYW5kIEluc3RpdHV0ZSBvZiBNZXRhYm9saXNtIGFuZCBT
eXN0ZW1zIFJlc2VhcmNoLCBVbml2ZXJzaXR5IG9mIEJpcm1pbmdoYW0sIEJpcm1pbmdoYW0sIFVu
aXRlZCBLaW5nZG9tLiYjeEQ7RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgU2Nob29sIG9mIENsaW5p
Y2FsIFNjaWVuY2VzLCBNb25hc2ggVW5pdmVyc2l0eSwgQ2xheXRvbiwgVmljdG9yaWEsIEF1c3Ry
YWxpYS4mI3hEO0F1c3RyYWxpYW4gSW5zdGl0dXRlIGZvciBNdXNjdWxvc2tlbGV0YWwgU2NpZW5j
ZSwgU3Vuc2hpbmUgSG9zcGl0YWwsIGFuZCBEZXBhcnRtZW50IG9mIFBhZWRpYXRyaWNzLCBVbml2
ZXJzaXR5IG9mIE1lbGJvdXJuZSxQYXJrdmlsbGUsIFZpY3RvcmlhLCBBdXN0cmFsaWEuJiN4RDtE
ZXBhcnRtZW50IG9mIFBoYXJtYWNldXRpY3MsIFVuaXZlcnNpdHkgb2YgV2FzaGluZ3RvbiwgU2Vh
dHRsZSwgV2FzaGluZ3RvbiwgVVNBLiYjeEQ7RGVwYXJ0bWVudCBvZiBGYW1pbHkgTWVkaWNpbmUs
IE1heW8gQ2xpbmljLCBSb2NoZXN0ZXIsIE1pbm5lc290YSwgVVNBLjwvYXV0aC1hZGRyZXNzPjx0
aXRsZXM+PHRpdGxlPkNZUDNBNCBtdXRhdGlvbiBjYXVzZXMgdml0YW1pbiBELWRlcGVuZGVudCBy
aWNrZXRzIHR5cGUgMzwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5KIENsaW4gSW52ZXN0PC9zZWNv
bmRhcnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+SiBDbGluIEludmVz
dDwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjE5MTMtMTkxODwvcGFnZXM+PHZvbHVt
ZT4xMjg8L3ZvbHVtZT48bnVtYmVyPjU8L251bWJlcj48ZWRpdGlvbj4yMDE4LzAyLzIxPC9lZGl0
aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5Cb25lIEJpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+Qm9u
ZSBkaXNlYXNlPC9rZXl3b3JkPjxrZXl3b3JkPkdlbmV0aWMgZGlzZWFzZXM8L2tleXdvcmQ+PGtl
eXdvcmQ+R2VuZXRpY3M8L2tleXdvcmQ+PC9rZXl3b3Jkcz48ZGF0ZXM+PHllYXI+MjAxODwveWVh
cj48cHViLWRhdGVzPjxkYXRlPk1heSAxPC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+
MTU1OC04MjM4IChFbGVjdHJvbmljKSYjeEQ7MDAyMS05NzM4IChMaW5raW5nKTwvaXNibj48YWNj
ZXNzaW9uLW51bT4yOTQ2MTk4MTwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1
cmw+aHR0cHM6Ly93d3cubmNiaS5ubG0ubmloLmdvdi9wdWJtZWQvMjk0NjE5ODE8L3VybD48L3Jl
bGF0ZWQtdXJscz48L3VybHM+PGN1c3RvbTI+UE1DNTkxOTg4NDwvY3VzdG9tMj48ZWxlY3Ryb25p
Yy1yZXNvdXJjZS1udW0+MTAuMTE3Mi9KQ0k5ODY4MDwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+
PC9yZWNvcmQ+PC9DaXRlPjwvRW5kTm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3dsaW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE.DATA (Roizen et al. 2018; Rowling, Matthew J et al. 2007). While the classical action of 1,25(OH)2D is to stimulate intestinal calcium absorption, 1,25(OH)2D also and systems including thehas been shown to regulate the serval other systems including cardiovascular health, immune system, lung health, anti-neoplastic action in several red blood cells, cancers cells, skin maturation as well multiple direct roles in bone homeostasis (as reviewed in the parathyroid gland, gut, and bone. REF).s a ligand with high affinity for the vitamin D receptor PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3dsaW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3dsaW5nPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48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ADDIN EN.CITE.DATA (Roizen et al. 2018; Rowling, Matthew J et al. 2007). Once synthesised, active vitamin D can act upon several tissues and systems including the immune system, red blood cells, cancer cells, the parathyroid gland, gut, and bone. Aside from bone diseases, inadequate vitamin D activity is associated with several other serious conditions such as chronic kidney disease (CKD), cancer, hepatic disease, cardiovascular disease, autoimmune disease, depression, and obesity ADDIN EN.CITE ;EndNote;;Cite;;Author;Rowling;/Author;;Year;2007;/Year;;RecNum;81;/RecNum;;DisplayText;(Rowling, Matthew J et al. 2007);/DisplayText;;record;;rec-number;81;/rec-number;;foreign-keys;;key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″;81;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Rowling, Matthew J;/author;;author;Gliniak, Christy;/author;;author;Welsh, JoEllen;/author;;author;Fleet, James C;/author;;/authors;;/contributors;;titles;;title;High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice;/title;;secondary-title;The Journal of nutrition;/secondary-title;;/titles;;periodical;;full-title;The Journal of nutrition;/full-title;;/periodical;;pages;2608-2615;/pages;;volume;137;/volume;;number;12;/number;;dates;;year;2007;/year;;/dates;;isbn;0022-3166;/isbn;;urls;;related-urls;;url;https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4;/url;;/related-urls;;/urls;;/record;;/Cite;;/EndNote;(Rowling, Matthew J et al. 2007). Nutritional vitamin D deficiency can be easily restored in the form of dietary modification, vitamin D analogues, or over the counter vitamin D metabolites. In vitamin D resistant rickets (VDRR), or XLH, excessive FGF23 actions results in lower renal 1,25(OH)D production. However, few studies have investigated the vitamin D status, as measured by 25(OH)D levels, in XLH patients. are often reported as only being slightly vitamin D deficient or even “vitamin D replete”, which, if they had normal phosphorus levels, would be correct. However, given the level of hypophosphatemia, one would expect the 1,25(OH)D3 to be far higher ADDIN EN.CITE ;EndNote;;Cite;;Author;Azam;/Author;;Year;2003;/Year;;RecNum;4275;/RecNum;;DisplayText;(Azam et al. 2003);/DisplayText;;record;;rec-number;4275;/rec-number;;foreign-keys;;key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599893″;4275;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Azam, N.;/author;;author;Zhang, M. Y.;/author;;author;Wang, X.;/author;;author;Tenenhouse, H. S.;/author;;author;Portale, A. A.;/author;;/authors;;/contributors;;titles;;title;Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice;/title;;secondary-title;Endocrinology;/secondary-title;;/titles;;periodical;;full-title;Endocrinology;/full-title;;abbr-1;Endocrinology;/abbr-1;;/periodical;;pages;3463-8;/pages;;volume;144;/volume;;number;8;/number;;dates;;year;2003;/year;;/dates;;label;22747512;/label;;urls;;/urls;;/record;;/Cite;;/EndNote;(Azam et al. 2003). This gap in the knowledge is not unexpected given the XLH disease is considered to be disorder that impacts in renal activation of 1,25(OH)D, and not 25(OH)D production. Thus the focus of current therapies include administering 1,25(OH)2D3 to restore levels or to use a synthetic vitamin D analogues to mimics 1,25(OH)2D3 activity ADDIN EN.CITE ;EndNote;;Cite;;Author;Makitie;/Author;;Year;2003;/Year;;RecNum;22;/RecNum;;DisplayText;(Makitie et al. 2003);/DisplayText;;record;;rec-number;22;/rec-number;;foreign-keys;;key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″;22;/key;;key app=”ENWeb” db-id=””;0;/key;;/foreign-keys;;ref-type name=”Journal Article”;17;/ref-type;;contributors;;authors;;author;Makitie, O.;/author;;author;Doria, A.;/author;;author;Kooh, S. W.;/author;;author;Cole, W. G.;/author;;author;Daneman, A.;/author;;author;Sochett, E.;/author;;/authors;;/contributors;;auth-address;Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected];/auth-address;;titles;;title;Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets;/title;;secondary-title;J Clin Endocrinol Metab;/secondary-title;;/titles;;periodical;;full-title;J Clin Endocrinol Metab;/full-title;;/periodical;;pages;3591-7;/pages;;volume;88;/volume;;number;8;/number;;keywords;;keyword;Age of Onset;/keyword;;keyword;Body Height/drug effects;/keyword;;keyword;Bone and Bones/diagnostic imaging;/keyword;;keyword;Calcitriol/blood;/keyword;;keyword;Child;/keyword;;keyword;Child, Preschool;/keyword;;keyword;Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). Treatment is often supplied with oral phosphate which can be effective in improving growth, healing, and biochemical parameters in children. However, many children fail to respond to treatment for reasons that are not clear ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003) and the concentration of vitamin D required to improve bone outcomes is far greater than usual and can lead to significant side effects. XLH patients are often reported as only being slightly vitamin D deficient or even “vitamin D replete”, which, if they had normal phosphorus levels, would be correct. However, given the level of hypophosphatemia, one would expect the 1,25(OH)D3 to be far higher ADDIN EN.CITE <EndNote><Cite><Author>Azam</Author><Year>2003</Year><RecNum>4275</RecNum><DisplayText>(Azam et al. 2003)</DisplayText><record><rec-number>4275</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599893″>4275</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Azam, N.</author><author>Zhang, M. Y.</author><author>Wang, X.</author><author>Tenenhouse, H. S.</author><author>Portale, A. A.</author></authors></contributors><titles><title>Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title><abbr-1>Endocrinology</abbr-1></periodical><pages>3463-8</pages><volume>144</volume><number>8</number><dates><year>2003</year></dates><label>22747512</label><urls></urls></record></Cite></EndNote>(Azam et al. 2003). Current Therapies in XLH: In clinical settings, the normalisation of serum alkaline phosphatase levels and a radiological confirmation of healing rickets is the usual endpoint of treatment for children PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA (Linglart et al. 2014). Current therapies include active vitamin D (1,25(OH)D3), synthetic vitamin D analogues, phosphate, growth hormones, and surgery ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). Treatment with 1,25(OH)D3, or comparable analogue, in addition to phosphate has been shown to improve growth, healing, and biochemistry in children. Some children however fail to respond ADDIN EN.CITE <EndNote><Cite><Author>Makitie</Author><Year>2003</Year><RecNum>22</RecNum><DisplayText>(Makitie et al. 2003)</DisplayText><record><rec-number>22</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519794285″>22</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Makitie, O.</author><author>Doria, A.</author><author>Kooh, S. W.</author><author>Cole, W. G.</author><author>Daneman, A.</author><author>Sochett, E.</author></authors></contributors><auth-address>Division of Endocrinology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada M5G 1X8. [email protected]</auth-address><titles><title>Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>3591-7</pages><volume>88</volume><number>8</number><keywords><keyword>Age of Onset</keyword><keyword>Body Height/drug effects</keyword><keyword>Bone and Bones/diagnostic imaging</keyword><keyword>Calcitriol/blood</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Growth/*drug effects</keyword><keyword>Humans</keyword><keyword>Hypophosphatemia/blood</keyword><keyword>Hypophosphatemia, Familial/diagnostic imaging/metabolism/*therapy</keyword><keyword>Infant</keyword><keyword>Radiography</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0021-972X (Print) 0021-972X (Linking)</isbn><accession-num>12915641</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/12915641</url></related-urls></urls><electronic-resource-num>10.1210/jc.2003-030036</electronic-resource-num></record></Cite></EndNote>(Makitie et al. 2003). Treatment usually occurs most rigorously during the child’s growth period and can consist of multiple daily phosphate intakes as well as twice daily intakes of 1,25(OH)D3 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA (Linglart et al. 2014). It comes with complications though. Although the vitamin D and phosphate improve the rickets, it often causesside-effects including hypercalcemia, nausea, vomiting, nephrocalcinosis, secondary hyperparathyroidism, and even higher FGF23 levels can occur PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Leifheit-Nestler et al. 2017; Liu et al. 2016a).
In an attempt to overcome some of the side-effects of using 1,25(OH)2D3, vVitamin D analogues are frequently used are a form of synthetic vitamin D and the three most common forms used in the treatment of XLH are Eldecalcitriol, Alfacalcidiol, and Calcitriol. For example, aAlphacalcidiol and calcitriol may be useful in lowering PTHnomralising biochemical parameters such as PTH in XLH patients. However, It has been shown to lower PTH effectively in patients with hyperparathyroidism and alleviate hyper parathyroid bone disease. It is risky though, hypercalcaemia remains a side-effect of alphacalcidiol treatment which, if sustained can lead to vascular and other soft tissue calcificationis likely and calcification of vascular tissue is a major risk. Experimentally, Eldecalcitriol (ED71) has been shown in the mosue model for XLH (HYP mice) to improve completely restored renal phosphate transport and Sodium-phosphate transporter protein levels in mice, despite levels of FGF23 increasing PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Kido et al. 2013). The mice increased in weight, their bone mineral content and serum phsopajhte levels increased, and the growth plate structure was improved. Serum phosphate levels normalised and the total bone volume increased. ED71 does not treat the underlying FGF23 excess, but may be a useful treatment in XLH in the future PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaWRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Kido et al. 2013), however, ED-71 also causes hypercalcemia in other studies related to osteoporosis-treatment.Many studies to propose vitamin D-related treatments for XLH have used the HYP mouse model as a homolog for XLH for proof-of-principle studies. This year, the FDA approved the use of an FGF23 antibody for use in XLH patients. Whilst beneficial in many aspects, there are many side effects that will make the treatment inappropriate for many patients. Mouse model for XLH: HYP mice were first discovered in Jackson Labs in 1966 and are now the well-established murine homolog for human XLH. The biochemical and skeletal responses to phosphate supplementation in HYP are very similar to human XLH patients and are thus a very valuable resource for researching this rare disease ADDIN EN.CITE <EndNote><Cite><Author>Eicher</Author><Year>1976</Year><RecNum>76</RecNum><DisplayText>(Eicher et al. 1976; Marie, Travers &amp; Glorieux 1981)</DisplayText><record><rec-number>76</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032419″>76</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Eicher, E. M</author><author>Southard, J. L</author><author>Scriver, C. R</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Hypophosphatemia: Mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets</title><secondary-title>Proc Natl Acad Sci USA</secondary-title></titles><periodical><full-title>Proc Natl Acad Sci USA</full-title></periodical><pages>4667-4671</pages><volume>73</volume><number>12</number><dates><year>1976</year></dates><urls></urls></record></Cite><Cite><Author>Marie</Author><Year>1981</Year><RecNum>17</RecNum><record><rec-number>17</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519793688″>17</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J.</author><author>Travers, R.</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse</title><secondary-title>Journal of Clinical Investigation</secondary-title></titles><periodical><full-title>Journal of Clinical Investigation</full-title></periodical><pages>911-914</pages><volume>67</volume><number>3</number><dates><year>1981</year></dates><isbn>0021-9738</isbn><urls></urls><electronic-resource-num>10.1172/jci110110</electronic-resource-num></record></Cite></EndNote>(Eicher et al. 1976; Marie, Travers & Glorieux 1981). HYP mice display many of the same phenotypic traits such as hypophosphatemia, rickets, high serum alkaline phosphatase, slight modest hypocalcaemia, and marked reduction ined bone growth and mineralisation content ADDIN EN.CITE <EndNote><Cite><Author>Eicher</Author><Year>1976</Year><RecNum>76</RecNum><DisplayText>(Eicher et al. 1976; Marie, P.J, Travers, R &amp; Glorieux, F.H 1982)</DisplayText><record><rec-number>76</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533032419″>76</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Eicher, E. M</author><author>Southard, J. L</author><author>Scriver, C. R</author><author>Glorieux, F. H.</author></authors></contributors><titles><title>Hypophosphatemia: Mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets</title><secondary-title>Proc Natl Acad Sci USA</secondary-title></titles><periodical><full-title>Proc Natl Acad Sci USA</full-title></periodical><pages>4667-4671</pages><volume>73</volume><number>12</number><dates><year>1976</year></dates><urls></urls></record></Cite><Cite><Author>Marie</Author><Year>1982</Year><RecNum>16</RecNum><record><rec-number>16</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519792889″>16</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P.J</author><author>Travers, R</author><author>Glorieux, F.H</author></authors></contributors><titles><title>Bone Response to Phosphate and Vitamin D Metabolites in the Hypophosphatemic mouse model</title><secondary-title>Calcified Tissue International</secondary-title></titles><periodical><full-title>Calcified Tissue International</full-title></periodical><pages>158-164</pages><volume>34</volume><number>1</number><dates><year>1982</year></dates><urls></urls></record></Cite></EndNote>(Eicher et al. 1976; Marie, P.J, Travers, R & Glorieux, F.H 1982). FGF23 levels in HYP mice are up to 5 to 25- fold higher than in WT mice, and CYP24A1 levels are significantly elevated ADDIN EN.CITE <EndNote><Cite><Author>Azam</Author><Year>2003</Year><RecNum>4275</RecNum><DisplayText>(Azam et al. 2003)</DisplayText><record><rec-number>4275</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599893″>4275</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Azam, N.</author><author>Zhang, M. Y.</author><author>Wang, X.</author><author>Tenenhouse, H. S.</author><author>Portale, A. A.</author></authors></contributors><titles><title>Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title><abbr-1>Endocrinology</abbr-1></periodical><pages>3463-8</pages><volume>144</volume><number>8</number><dates><year>2003</year></dates><label>22747512</label><urls></urls></record></Cite></EndNote>(Azam et al. 2003). Similarly to XLH patients, HYP mice display an “intestinal resistance” to vitamin D therapy and defective renal CYP27B1 activity ADDIN EN.CITE <EndNote><Cite><Author>Meyer</Author><Year>1996</Year><RecNum>15</RecNum><DisplayText>(Meyer, Meyer &amp; Morgan 1996)</DisplayText><record><rec-number>15</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519792619″>15</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Meyer, R.A</author><author>Meyer, M. H</author><author>Morgan, P.L</author></authors></contributors><titles><title><style face=”normal” font=”default” size=”100%”>Effects of Altered Diet on Serum levels of 1,25-Dihydroxyvitamin D and Parathyroid Hormone in X-Linked Hypophosphatemic </style><style face=”italic” font=”default” size=”100%”>(HYP and Gy) </style><style face=”normal” font=”default” size=”100%”>Mice</style></title><secondary-title>Bone</secondary-title></titles><periodical><full-title>Bone</full-title></periodical><pages>23-28</pages><volume>18</volume><number>1</number><dates><year>1996</year></dates><urls></urls></record></Cite></EndNote>(Meyer, Meyer & Morgan 1996). HYP mice have been reported to have low 1,25(OH)2D3 and 25(OH)D3 levels, and indeed, our group has also found this. More recent literature suggests that the disorder lies in the HYP kidney and that if the kidney were removed and replaced with a WT kidney, the hypophosphatemia would be rescued. It wasn’t ADDIN EN.CITE <EndNote><Cite><Author>Panda</Author><Year>2001</Year><RecNum>56</RecNum><DisplayText>(Panda et al. 2001)</DisplayText><record><rec-number>56</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533031870″>56</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Panda, D. K</author><author>Miao, D</author><author>Tremblay, M. L</author><author>Sirois, J</author><author>Farookhi, R</author><author>Hendy, G. N</author><author>Goltzman, D.</author></authors></contributors><titles><title>Targeted ablation of the 25-hydroxyvitamin D 1a-hydroxlylase enzyme: Evidence for skeletal, reproductive, and immune dysfunction</title><secondary-title>PNAS</secondary-title></titles><periodical><full-title>PNAS</full-title></periodical><pages>7498-7503</pages><volume>98</volume><number>13</number><dates><year>2001</year></dates><urls></urls></record></Cite></EndNote>(Panda et al. 2001). The focus therefore has moved to counteracting the effects of FGF23 excess PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+
PFJlY051bT44OTwvUmVjTnVtPjxEaXNwbGF5VGV4dD4oTGluZ2xhcnQgZXQgYWwuIDIwMTQpPC9E
aXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjg5PC9yZWMtbnVtYmVyPjxmb3JlaWduLWtl
eXM+PGtleSBhcHA9IkVOIiBkYi1pZD0ieGZ3ZnhzOXYyenJwZTllcjJhOXB3ZDlmeHY1ejJ2OTJ3
ZTVkIiB0aW1lc3RhbXA9IjE1MzM1Mjc5NTUiPjg5PC9rZXk+PGtleSBhcHA9IkVOV2ViIiBkYi1p
ZD0iIj4wPC9rZXk+PC9mb3JlaWduLWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNs
ZSI+MTc8L3JlZi10eXBlPjxjb250cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5MaW5nbGFydCwg
QS48L2F1dGhvcj48YXV0aG9yPkJpb3NzZS1EdXBsYW4sIE0uPC9hdXRob3I+PGF1dGhvcj5Ccmlv
dCwgSy48L2F1dGhvcj48YXV0aG9yPkNoYXVzc2FpbiwgQy48L2F1dGhvcj48YXV0aG9yPkVzdGVy
bGUsIEwuPC9hdXRob3I+PGF1dGhvcj5HdWlsbGF1bWUtQ3ppdHJvbSwgUy48L2F1dGhvcj48YXV0
aG9yPkthbWVuaWNreSwgUC48L2F1dGhvcj48YXV0aG9yPk5ldm91eCwgSi48L2F1dGhvcj48YXV0
aG9yPlByaWUsIEQuPC9hdXRob3I+PGF1dGhvcj5Sb3RoZW5idWhsZXIsIEEuPC9hdXRob3I+PGF1
dGhvcj5XaWNhcnQsIFAuPC9hdXRob3I+PGF1dGhvcj5IYXJ2ZW5ndCwgUC48L2F1dGhvcj48L2F1
dGhvcnM+PC9jb250cmlidXRvcnM+PGF1dGgtYWRkcmVzcz5TZXJ2aWNlIGQmYXBvcztFbmRvY3Jp
bm9sb2dpZSBldCBEaWFiZXRvbG9naWUgZGUgbCZhcG9zO0VuZmFudCBTZXJ2aWNlIGRlIFBlZGlh
dHJpZSBnZW5lcmFsZSAtIENvbnN1bHRhdGlvbiBkZSByaHVtYXRvbG9naWUgU2VydmljZSBkJmFw
b3M7RW5kb2NyaW5vbG9naWUgZXQgZGVzIE1hbGFkaWVzIGRlIGxhIFJlcHJvZHVjdGlvbiBTZXJ2
aWNlIGQmYXBvcztPUkwgZXQgY2hpcnVyZ2llIGNlcnZpY28tbWF4aWxsby1mYWNpYWxlSG9waXRh
bCBCaWNldHJlLCBBUEhQLCA3OCBydWUgZHUgR2VuZXJhbCBMZWNsZXJjLCA5NDI3MCBMZSBLcmVt
bGluIEJpY2V0cmUsIEZyYW5jZSBVbml2ZXJzaXRlIFBhcmlzIDExRmFjdWx0ZSBkZSBNZWRlY2lu
ZSwgSG9waXRhbCBCaWNldHJlLCA3MCBydWUgZHUgR2VuZXJhbCBMZWNsZXJjLCA5NDI3MCBMZSBL
cmVtbGluLUJpY2V0cmUsIEZyYW5jZSBDZW50cmUgZGUgUmVmZXJlbmNlIGRlcyBNYWxhZGllcyBS
YXJlcyBkdSBNZXRhYm9saXNtZSBkdSBDYWxjaXVtIGV0IGR1IFBob3NwaG9yZUxlIEtyZW1saW4t
QmljZXRyZSwgRnJhbmNlIFNlcnZpY2UgZCZhcG9zO09kb250b2xvZ2llLU1hbGFkaWVzIFJhcmVz
IEhvcGl0YWwgQnJldG9ubmVhdSAyIHJ1ZSBDYXJwZWF1eDc1MDE4IFBhcmlzLCBGcmFuY2UgVW5p
dmVyc2l0ZSBQYXJpcyBEZXNjYXJ0ZXMgMTIgUnVlIGRlIGwmYXBvcztFY29sZSBkZSBNZWRlY2lu
ZTc1MDA2IFBhcmlzLCBGcmFuY2UgU2VydmljZSBSaHVtYXRvbG9naWUgQiBIb3BpdGFsIENvY2hp
bkFQSFAsIDI3LCBydWUgZHUgRmF1Ym91cmcgU2FpbnQtSmFjcXVlcywgNzUwMTQgUGFyaXMsIEZy
YW5jZSBDZW50cmUgZGUgUmVmZXJlbmNlIGRlcyBNYWxhZGllcyBSYXJlcyBkZXMgTWFsYWRpZXMg
QXV0by1JbmZsYW1tYXRvaXJlcyBSYXJlcyBkZSBsJmFwb3M7RW5mYW50TGUgS3JlbWxpbiBCaWNl
dHJlLCBGcmFuY2UgU2VydmljZSBkJmFwb3M7ZXhwbG9yYXRpb25zIGZvbmN0aW9ubmVsbGVzIHJl
bmFsZXMgU2VydmljZSBkZSBDaGlydXJnaWUgaW5mYW50aWxlIG9ydGhvcGVkaXF1ZUhvcGl0YWwg
TmVja2VyLUVuZmFudHMgTWFsYWRlcywgMTQ5IHJ1ZSBkZSBTZXZyZXMsIDc1MDE1IFBhcmlzLCBG
cmFuY2UgQXNzb2NpYXRpb24gZGUgcGF0aWVudHMgUlZSSC1YTEgyMCBydWUgTWVybGluIGRlIFRo
aW9udmlsbGUsIDkyMTUwIFN1cmVzbmVzLCBGcmFuY2UuPC9hdXRoLWFkZHJlc3M+PHRpdGxlcz48
dGl0bGU+VGhlcmFwZXV0aWMgbWFuYWdlbWVudCBvZiBoeXBvcGhvc3BoYXRlbWljIHJpY2tldHMg
ZnJvbSBpbmZhbmN5IHRvIGFkdWx0aG9vZDwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5FbmRvY3Ig
Q29ubmVjdDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxl
PkVuZG9jciBDb25uZWN0PC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFnZXM+UjEzLTMwPC9w
YWdlcz48dm9sdW1lPjM8L3ZvbHVtZT48bnVtYmVyPjE8L251bWJlcj48ZWRpdGlvbj4yMDE0LzAy
LzIwPC9lZGl0aW9uPjxrZXl3b3Jkcz48a2V5d29yZD5YLWxpbmtlZCBoeXBvcGhvc3BoYXRlbWlj
IHJpY2tldHM8L2tleXdvcmQ+PGtleXdvcmQ+Ym9uZTwva2V5d29yZD48a2V5d29yZD5jYWxjaXVt
PC9rZXl3b3JkPjxrZXl3b3JkPnJhcmUgZGlzZWFzZXMvc3luZHJvbWVzPC9rZXl3b3JkPjwva2V5
d29yZHM+PGRhdGVzPjx5ZWFyPjIwMTQ8L3llYXI+PC9kYXRlcz48aXNibj4yMDQ5LTM2MTQgKFBy
aW50KSYjeEQ7MjA0OS0zNjE0IChMaW5raW5nKTwvaXNibj48YWNjZXNzaW9uLW51bT4yNDU1MDMy
MjwvYWNjZXNzaW9uLW51bT48dXJscz48cmVsYXRlZC11cmxzPjx1cmw+aHR0cHM6Ly93d3cubmNi
aS5ubG0ubmloLmdvdi9wdWJtZWQvMjQ1NTAzMjI8L3VybD48L3JlbGF0ZWQtdXJscz48L3VybHM+
PGN1c3RvbTI+UE1DMzk1OTczMDwvY3VzdG9tMj48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAu
MTUzMC9FQy0xMy0wMTAzPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+
PC9FbmROb3RlPgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaW5nbGFydDwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA (Linglart et al. 2014). in recent unpublished observations.The mMajority of interventions on HYP mice have used tested the efficacy of either phosphate, 1,25(OH)D3, or a combination of the two.
Therapy with dietary Vitamin D: Williamson et al in 2017 demonstrated that when WT mice are fed 20,000IU/kg of vitamin D during their growth period, they had tougher bone that was more ductile and less brittle. They concluded that Vitamin D3 increases bone strength and peak bone mass PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtc29uPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtc29uPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh
cj48UmVjTnVtPjIxPC9SZWNOdW0+PERpc3BsYXlUZXh0PihXaWxsaWFtc29uIGV0IGFsLiAyMDE3
KTwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj4yMTwvcmVjLW51bWJlcj48Zm9yZWln
bi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9Inhmd2Z4czl2MnpycGU5ZXIyYTlwd2Q5Znh2NXoy
djkyd2U1ZCIgdGltZXN0YW1wPSIxNTE5Nzk0MjA0Ij4yMTwva2V5PjxrZXkgYXBwPSJFTldlYiIg
ZGItaWQ9IiI+MDwva2V5PjwvZm9yZWlnbi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFy
dGljbGUiPjE3PC9yZWYtdHlwZT48Y29udHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+V2lsbGlh
bXNvbiwgTC48L2F1dGhvcj48YXV0aG9yPkhheWVzLCBBLjwvYXV0aG9yPjxhdXRob3I+SGFuc29u
LCBFLiBELjwvYXV0aG9yPjxhdXRob3I+UGl2b25rYSwgUC48L2F1dGhvcj48YXV0aG9yPlNpbXMs
IE4uIEEuPC9hdXRob3I+PGF1dGhvcj5Hb29pLCBKLiBILjwvYXV0aG9yPjwvYXV0aG9ycz48L2Nv
bnRyaWJ1dG9ycz48YXV0aC1hZGRyZXNzPkRlcGFydG1lbnQgb2YgTWVkaWNpbmUsIFN0LiBWaW5j
ZW50JmFwb3M7cyBIb3NwaXRhbCBNZWxib3VybmUsIFRoZSBVbml2ZXJzaXR5IG9mIE1lbGJvdXJu
ZSwgTWVsYm91cm5lLCBWSUMgMzA2NSwgQXVzdHJhbGlhLiYjeEQ7SW5zdGl0dXRlIGZvciBTcG9y
dCwgRXhlcmNpc2UgYW5kIEFjdGl2ZSBMaXZpbmcgKElTRUFMKSwgQ29sbGVnZSBvZiBIZWFsdGgg
YW5kIEJpb21lZGljaW5lLCBWaWN0b3JpYSBVbml2ZXJzaXR5LCBNZWxib3VybmUsIFZJQyA4MDAx
LCBBdXN0cmFsaWE7IEF1c3RyYWxpYW4gSW5zdGl0dXRlIGZvciBNdXNjdWxvc2tlbGV0YWwgU2Np
ZW5jZSAoQUlNU1MpLCBXZXN0ZXJuIEhlYWx0aCwgTWVsYm91cm5lLCBWSUMgMzAyMSwgQXVzdHJh
bGlhLiYjeEQ7SW5zdGl0dXRlIGZvciBTcG9ydCwgRXhlcmNpc2UgYW5kIEFjdGl2ZSBMaXZpbmcg
KElTRUFMKSwgQ29sbGVnZSBvZiBIZWFsdGggYW5kIEJpb21lZGljaW5lLCBWaWN0b3JpYSBVbml2
ZXJzaXR5LCBNZWxib3VybmUsIFZJQyA4MDAxLCBBdXN0cmFsaWE7IERlcGFydG1lbnQgb2YgRXhl
cmNpc2UgJmFtcDsgU3BvcnQgU2NpZW5jZSwgVW5pdmVyc2l0eSBvZiBOb3J0aCBDYXJvbGluYSwg
Q2hhcGVsIEhpbGwsIE5DLCBVU0EuJiN4RDtTdCBWaW5jZW50JmFwb3M7cyBEZXBhcnRtZW50IG9m
IFN1cmdlcnksIFRoZSBVbml2ZXJzaXR5IG9mIE1lbGJvdXJuZSwgTWVsYm91cm5lLCBWSUMgMzA2
NSwgQXVzdHJhbGlhLiYjeEQ7RGVwYXJ0bWVudCBvZiBNZWRpY2luZSwgU3QuIFZpbmNlbnQmYXBv
cztzIEhvc3BpdGFsIE1lbGJvdXJuZSwgVGhlIFVuaXZlcnNpdHkgb2YgTWVsYm91cm5lLCBNZWxi
b3VybmUsIFZJQyAzMDY1LCBBdXN0cmFsaWE7IFN0LiBWaW5jZW50JmFwb3M7cyBJbnN0aXR1dGUg
b2YgTWVkaWNhbCBSZXNlYXJjaCwgOSBQcmluY2VzIFN0LCBGaXR6cm95LCBWSUMgMzA2NSwgQXVz
dHJhbGlhLjwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkhpZ2ggZG9zZSBkaWV0YXJ5IHZp
dGFtaW4gRDMgaW5jcmVhc2VzIGJvbmUgbWFzcyBhbmQgc3RyZW5ndGggaW4gbWljZTwvdGl0bGU+
PHNlY29uZGFyeS10aXRsZT5Cb25lIFJlcDwvc2Vjb25kYXJ5LXRpdGxlPjwvdGl0bGVzPjxwZXJp
b2RpY2FsPjxmdWxsLXRpdGxlPkJvbmUgUmVwPC9mdWxsLXRpdGxlPjwvcGVyaW9kaWNhbD48cGFn
ZXM+NDQtNTA8L3BhZ2VzPjx2b2x1bWU+Njwvdm9sdW1lPjxrZXl3b3Jkcz48a2V5d29yZD4zIHBv
aW50IGJlbmRpbmc8L2tleXdvcmQ+PGtleXdvcmQ+Qm9uZSBzdHJlbmd0aDwva2V5d29yZD48a2V5
d29yZD5DaG9sZWNhbGNpZmVyb2w8L2tleXdvcmQ+PGtleXdvcmQ+Vml0YW1pbiBEMzwva2V5d29y
ZD48L2tleXdvcmRzPjxkYXRlcz48eWVhcj4yMDE3PC95ZWFyPjxwdWItZGF0ZXM+PGRhdGU+SnVu
PC9kYXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGlzYm4+MjM1Mi0xODcyIChQcmludCkmI3hEOzIz
NTItMTg3MiAoTGlua2luZyk8L2lzYm4+PGFjY2Vzc2lvbi1udW0+MjgzNzc5ODE8L2FjY2Vzc2lv
bi1udW0+PHVybHM+PHJlbGF0ZWQtdXJscz48dXJsPmh0dHBzOi8vd3d3Lm5jYmkubmxtLm5paC5n
b3YvcHVibWVkLzI4Mzc3OTgxPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxjdXN0b20yPlBN
QzUzNjUzMDU8L2N1c3RvbTI+PGVsZWN0cm9uaWMtcmVzb3VyY2UtbnVtPjEwLjEwMTYvai5ib25y
LjIwMTcuMDIuMDAxPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9F
bmROb3RlPn==
ADDIN EN.CITE.DATA (Williamson et al. 2017). High dietary vitamin D in the order of 10-20,000IU has been shown to restore vitamin D regulated genes in the intestine and kidney of CYP27B1KO mice ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>81</RecNum><DisplayText>(Rowling, Matthew J et al. 2007)</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″>81</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, Matthew J</author><author>Gliniak, Christy</author><author>Welsh, JoEllen</author><author>Fleet, James C</author></authors></contributors><titles><title>High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice</title><secondary-title>The Journal of nutrition</secondary-title></titles><periodical><full-title>The Journal of nutrition</full-title></periodical><pages>2608-2615</pages><volume>137</volume><number>12</number><dates><year>2007</year></dates><isbn>0022-3166</isbn><urls><related-urls><url>https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4</url></related-urls></urls></record></Cite></EndNote>(Rowling, Matthew J et al. 2007). This suggests that if given in a high enough dose, vitamin D can overcome a lack of CYP27B1 activity in the kidney and even normalise calcium levels. Very high levels of 25(OH)D3, the inactive prohormone, can also influence calcium and bone metabolism independent of its conversion to 1,25(OH)D3 ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>81</RecNum><DisplayText>(Rowling, Matthew J et al. 2007)</DisplayText><record><rec-number>81</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113728″>81</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, Matthew J</author><author>Gliniak, Christy</author><author>Welsh, JoEllen</author><author>Fleet, James C</author></authors></contributors><titles><title>High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice</title><secondary-title>The Journal of nutrition</secondary-title></titles><periodical><full-title>The Journal of nutrition</full-title></periodical><pages>2608-2615</pages><volume>137</volume><number>12</number><dates><year>2007</year></dates><isbn>0022-3166</isbn><urls><related-urls><url>https://watermark.silverchair.com/2608.pdf?token=AQECAHi208BE49Ooan9kkhW_Ercy7Dm3ZL_9Cf3qfKAc485ysgAAAcAwggG8BgkqhkiG9w0BBwagggGtMIIBqQIBADCCAaIGCSqGSIb3DQEHATAeBglghkgBZQMEAS4wEQQMpmD_KmwRd4sGvFgjAgEQgIIBc6dnUxoCZL1YaBZdkc2ucI5X1-RQfXvPZWKQ02OVcRZZvOFjl1Fz9SCa38bb7d0d5Vcljd1q1Vk8la1MlnM7PMUNOyzIRx45OQEB8TooskRO12tczIL0gsaABrtQppQkj0WZQua03_RzIAmUbsDWE_cdlbotQBj7iAISYqr0c1s7JT8xPz7I3tRf6i2QNLpI106GHBW_VJGveUsgo1UDr3ZvlVx0esTI587hPzZaRYsGaYI6NPZI5RqgjQoCMaIaIOfLdD2wB7r094DMgSOrQLtaGD3HUoBbsaJBgOX_Uq7WA3m4leOAGp2gsvWHh8zXyWH4bzJZP6Rcb_Y1m4T4pRO_jRrFNDOngvpP-REW63Mx55_cj3vzDYXc8J7Erzi-NMh47kE2n53mnes4hDMin3TpPqg0LV9f958aKTvcVHdD1ih-kicgSYa12aDVlKfjb3hpP90p13eZfJh3dvEDS8OmEgBaLHu9TbopBiELK2nrEm-4</url></related-urls></urls></record></Cite></EndNote>(Rowling, Matthew J et al. 2007). Therapy with injections of 1,25(OH)D3 or FGF23 Antibodies: Daily injections of 1,25(OH)2D3 and/or FGF23 antibody in HYP mice were shown to improve cortical microarchitecture and whole bone biomechanical properties PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Liu et al. 2016a). The daily treatment of 1,25(OH)2D3 also led to a decrease in urine phosphate wasting despite the increasing FGF23 levels. Mice had normocalcaemia, normal PTH, and increased serum phosphate levels. The sodium-phosphate transporters in the gut were upregulated, and body weight increased. The bone growth plate and metaphyseal organisation were improved, along with the lumbar vertebral height, and trabecular structure PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxSZWNO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ADDIN EN.CITE.DATA (Liu et al. 2016a). However, 1,25(OH)2D3 treatment at this scale in humans would cause hypercalcaemia and nephrocalcinosis.

Only one previous Researchers have treated HYP mice with FGF23 antibodies and found a correction in the phosphate and vitamin D levels, an increase in function of sodium-phosphate cotransporters, and suppressed CYP24A1 expression in the kidney. Antibodies administered during the growth phase had the best effect and resulted in elongation of the femur, improved mineralisation, and normalised cartilage development PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bb25vPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Bb25vPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj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ADDIN EN.CITE.DATA (Aono et al. 2009).Therapy with 25D: Onlystudy has used one very old study from 1982 used the inactive from of vitamin D, 25(OH)D3, to try rescue the bone phenotype ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1982</Year><RecNum>80</RecNum><DisplayText>(Marie, P. J, Travers, R &amp; Glorieux, F. H 1982)</DisplayText><record><rec-number>80</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1533113679″>80</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P. J</author><author>Travers, R</author><author>Glorieux, F. H</author></authors></contributors><titles><title>Healing of bone lesions with 1, 25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title></periodical><pages>904-911</pages><volume>111</volume><number>3</number><dates><year>1982</year></dates><isbn>0013-7227</isbn><urls><related-urls><url><style face=”underline” font=”default” size=”100%”>https://academic.oup.com/endo/article-abstract/111/3/904/2591271?redirectedFrom=fulltext</style></url></related-urls></urls></record></Cite></EndNote>(Marie, P. J, Travers, R & Glorieux, F. H 1982). Marie et al infused a very relatively low doses of 25(OH)D3 into HYP mice over a 3 week period,. iIn addition to phosphate salts in the drinking water., the While 25(OH)D3 levels were shown to marginally improve, the underminerlised bone improved the serum calcium and phosphate levels, and suppressed bone turnover. Despite the normalisation in serum parameters, osteomalacia persisted. This suggested to the authors that there is was a specific bone cell resistance to mineral and/or hormonal treatment ADDIN EN.CITE <EndNote><Cite><Author>Marie</Author><Year>1982</Year><RecNum>16</RecNum><DisplayText>(Marie, P.J, Travers, R &amp; Glorieux, F.H 1982)</DisplayText><record><rec-number>16</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1519792889″>16</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Marie, P.J</author><author>Travers, R</author><author>Glorieux, F.H</author></authors></contributors><titles><title>Bone Response to Phosphate and Vitamin D Metabolites in the Hypophosphatemic mouse model</title><secondary-title>Calcified Tissue International</secondary-title></titles><periodical><full-title>Calcified Tissue International</full-title></periodical><pages>158-164</pages><volume>34</volume><number>1</number><dates><year>1982</year></dates><urls></urls></record></Cite></EndNote>(Marie, P.J, Travers, R & Glorieux, F.H 1982). While this conclusion may be true, no further investigations have been performed to elevate 25(OH)D to levels that, more recently, have shown to improve bone mineralisation in other settings. For example, 20,000IU/kg of vitamin D fed to mice resulting increased bone mineralisation and stronger bones without causing hypercalcemia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtc29uPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtc29uPC9BdXRob3I+PFllYXI+MjAxNzwvWWVh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ADDIN EN.CITE.DATA (Williamson et al. 2017).The role of vitamin D catabolism in XLH25(OH)D3, and indeed 24,25(OH)D3, are often used in conjunction with 1,25D treatment in XLH patients despite little evidence of benefits, and unfortunately there is no further literature about 25(OH)D3 supplementation in HYP mice. We hypothesise that if we are able to increase 25(OH)D3 levels high enough in HYP mice by feeding or infusing at even higher doses, we may begin to overcome any disorder of CYP27B1 in the kidney, or phosphate wasting in the gut. Increasing phosphate and 1,25(OH)D3 supplementation again and again would only increase phosphate wasting, FGF23, PTH, and the risk of hypercalcaemia. We aim to raise 25(OH)D3 levels by feeding the parent calciferols or infusing the inactive metabolite 25(OH)D3.CInhibition of CYP24A1YP24A1 is the sole enzyme involved in the catabolism of vitamin D. While the classical view is that CYP24A1 limits the tissue activity of 1,25(OH)2D, renal CYP24A1 activity has been shown to regulate circulating 1,25(OH)2D levels which also impacts tissue-level activity as well (Anderson et al 2004). Furthermore, in bone CYP24A1 activity has been shown to be regulated independently of circulating 1,25(OH)2D levels, indicating that autocrine regulation of 1,25(OH)2D activity in bone is independent or renal vitamin D metabolism regulation (Anderson et al 2005). We have recently also demonstrated that the genetic deletion of CYP24A1 in osteocytes using Cre-lox technology, increases bone volume in young mice suggesting that the CYP24A1 in osteocytes plays an inhibitory role on bone mineralisation (Barratt et al, in preparation).
In Hyp mice, renal CYP24A1 levels have been shown to be 2-fold higher in HYP mice ADDIN EN.CITE <EndNote><Cite><Author>Azam</Author><Year>2003</Year><RecNum>4275</RecNum><DisplayText>(Azam et al. 2003)</DisplayText><record><rec-number>4275</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599893″>4275</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Azam, N.</author><author>Zhang, M. Y.</author><author>Wang, X.</author><author>Tenenhouse, H. S.</author><author>Portale, A. A.</author></authors></contributors><titles><title>Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice</title><secondary-title>Endocrinology</secondary-title></titles><periodical><full-title>Endocrinology</full-title><abbr-1>Endocrinology</abbr-1></periodical><pages>3463-8</pages><volume>144</volume><number>8</number><dates><year>2003</year></dates><label>22747512</label><urls></urls></record></Cite></EndNote>(Azam et al. 2003) which contributes to lower circulating 1,25(OH)2D levels. No investigations have yet been performed to demonstrate whether osteocytic CYP24A1 levels are in increased in Hyp mice. However, it is unclear whether the bones of HYP mice have aberrantly high CYP24A1, which would frustrate the anabolic activities of 1,25(OH)2D. It is worth noting however, that low phosphate levels may directly contribute to the high expression of CYP24A1, in osteocytes at least, given that decreasing phosphate levels in media of the osteocyte cell line, IDG-SW3, enhances the induction of Cyp24a1 by 1,25(OH)2D ADDIN EN.CITE <EndNote><Cite><Author>Ito</Author><Year>2013</Year><RecNum>1</RecNum><DisplayText>17</DisplayText><record><rec-number>1</rec-number><foreign-keys><key app=”EN” db-id=”r9a0z5fzo02xtzexaf6v552vztvxfwwfexdp” timestamp=”1455686794″>1</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Ito, N.</author><author>Findlay, D. M.</author><author>Anderson, P. H.</author><author>Bonewald, L. F.</author><author>Atkins, G. J.</author></authors></contributors><auth-address>Discipline of Orthopaedics and Trauma, University of Adelaide, Adelaide 5005, Australia.</auth-address><titles><title>Extracellular phosphate modulates the effect of 1alpha,25-dihydroxy vitamin D3 (1,25D) on osteocyte like cells</title><secondary-title>J Steroid Biochem Mol Biol</secondary-title><alt-title>The Journal of steroid biochemistry and molecular biology</alt-title></titles><periodical><full-title>J Steroid Biochem Mol Biol</full-title><abbr-1>The Journal of steroid biochemistry and molecular biology</abbr-1></periodical><alt-periodical><full-title>J Steroid Biochem Mol Biol</full-title><abbr-1>The Journal of steroid biochemistry and molecular biology</abbr-1></alt-periodical><pages>183-6</pages><volume>136</volume><keywords><keyword>Animals</keyword><keyword>Calcitriol/metabolism/*pharmacology</keyword><keyword>Cell Differentiation/drug effects</keyword><keyword>Cell Line</keyword><keyword>Extracellular Space/chemistry/*physiology</keyword><keyword>Mice</keyword><keyword>Osteocytes/cytology/*drug effects/*metabolism</keyword><keyword>Osteogenesis/*drug effects/physiology</keyword><keyword>Phosphates/chemistry/*physiology</keyword></keywords><dates><year>2013</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1879-1220 (Electronic) 0960-0760 (Linking)</isbn><accession-num>23064198</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23064198</url></related-urls></urls><electronic-resource-num>10.1016/j.jsbmb.2012.09.029</electronic-resource-num></record></Cite></EndNote>17. Furthermore, HYP primary osteocytes exposed to 1,25(OH)2D do not induce mRNA levels for vitamin D responsive genes such as VDR or Fgf23 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXlhZ2F3YTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaXlhZ2F3YTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+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ADDIN EN.CITE.DATA 18, perhaps suggesting that excessive CYP24A1 catabolises 1,25(OH)2D. However, the authors of this study did not directly measure CYP24A1 or 1,25(OH)2D clearance (Prof T. Michigami, personal communications). Regardless, these data suggest that Cyp24a1 activity in bone, possibly osteoblasts, osteocytes or chondrocytes during phosphate wasting disorders, may reduce 1,25D activity in bone, resulting in under-mineralisation. A recent key study in investigating the role of CYP24A1 in HYP mice was performed by crossing the global CYP24A1-knockout mice with HYP mice. The hypothesis was that the absence of CYP24A1 would elevate circulating 1,25(OH)2D levels and contribute to the healing of the XLH bone phenotype. To the surprise of the authors, the absence of CYP24A1 resulted in the complete prevention of growth and mineralisation disorder in HYP mice ADDIN EN.CITE <EndNote><Cite><Author>Bai</Author><Year>2016</Year><RecNum>7956</RecNum><DisplayText>(Bai et al. 2016)</DisplayText><record><rec-number>7956</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1472745196″>7956</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Bai, X.</author><author>Miao, D.</author><author>Xiao, S.</author><author>Qiu, D.</author><author>St-Arnaud, R.</author><author>Petkovich, M.</author><author>Gupta, A.</author><author>Goltzman, D.</author><author>Karaplis, A. C.</author></authors></contributors><titles><title>CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders</title><secondary-title>J Clin Invest</secondary-title></titles><periodical><full-title>Journal of Clinical Investigations</full-title><abbr-1>J Clin Invest</abbr-1></periodical><pages>667-80</pages><volume>126</volume><number>2</number><keywords><keyword>Animals</keyword><keyword>Cytochrome P-450 Enzyme Inhibitors/*pharmacology</keyword><keyword>Disease Models, Animal</keyword><keyword>Female</keyword><keyword>Fibroblast Growth Factors/genetics/*metabolism</keyword><keyword>Humans</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Phosphates/*urine</keyword><keyword>*Renal Insufficiency, Chronic/drug therapy/genetics/pathology/urine</keyword><keyword>Vitamin D3 24-Hydroxylase/*antagonists &amp; inhibitors/genetics/metabolism</keyword><keyword>*Wasting Syndrome/drug therapy/genetics/pathology/urine</keyword></keywords><dates><year>2016</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1558-8238 (Electronic) 0021-9738 (Linking)</isbn><accession-num>26784541</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/26784541</url></related-urls></urls><custom2>PMC4731193</custom2><electronic-resource-num>10.1172/JCI81928</electronic-resource-num></record></Cite></EndNote>(Bai et al. 2016). Interestingly, while growth plate and cortical bone mineral was restored, the key biochemical indices of HYP disorder, namely hypophosphatemia and low 1,25(OH)2D levels, remained low and unchanged. These exciting data suggest that the current therapy of correcting blood phosphate and circulating 1,25(OH)2D is not essential to normalise bone health in XLH. Furthermore, these data suggest that CYP24A1 deletion in tissues other than the kidney, play a major role in allowing normal bone mineral levels. Given the evidence for the role of CYP24A1 in bone homeostasis, a key tissue to investigate further is the bone with respect to CYP24A1 and its role in XLH.

RESAERCH DESIGN: AIMS AND METHODS:Model 1Model 2Aim 1: To determine whether raising levels of 25(OH)D3 in HYP mice improves the bone phenotypeMale HYP miceDietary feedingn=12 per group4 groups= total of 48 miceOsmotic pumpsn=6 per group3 groups=total 18 miceAim 2: The role of CYP24A1 inhibition in XLHMale HYP-OBCYP24KODietary feedingn=12 per group4 groups= total of 48 miceOsmotic pumpsn=6 per group3 groups=total 18 miceAim 1: To determine whether raising circulating 25-hydroxyvitamin D (25D) levels heal the bone in Hyp mice.Aim 1: To determine whether raising levels of 25(OH)D3 in HYP mice improves the bone phenotypeRationale: The disorder of XLH, was previously known as vitamin D-resistant rickets owing to the fact the renal conversion of 25(OH)D3 to 1,25(OH)D3 was impeded by FGF23. We know that bone is a major site for local synthesis and activity of 1,25(OH)D3 and is dependent on the circulating supply of 25(OH)D3. There have been no previous studies to examine whether raising 25(OH)D3 to high levels through dietary vitamin D administration can heal the bone phenotype more easily than 1,25(OH)D3. Thus, it is valuable to assess whether the HYP bone can be healed through raising the serum 25(OH)D levels either by dietary vitamin D supplementation or direct infusion of 25(OH)D.

Model 1: Male HYP (XHypY) mice will be supplemented with vitamin D from 3 weeks of age until 12 weeks of age. Mice (n=12/grp) will receive diets containing 1000 IU/kg (standard) or 20,000IU/kg of vitamin D plus either 0.625% phosphorus (standard) or 1.25% phosphorus (high). These levels of vitamin D should significantly raise 25(OH)D3 levels to an approximate maximum of 200 nmol/L without causing direct activation of the VDR ADDIN EN.CITE <EndNote><Cite><Author>Rowling</Author><Year>2007</Year><RecNum>6750</RecNum><DisplayText>(Rowling, M. J. et al. 2007)</DisplayText><record><rec-number>6750</rec-number><foreign-keys><key app=”EN” db-id=”5ardrpxr60pvfnef52axpsxpptazw02s9pvw” timestamp=”1253599895″>6750</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Rowling, M. J.</author><author>Gliniak, C.</author><author>Welsh, J.</author><author>Fleet, J. C.</author></authors></contributors><auth-address>Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556 4Interdepartmental Nutrition Program and Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47906.</auth-address><titles><title>High Dietary Vitamin D Prevents Hypocalcemia and Osteomalacia in CYP27B1 Knockout Mice</title><secondary-title>J Nutr</secondary-title></titles><pages>2608-15</pages><volume>137</volume><number>12</number><dates><year>2007</year><pub-dates><date>Dec</date></pub-dates></dates><accession-num>18029472</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;dopt=Citation&amp;list_uids=18029472</url></related-urls></urls></record></Cite></EndNote>(Rowling, M. J. et al. 2007).

Model 2; Male HYP (XHypY) mice will be fed a standard level of phosphorus from 3 weeks of age until 8 weeks of age. At 4 weeks of age, mice will undergo minor surgery to insert a mini osmotic pump (Alzet 1004) subcutaneously containing 25(OH)D3 (100ng or 200ng/day), or saline, at a constant rate over a 4 week period.
At time of death, we will collect tissues and employ our suite of established analyses described in previous publications PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNvbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+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==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbmRlcnNvbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+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==
ADDIN EN.CITE.DATA 23, 26, 36. Biochemical analyses: serum levels of calcium, phosphate, ALP (Kone Chemistry Analyser), 25(OH)D3 and 1,25(OH)D3 (LC-MS/MS), PTH, and intact FGF23 (commercially available ELISA assays). Ex-vivo micro-CT analyses: For Model 1,femoral and vertebral scans will be performs as per laboratory SOPs. This provides a non-destructive 3D image of the inner bone structure and allows for evaluation of the treatment on bone health. and regions of interest (ROI) adjusted based on the average femur length for each of the groups. In vivo micro-CT analyses: For Model 2, 2 weeks post-surgery (6 weeks of age), mice will be anaesthetised for a lower-leg micro-CT scan (Skyscan 1276). This provides a non-destructive 3D image of the inner bone structure and allows a mid-treatment evaluation of the treatment on bone health. Tissue histology and histomorphometric analyses: To evaluate mineralisation, sections of the left femur (after microCT scanning) will be embedded in methylmethacrylate before sectioning. Histomorphometry will use Osteomeasure (Osteometrics), in accordance to criteria of the American Society of Bone and Mineral Research ADDIN EN.CITE <EndNote><Cite><Author>Dempster</Author><Year>2013</Year><RecNum>93</RecNum><DisplayText>(Dempster et al. 2013)</DisplayText><record><rec-number>93</rec-number><foreign-keys><key app=”EN” db-id=”xfwfxs9v2zrpe9er2a9pwd9fxv5z2v92we5d” timestamp=”1534470947″>93</key><key app=”ENWeb” db-id=””>0</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Dempster, D. W.</author><author>Compston, J. E.</author><author>Drezner, M. K.</author><author>Glorieux, F. H.</author><author>Kanis, J. A.</author><author>Malluche, H.</author><author>Meunier, P. J.</author><author>Ott, S. M.</author><author>Recker, R. R.</author><author>Parfitt, A. M.</author></authors></contributors><auth-address>Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, NY, USA. [email protected]</auth-address><titles><title>Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee</title><secondary-title>J Bone Miner Res</secondary-title></titles><periodical><full-title>J Bone Miner Res</full-title></periodical><pages>2-17</pages><volume>28</volume><number>1</number><edition>2012/12/01</edition><keywords><keyword>Animals</keyword><keyword>Bone and Bones/*anatomy &amp; histology</keyword><keyword>Guidelines as Topic</keyword><keyword>Humans</keyword><keyword>Reference Standards</keyword><keyword>*Research Report</keyword><keyword>*Terminology as Topic</keyword></keywords><dates><year>2013</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1523-4681 (Electronic) 0884-0431 (Linking)</isbn><accession-num>23197339</accession-num><urls><related-urls><url>https://www.ncbi.nlm.nih.gov/pubmed/23197339</url></related-urls></urls><custom2>PMC3672237</custom2><electronic-resource-num>10.1002/jbmr.1805</electronic-resource-num></record></Cite></EndNote>(Dempster et al. 2013), and include measures of bone formation (dual fluorochrome labelling prior to death), osteoid volume and growth plate height (Massons’-Goldner’s Modified Trichrome), osteoblast surface (toluidine blue staining), and osteoclasts (TRAP stain). Messenger RNA analyses: Soft tissues will be snap frozen and RNA extracted using the TRIZOL RNA isolation protocol. cDNA will be synthesised for the purpose of RT PCR’s. Relative expression of CYP24A1, CYP27B1, NaPi2a, NaPi2c, CYP2R1 and CYP24A1 will be reported.

Outcomes
This study is a necessary dietary intervention for HYP mice that frankly should have been done years ago. It will assess if there is resistance to vitamin D synthesis and activity in the bone of HYP mice, be it due to excessive FGF23 or another factor, even with high circulating levels of 25(OH)D and dietary phosphate supplementation.

Aim 2: To determine whether raising osteocyte levels of active vitamin D (1,25(OH)2D) heals the bone of Hyp mice.Rationale: As discussed above, global deletion of CYP24A1 heals the under-mineralised and disturbed growth plate phenotype in HYP mice. This occurs despite the persistence of hypophosphataemia and an even lower serum 1,25(OH)D levels ADDIN EN.CITE <EndNote><Cite><Author>Bai</Author><Year>2016</Year><RecNum>42</RecNum><DisplayText>15</DisplayText><record><rec-number>42</rec-number><foreign-keys><key app=”EN” db-id=”r9a0z5fzo02xtzexaf6v552vztvxfwwfexdp” timestamp=”1455689710″>42</key></foreign-keys><ref-type name=”Journal Article”>17</ref-type><contributors><authors><author>Bai, X.</author><author>Miao, D.</author><author>Xiao, S.</author><author>Qiu, D.</author><author>St-Arnaud, R.</author><author>Petkovich, M.</author><author>Gupta, A.</author><author>Goltzman, D.</author><author>Karaplis, A. C.</author></authors></contributors><titles><title>CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders</title><secondary-title>J Clin Invest</secondary-title></titles><periodical><full-title>J Clin Invest</full-title></periodical><pages>667-80</pages><volume>126</volume><number>2</number><dates><year>2016</year><pub-dates><date>Feb 1</date></pub-dates></dates><isbn>1558-8238 (Electronic) 0021-9738 (Linking)</isbn><accession-num>26784541</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/26784541</url></related-urls></urls><custom2>PMC4731193</custom2><electronic-resource-num>10.1172/JCI81928</electronic-resource-num></record></Cite></EndNote>15. These data demonstrate that low serum phosphate and low circulating 1,25D levels are not primarily responsible for the under-mineralisation. While strongly suggestive, the limitation of this study is the inability to definitively implicate bone CYP24A1. The two most likely candidate cell-types in bone that are responsible for the HYP bone phenotype are osteocytes or chondrocytes. Both cell-types have been shown to produce FGF23, control phosphate homeostasis, and are involved in process of bone formation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXN1eWFtYTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXN1eWFtYTwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+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ADDIN EN.CITE.DATA 38. Thus, to determine whether abrogating Cyp24a1 activity in bone improves the bone phenotype of the HYP mice, conditional knockout mouse models are required. We will utilise Cre-lox systems to delete Cyp24a1 in osteocytes. We have previously created the osteocyte-specific CYP24A1KO mice. These mice will be crossed with HYP mice to determine whether the absence of Cyp24a1 activity in either osteoblast/osteocytes or chondrocytes in HYP mice is capable of promoting mineralisation and overcoming bone under-mineralisation.

Model: Our team has previously created the floxed Cyp24a1 (Cyp24a1flox/+) and OcyCYP24KO (OcyCyp24a1-/-) mouse models. Male HYP mice are far less virile that the females so generation of a HYP mouse in which Cyp24a1 has been specifically deleted in osteocytes (HYP/OcyCyp24a1-/-) requires a particular breeding strategy. Heterozygous female HYP (XXHyp) will be crossed with Cyp24a1flox/flox males to obtain HYP/Cyp24a1flox/+ double heterozygous females. Then HYP/Cyp24a1flox/+ females will be crossed with Cyp24a1flox/flox males to generate HYP/Cyp24a1flox/flox females. Finally, HYP/Cyp24a1flox/flox females will be crossed with OcyCyp24a1-/+ males to obtain the osteoblast/osteocyte-specific deletion of Cyp24a1 in HYP mice. Studies will include the following four genotypes: Cyp24a1flox/+ (wild-type equivalent) control, OcyCyp24a1-/-, HYP (XHypY), and compound HYP/OcyCyp24a1-/- male littermates as well as Cyp24a1flox/- and HYP/Cyp24a1flox/- male mice.

Male HYP (XHypY) mice will be supplemented with vitamin D from 3 weeks of age until 12 weeks of age (as in Aim 1, Model 1), and infused with 25(OH)D (as in Aim 1, Model 2).
At time of death, analyses will include Biochemical analyses,ex-vivo micro-CT analyses, in vivo micro-CT analyses, tissue histology and histomorphometric analyses and messenger RNA analyses as described in Aim 1.

Outcomes: Central to the hypothesis of this project is whether the absence of CYP24A1 activity within osteoblasts/osteocytes as well as chondrocytes enhances healing of bone in HYP mice, despite their elevated levels of FGF23. Examining HYP/conditional CYP24A1KO mice in the context of 25(OH)D supplementation, phosphorus supplementation and 1,25(OH)2D administration will reveal the importance of raised 1,25D within the key bone cell types in this context of healing HYP bone. As well, using definitive in vitro cell models will determine whether the absence of osteoblastic/osteocytic or chondrocytic Cyp24a1 activity alters differentiation and/or apoptosis of HYP cells independently of confounding factors that could occur in the in vivo studies. At the same time these in vitro studies will seek to establish whether key players in inhibiting mineralisation (such as ASARM peptides and sclerostin) are modulated by vitamin D, phosphate and/or CYP24A1 deletion. These studies will provide important insights into targeting CYP24A1 activity in bone in the condition of XLH.

.GANTT CHART AND PLANNED PUBLICATIONS:201820192020Tasks/MilestonesMAMJJASONDJFMAMJJASONDJFMEthics approval process                         RESA ‘Continuing to Completing’ series                         Literature review                         Animal research Aim 1                         Data analysis Aim 1                         Write up Aim 1                         Animal research Aim 2                         Data analysis Aim 2                         Write up Aim 2                         Submission                         Osteoblast Specific deletion of CYP24 data to be published in conjunction with data from the research team- Publish 2018HYP Aim 1: To determine whether raising levels of 25(OH)D3 in HYP mice improves the bone phenotype- Publish 2020HYP Aim 2: The role of CYP24A1 inhibition in XLH- Publish 2021REFERENCES:
ADDIN EN.REFLIST Azam, N, Zhang, MY, Wang, X, Tenenhouse, HS & Portale, AA 2003, ‘Disordered regulation of renal 25-hydroxyvitamin D-1alpha-hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (hyp) mice’, Endocrinology, vol. 144, no. 8, pp. 3463-3468.

Bai, X, Miao, D, Xiao, S, Qiu, D, St-Arnaud, R, Petkovich, M, Gupta, A, Goltzman, D & Karaplis, AC 2016, ‘CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders’, Journal of Clinical Investigations, vol. 126, no. 2, Feb, pp. 667-680.

Carpenter, TO, Imel, EA, Holm, IA, Jan de Beur, SM & Insogna, KL 2011, ‘A clinician’s guide to X-linked hypophosphatemia’, J Bone Miner Res, vol. 26, no. 7, Jul, pp. 1381-1388.

Che, H, Roux, C, Etcheto, A, Rothenbuhler, A, Kamenicky, P, Linglart, A & Briot, K 2016, ‘Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms’, Eur J Endocrinol, vol. 174, no. 3, Mar, pp. 325-333.

David, V & Wolf, M 2016, ‘Pruning the ricket thicket’, J Clin Invest, vol. 126, no. 2, Feb, pp. 473-476.

Dempster, DW, Compston, JE, Drezner, MK, Glorieux, FH, Kanis, JA, Malluche, H, Meunier, PJ, Ott, SM, Recker, RR & Parfitt, AM 2013, ‘Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee’, J Bone Miner Res, vol. 28, no. 1, Jan, pp. 2-17.

Eicher, EM, Southard, JL, Scriver, CR & Glorieux, FH 1976, ‘Hypophosphatemia: Mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets’, Proc Natl Acad Sci USA, vol. 73, no. 12, pp. 4667-4671.

Erben, RG 2017, ‘Pleiotropic Actions of FGF23’, Toxicol Pathol, vol. 45, no. 7, Oct, pp. 904-910.

Kido, S, Kaneko, I, Tatsumi, S, Segawa, H & Miyamoto, K 2013, ‘Vitamin D and type II sodium-dependent phosphate cotransporters’, Contrib Nephrol, vol. 180, pp. 86-97.

Ko, FC, Martins, JS, Reddy, P, Bragdon, B, Hussein, AI, Gerstenfeld, LC & Demay, MB 2016, ‘Acute Phosphate Restriction Impairs Bone Formation and Increases Marrow Adipose Tissue in Growing Mice’, J Bone Miner Res, vol. 31, no. 12, Dec, pp. 2204-2214.

Leifheit-Nestler, M, Kucka, J, Yoshizawa, E, Behets, G, D’Haese, P, Bergen, C, Meier, M, Fischer, DC & Haffner, D 2017, ‘Comparison of calcimimetic R568 and calcitriol in mineral homeostasis in the Hyp mouse, a murine homolog of X-linked hypophosphatemia’, Bone, vol. 103, Oct, pp. 224-232.

Linglart, A, Biosse-Duplan, M, Briot, K, Chaussain, C, Esterle, L, Guillaume-Czitrom, S, Kamenicky, P, Nevoux, J, Prie, D, Rothenbuhler, A, Wicart, P & Harvengt, P 2014, ‘Therapeutic management of hypophosphatemic rickets from infancy to adulthood’, Endocr Connect, vol. 3, no. 1, pp. R13-30.

Liu, ES, Martins, JS, Raimann, A, Chae, BT, Brooks, DJ, Jorgetti, V, Bouxsein, ML & Demay, MB 2016a, ‘1,25-Dihydroxyvitamin D Alone Improves Skeletal Growth, Microarchitecture, and Strength in a Murine Model of XLH, Despite Enhanced FGF23 Expression’, J Bone Miner Res, vol. 31, no. 5, May, pp. 929-939.

Liu, ES, Martins, JS, Raimann, A, Chae, BT, Brooks, DJ, Jorgetti, V, Bouxsein, ML & Demay, MB 2016b, ‘1,25-Dihydroxyvitamin D Alone Improves Skeletal Growth, Microarchitecture and Strength in a Murine Model of XLH, Despite Enhanced FGF23 Expression’, J Bone Miner Res, Jan 11.

Makitie, O, Doria, A, Kooh, SW, Cole, WG, Daneman, A & Sochett, E 2003, ‘Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets’, J Clin Endocrinol Metab, vol. 88, no. 8, Aug, pp. 3591-3597.

Marie, PJ, Travers, R & Glorieux, FH 1981, ‘Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse’, Journal of Clinical Investigation, vol. 67, no. 3, pp. 911-914.

Marie, PJ, Travers, R & Glorieux, FH 1982, ‘Bone Response to Phosphate and Vitamin D Metabolites in the Hypophosphatemic mouse model’, Calcified Tissue International, vol. 34, no. 1, pp. 158-164.

Marie, PJ, Travers, R & Glorieux, FH 1982, ‘Healing of bone lesions with 1, 25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse’, Endocrinology, vol. 111, no. 3, pp. 904-911.

Marie, PJ, Travers, R & Glorieux, FH 1982, ‘Healing of bone lesions with 1,25-dihydroxyvitamin D3 in the young X-linked hypophosphatemic male mouse’, Endocrinology, vol. 111, no. 3, Sep, pp. 904-911.

Meyer, RA, Meyer, MH & Morgan, PL 1996, ‘Effects of Altered Diet on Serum levels of 1,25-Dihydroxyvitamin D and Parathyroid Hormone in X-Linked Hypophosphatemic (HYP and Gy) Mice’, Bone, vol. 18, no. 1, pp. 23-28.

Portale, AA, Perwad, F & Miller, WL 2012, ‘Rickets Due to Hereditary Abnormalities of Vitamin D Synthesis or Action’, Pediatric Bone, pp. 679-698.

Roizen, JD, Li, D, O’Lear, L, Javaid, MK, Shaw, NJ, Ebeling, PR, Nguyen, HH, Rodda, CP, Thummel, KE, Thacher, TD, Hakonarson, H & Levine, MA 2018, ‘CYP3A4 mutation causes vitamin D-dependent rickets type 3’, J Clin Invest, vol. 128, no. 5, May 1, pp. 1913-1918.

Rowling, MJ, Gliniak, C, Welsh, J & Fleet, JC 2007, ‘High dietary vitamin D prevents hypocalcemia and osteomalacia in CYP27B1 knockout mice’, The Journal of nutrition, vol. 137, no. 12, pp. 2608-2615.

Rowling, MJ, Gliniak, C, Welsh, J & Fleet, JC 2007, ‘High Dietary Vitamin D Prevents Hypocalcemia and Osteomalacia in CYP27B1 Knockout Mice’, J Nutr, vol. 137, no. 12, Dec, pp. 2608-2615.

Williamson, L, Hayes, A, Hanson, ED, Pivonka, P, Sims, NA & Gooi, JH 2017, ‘High dose dietary vitamin D3 increases bone mass and strength in mice’, Bone Rep, vol. 6, Jun, pp. 44-50.

GANTT CHART AND PLANNED PUBLICATIONS:201820192020Tasks/MilestonesMAMJJASONDJFMAMJJASONDJFMEthics approval process                         RESA ‘Continuing to Completing’ series                         Literature review                         Animal research Aim 1                         Data analysis Aim 1                         Write up Aim 1                         Animal research Aim 2                         Data analysis Aim 2                         Write up Aim 2                         Submission