Chemotherapy in childhood cancer patients is associated with reduced bone density that can result in osteoporotic fracture in survivors. A significant proportion of paediatric patients experience a reduction in plasma 25 - hydroxyvitamin D3 [ 25 ( OH ) D3 ] and 1,25 - dihydroxyvitamin D3 [ 1,25 ( OH ) 2D3 ] levels during treatment, the basis of which is unknown. A balance between the bioactivation and degradation of 1,25 ( OH ) 2D3 is responsible for maintaining homoeostatic levels of 1,25 ( OH ) 2D3 at the correct set - point. Whereas the cytochrome P450 enzyme, CYP27B1 ( 25 - hydroxyvitamin D3 1 α - hydroxylase ), catalyses the hydroxylation of the precursor 25 ( OH ) D3 to generate 1,25 ( OH ) 2D3, catabolic inactivation and cleavage of 1,25 ( OH ) 2D3 is achieved by the mitochondrial cytochrome P450 enzyme, 25 - hydroxyvitamin D3 24 - hydroxylase ( CYP24 ), which is highly expressed in bone and kidney cells. Since many of the signalling pathways which regulate the expression of CYP24 are also activated by chemotherapeutic drugs, we hypothesised that the drugs could cause the degradation of plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3 by increasing CYP24 expression, the principal means of facilitating the bio - inactivation and degradation of plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3. Using the kidney cell - lines, COS - 1 and HEK293T cells, we now report that chemotherapeutic drugs, represented by daunorubicin hydrochloride ( an anthracycline antibiotics ), etoposide and vincristine sulphate ( vinca alkaloids and related compounds ) and cisplatin ( an alkylating agent ), were able to enhance CYP24 promoter activity in kidney cell lines transfected with a CYP24 promoter - luciferase construct, either by themselves or in the presencedaunorubicin hydrochloride and etoposide, two of the strongest inducers of CYP24 promoter activation under our experimental conditions, demonstrate that these drugs acted in a concentration - dependent manner. In addition to stimulating promoter activity on their own, the drugs also amplified the induction of the CYP24 promoter by 1,25 ( OH ) 2D3. Synergistic increases were generally observed when the cells were treated simultaneously with 1,25 ( OH ) 2D3 and a drug. The two kidney cell lines generally responded in a similar manner when challenged with the drugs, either in the presence or absence of 1,25 ( OH ) 2D3. Interestingly, the hydroxylated derivative of daunorubicin hydrochloride, doxorubicin hydrochloride which is also a commonly used chemotherapeutic drug, had no effect of promoter activity. Further studies with daunorubicin hydrochloride demonstrated that the effects of the drug per se were not mediated by oxidative stress and the vitamin D receptor was not required for daunorubicin hydrochloride per se to stimulate CYP24 promoter activity. However, daunorubicin hydrochloride caused a modest increase in the expression of the vitamin D receptor and this could contribute to its synergistic activity with 1,25 ( OH ) 2D3. In the presence of etoposide, there was also a tendency for the kidney cells to express higher levels of the vitamin D receptor. A key role for the extracellular signal - regulated protein kinase ( ERK ) 1, ERK2 and ERK5 mitogen - activated protein ( MAP ) kinases was demonstrated for the inductive action of daunorubicin hydrochloride and etoposide, with CYP24 promoter - specific transcription factors located in the first - 298bp being likely targets of the ERK activity. Studies with a dominant negative mutant of MKK4, one of the two immediate upstream activators of the c - jun N - terminal kinase isoforms, demonstrated that this MAP kinase also played a crucial role in inductive actions of the of 1,25 ( OH ) 2D3. Dose - response studies with drugs. Consistent with their use in anti - cancer therapy, all of the above drugs killed the human promyelocytic HL60 leukaemic cells at very low concentrations but had no effect on the viability of kidney or liver cells, either at concentrations used in our experiments or at higher levels. Our data provide novel biochemical evidence that some of the commonly used chemotherapeutic drugs could cause an increase in the transcriptional activation of the promoter, most likely via the MAP kinases activating the transcription factors which bind to the CYP24 promoter. Such an effect could contribute to the reduction in plasma 25 ( OH ) D3 and 1,25 ( OH ) 2D3 in some of the patients undergoing chemotherapy. / Thesis (Ph.D.)--School of Paediatrics and Reproductive Health, 2005.

Biochemical assays and radioabsorptiometry evaluated the relationship of mineral and bone metabolism to the systemic response to neurotrauma or orthopaedic trauma of adult males. Forty-one adult males (29.4±9.3 years) participated of which 37 had a primary diagnosis of traumatic spinal cord injury (SCI) and four were vertebral fracture controls. Biochemical abnormalities found included hyperphosphataemia, in association with low or low normal serum levels of 1,25-dihydroxyvitmain D (1,25(OH)₂D) and of parathyroid hormone (PTH), whilst patients remained normocalcaemic. These disturbances of phosphate and vitamin D metabolism and the markedly accelerated resorption of bone were strongly associated with the interval since injury and the severity of injury, but none of these relationships was correlated with the level of the injury, the sensory status of a patient or the presence of spine fracture. The disturbances of phosphate and vitamin D metabolism and the markedly accelerated resorption of bone found in this study are a mirror image of the data of patients with the heritable disorders autosomal dominant hyperphosphataemic rickets (ADHR), which results from an inactivating mutation of the gene encoding fibroblast growth factor 23 (FGF23) and autosomal recessive hypophosphataemic rickets (ARHR), which is caused by a mutation of the gene encoding dentin matrix protein-1 (DMP-1). It is potentially important that the hormone/proteolytic enzyme/extra-cellular matrix protein cascade associated with these disorders is counter-regulated by 1,25(OH)₂D, acting either directly or indirectly. The present results suggest that the serum levels of 1,25(OH)₂D of the neurotrauma patients chosen for study may have been inappropriately high with respect to the “physiological and metabolic set” of serum levels of phosphate and ionised calcium in the period corresponding to the uncoupling of the resorption and formation of bone, at least in males, prompting further investigation. The findings are consistent with a new “physiological set,” possibly involving an abnormality in the synthesis or processing of the endocrine fibroblast growth factors or other circulating phosphatonins, which may act as an additional level of regulation of the renal–bone axis, rather than renal failure. Strongly supporting this was the dynamic pattern of the biochemistry and radiological data of these neurotrauma patients and also, preliminary evidence of disturbances in circulating levels of other systemic modulators of mineral and bone metabolism. The relationships that were observed potentially may be explained by the diversity of the physiological activities of the endocrine fibroblast growth factors and the modes of actions of secreted FGF23 in bone. The findings provide an understanding of why bone loss occurs and may form the target for safe and cost effective interventions. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1345019 / Thesis (Ph.D.) - University of Adelaide, School of Medicine, Discipline of Orthopaedics and Trauma, 2008

Biochemical assays and radioabsorptiometry evaluated the relationship of mineral and bone metabolism to the systemic response to neurotrauma or orthopaedic trauma of adult males. Forty-one adult males (29.4±9.3 years) participated of which 37 had a primary diagnosis of traumatic spinal cord injury (SCI) and four were vertebral fracture controls. Biochemical abnormalities found included hyperphosphataemia, in association with low or low normal serum levels of 1,25-dihydroxyvitmain D (1,25(OH)₂D) and of parathyroid hormone (PTH), whilst patients remained normocalcaemic. These disturbances of phosphate and vitamin D metabolism and the markedly accelerated resorption of bone were strongly associated with the interval since injury and the severity of injury, but none of these relationships was correlated with the level of the injury, the sensory status of a patient or the presence of spine fracture. The disturbances of phosphate and vitamin D metabolism and the markedly accelerated resorption of bone found in this study are a mirror image of the data of patients with the heritable disorders autosomal dominant hyperphosphataemic rickets (ADHR), which results from an inactivating mutation of the gene encoding fibroblast growth factor 23 (FGF23) and autosomal recessive hypophosphataemic rickets (ARHR), which is caused by a mutation of the gene encoding dentin matrix protein-1 (DMP-1). It is potentially important that the hormone/proteolytic enzyme/extra-cellular matrix protein cascade associated with these disorders is counter-regulated by 1,25(OH)₂D, acting either directly or indirectly. The present results suggest that the serum levels of 1,25(OH)₂D of the neurotrauma patients chosen for study may have been inappropriately high with respect to the “physiological and metabolic set” of serum levels of phosphate and ionised calcium in the period corresponding to the uncoupling of the resorption and formation of bone, at least in males, prompting further investigation. The findings are consistent with a new “physiological set,” possibly involving an abnormality in the synthesis or processing of the endocrine fibroblast growth factors or other circulating phosphatonins, which may act as an additional level of regulation of the renal–bone axis, rather than renal failure. Strongly supporting this was the dynamic pattern of the biochemistry and radiological data of these neurotrauma patients and also, preliminary evidence of disturbances in circulating levels of other systemic modulators of mineral and bone metabolism. The relationships that were observed potentially may be explained by the diversity of the physiological activities of the endocrine fibroblast growth factors and the modes of actions of secreted FGF23 in bone. The findings provide an understanding of why bone loss occurs and may form the target for safe and cost effective interventions. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1345019 / Thesis (Ph.D.) - University of Adelaide, School of Medicine, Discipline of Orthopaedics and Trauma, 2008

Biochemical assays and radioabsorptiometry evaluated the relationship of mineral and bone metabolism to the systemic response to neurotrauma or orthopaedic trauma of adult males. Forty-one adult males (29.4±9.3 years) participated of which 37 had a primary diagnosis of traumatic spinal cord injury (SCI) and four were vertebral fracture controls. Biochemical abnormalities found included hyperphosphataemia, in association with low or low normal serum levels of 1,25-dihydroxyvitmain D (1,25(OH)₂D) and of parathyroid hormone (PTH), whilst patients remained normocalcaemic. These disturbances of phosphate and vitamin D metabolism and the markedly accelerated resorption of bone were strongly associated with the interval since injury and the severity of injury, but none of these relationships was correlated with the level of the injury, the sensory status of a patient or the presence of spine fracture. The disturbances of phosphate and vitamin D metabolism and the markedly accelerated resorption of bone found in this study are a mirror image of the data of patients with the heritable disorders autosomal dominant hyperphosphataemic rickets (ADHR), which results from an inactivating mutation of the gene encoding fibroblast growth factor 23 (FGF23) and autosomal recessive hypophosphataemic rickets (ARHR), which is caused by a mutation of the gene encoding dentin matrix protein-1 (DMP-1). It is potentially important that the hormone/proteolytic enzyme/extra-cellular matrix protein cascade associated with these disorders is counter-regulated by 1,25(OH)₂D, acting either directly or indirectly. The present results suggest that the serum levels of 1,25(OH)₂D of the neurotrauma patients chosen for study may have been inappropriately high with respect to the “physiological and metabolic set” of serum levels of phosphate and ionised calcium in the period corresponding to the uncoupling of the resorption and formation of bone, at least in males, prompting further investigation. The findings are consistent with a new “physiological set,” possibly involving an abnormality in the synthesis or processing of the endocrine fibroblast growth factors or other circulating phosphatonins, which may act as an additional level of regulation of the renal–bone axis, rather than renal failure. Strongly supporting this was the dynamic pattern of the biochemistry and radiological data of these neurotrauma patients and also, preliminary evidence of disturbances in circulating levels of other systemic modulators of mineral and bone metabolism. The relationships that were observed potentially may be explained by the diversity of the physiological activities of the endocrine fibroblast growth factors and the modes of actions of secreted FGF23 in bone. The findings provide an understanding of why bone loss occurs and may form the target for safe and cost effective interventions. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1345019 / Thesis (Ph.D.) - University of Adelaide, School of Medicine, Discipline of Orthopaedics and Trauma, 2008

Biochemical assays and radioabsorptiometry evaluated the relationship of mineral and bone metabolism to the systemic response to neurotrauma or orthopaedic trauma of adult males. Forty-one adult males (29.4±9.3 years) participated of which 37 had a primary diagnosis of traumatic spinal cord injury (SCI) and four were vertebral fracture controls. Biochemical abnormalities found included hyperphosphataemia, in association with low or low normal serum levels of 1,25-dihydroxyvitmain D (1,25(OH)₂D) and of parathyroid hormone (PTH), whilst patients remained normocalcaemic. These disturbances of phosphate and vitamin D metabolism and the markedly accelerated resorption of bone were strongly associated with the interval since injury and the severity of injury, but none of these relationships was correlated with the level of the injury, the sensory status of a patient or the presence of spine fracture. The disturbances of phosphate and vitamin D metabolism and the markedly accelerated resorption of bone found in this study are a mirror image of the data of patients with the heritable disorders autosomal dominant hyperphosphataemic rickets (ADHR), which results from an inactivating mutation of the gene encoding fibroblast growth factor 23 (FGF23) and autosomal recessive hypophosphataemic rickets (ARHR), which is caused by a mutation of the gene encoding dentin matrix protein-1 (DMP-1). It is potentially important that the hormone/proteolytic enzyme/extra-cellular matrix protein cascade associated with these disorders is counter-regulated by 1,25(OH)₂D, acting either directly or indirectly. The present results suggest that the serum levels of 1,25(OH)₂D of the neurotrauma patients chosen for study may have been inappropriately high with respect to the “physiological and metabolic set” of serum levels of phosphate and ionised calcium in the period corresponding to the uncoupling of the resorption and formation of bone, at least in males, prompting further investigation. The findings are consistent with a new “physiological set,” possibly involving an abnormality in the synthesis or processing of the endocrine fibroblast growth factors or other circulating phosphatonins, which may act as an additional level of regulation of the renal–bone axis, rather than renal failure. Strongly supporting this was the dynamic pattern of the biochemistry and radiological data of these neurotrauma patients and also, preliminary evidence of disturbances in circulating levels of other systemic modulators of mineral and bone metabolism. The relationships that were observed potentially may be explained by the diversity of the physiological activities of the endocrine fibroblast growth factors and the modes of actions of secreted FGF23 in bone. The findings provide an understanding of why bone loss occurs and may form the target for safe and cost effective interventions. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1345019 / Thesis (Ph.D.) - University of Adelaide, School of Medicine, Discipline of Orthopaedics and Trauma, 2008

No description available.

Bakgrund: Det finns läkemedel som ger ökad risk för vitamin D-brist. En kartläggningsstudie av hur patientgrupper med olika riskläkemedel hanteras i Landstinget i Kalmar län har inte gjorts tidigare. En sådan studie är önskvärd, för att få en nulägesanalys och öka medvetenheten bland hälso-och sjukvårdspersonal om hur läkemedel påverkar D-vitaminstatus. Syfte: Syftet var att undersöka omfattningen av ordinerade riskläkemedel hos samtliga patienter, samt hos patientgruppen ≥75år och hur dessa handläggs avseende ordination av supplementering (samtidig behandling med läkemedel innehållande vitamin D3 / kalcium och vitamin D3,), provtagning och analysresultat avseende kalcidiol i serum. Metod: Riskläkemedel för vitamin D-brist identifierades. Inklusionskriterier för studien var patienter med de fördefinierade riskläkemedlen med ordinationer under 2012 och/eller 2013. Populationen som ingick i studien var patienter i Landstinget i Kalmar län. Data hämtades från patientdatasystemet Cambio Cosmic. Utifrån dessa data analyserades förekomst av supplementering, provtagning för S-25(OH)D kalcidiol och analyssvar. Materialet strukturerades efter respektive läkemedel avseende kön och ålder (≥75 år.) Resultat: 9118 individer ordinerades något av riskläkemedelen orlistat, sevelamer, kolestyramin, kolestipol, efavirenz, prednison, prednisolon, fenytoin, fenobarbital eller karbamazepin. 31% av patienterna som ordinerats riskläkemedel var ≥75 år. Totalt behandlades 22% med supplementationspreparat av de som ordinerats riskläkemedel. I åldersgruppen ≥75 år behandlades 43% med supplement. 61% av de supplementerade patienterna var ≥75 år. Totalt provtogs enbart 4,1% avseende kalcidiol av de som ordinerats riskläkemedel. Av dessa hade 37% av de provtagna en bristnivå av S-25(OH)D (≤50 nmol/L) vid första provtillfället. 57% av de som visade brist supplementerades. Endast 8,3% av de som hade en brist följdes upp med ytterligare en eller flera provtagningar. Av patienterna ≥75 år provtogs 4,1% av patienterna i åldersgruppen. Detta innebär att 31% av de som provtogs var ≥75år. 39% led brist. Av de patienter ≥75 år som hade led brist supplementerades 65% av individerna. Konklusion: Det finns förbättringsutrymme för implementering av kunskap kring riskläkemedel i Landstinget i Kalmar län. / Introduction: Some drugs increase the risk for vitamin D deficiency. To date, no survey has been performed in Kalmar County about how patients medicated with risk pharmaceuticals are handled. Such a survey would be desirable in order to increase knowledge among healthcare workers about how substances interfere with vitamin D status. Aim: The aim was to examine the extent to which risk pharmaceuticals are prescribed among all patients and among patients aged ≥75, and to investigate how these patients are treated with respect to supplementation (drugs containing vitamin D3 / Calcuim and vitamin D3), blood sampling and analysis of serum calcidiol levels. Method: Drugs interfering with vitamin D were identified. Inclusion criteria for the survey were patients that had been prescribed the pre-defined risk pharmaceuticals during 2012 and/ or 2013. The surveyed population was residents in Kalmar County. Data were collected from the patient database Cambio Cosmic. From these data analyzes were made about the occurrence of: supplementation, sampling of S-25(OH)D calcidiol and test results. The collected data were arranged by substance, gender and age (elderly aged ≥75). Results: 9118 patients were prescribed at least one of the risk pharmaceuticals; orlistat, sevelamer, cholestyramine, colestipol, efavirenz, prednisol, prednison, phenytoin, phenobarbital or carbamazepine. 31% of these were aged ≥75. Overall, 22% of the patients were prescribed supplements. Out of these, 61% were elderly. Among the patients that had been prescribed risk pharmaceuticals a minority, 4,1% of the patients were sampled for calcidiol. 37% of these had deficiency in S-25(OH)D (≤50 nmol/L). 8.3% of patients with a vitamin D deficiency were sampled more than once. Out of the patients with deficiency 57% were treated with supplements. Out of the elderly patients prescribed risk pharmaceuticals, 4.1% of the patients were tested for calcidiol. This means that 31% of the tested patients were aged ≥75 and 39% of these had a deficiency. Out of the elderly patients with deficiency, 65% were treated with supplements. Conclusion: In Kalmar County, much can be done in order to better implement the existing knowledge about drugs that increase the risk for vitamin D deficiency. / Betydelsen av bra D-vitaminstatus för äldres hälsa – Hur stor är förekomsten av D-vitaminbrist hos äldre i Kalmar län och hur påverkar läkemedel D-vitaminstatus

<p>The regulation of serum phosphate (Pi) concentrations is a complex process and our current models are far from complete. Due to major advancements in biotechnology and the development of more powerful research tools, recent advances in the field of genetics has led to the identification of several candidates for the long sought-after phosphatonin(s), or Pi regulating hormones. One of these candidates is fibroblast growth factor 23 (FGF-23) and this thesis is based upon studies of the role of FGF-23 in Pi homeostasis. We demonstrate that FGF-23 is a secreted protein which is highly expressed in tumors giving rise to oncogenic hypophosphatemic osteomalacia (OOM). Furthermore, we have developed a two-site enzyme-linked immunosorbent assay for the detection of circulating FGF-23 and established that FGF-23 is present in the circulation of healthy individuals. Also, FGF-23 serum levels are elevated in patients with disturbances in Pi homeostasis such as OOM, X-linked hypophosphatemic rickets (XLH) and chronic kidney disease and are likely to play an important role in the pathogenesis of these disorders. A transgenic mouse model that express human FGF-23 under the control of the α1(I) collagen promoter exhibit similar clinical and biochemical characteristics as do patients with OOM, XLH and autosomal dominant hypophosphatemic rickets indicating that FGF-23 is an important determinant of Pi homeostasis, vitamin D metabolism and bone mineralization.</p>

The regulation of serum phosphate (Pi) concentrations is a complex process and our current models are far from complete. Due to major advancements in biotechnology and the development of more powerful research tools, recent advances in the field of genetics has led to the identification of several candidates for the long sought-after phosphatonin(s), or Pi regulating hormones. One of these candidates is fibroblast growth factor 23 (FGF-23) and this thesis is based upon studies of the role of FGF-23 in Pi homeostasis. We demonstrate that FGF-23 is a secreted protein which is highly expressed in tumors giving rise to oncogenic hypophosphatemic osteomalacia (OOM). Furthermore, we have developed a two-site enzyme-linked immunosorbent assay for the detection of circulating FGF-23 and established that FGF-23 is present in the circulation of healthy individuals. Also, FGF-23 serum levels are elevated in patients with disturbances in Pi homeostasis such as OOM, X-linked hypophosphatemic rickets (XLH) and chronic kidney disease and are likely to play an important role in the pathogenesis of these disorders. A transgenic mouse model that express human FGF-23 under the control of the α1(I) collagen promoter exhibit similar clinical and biochemical characteristics as do patients with OOM, XLH and autosomal dominant hypophosphatemic rickets indicating that FGF-23 is an important determinant of Pi homeostasis, vitamin D metabolism and bone mineralization.