| 1. |
- Wagner, Helene, 1966-
(author)
-
Genetic and Environmental Influences on Bone and Fractures
- 2012
-
Doctoral thesis (other academic/artistic)abstract
- Sweden and Norway have the worldwide highest incidence of osteoporotic fractures. As these fractures constitute a tremendous and growing problem, primary prevention is of great importance. The principal causes of an osteoporotic fracture are a fall and a fragile skeleton. The aim of the studies reported in these papers was therefore to determine the genetic and environmental influences on fractures and the genetic influence on the two main reasons to the emergence of osteoporotic fractures; bone mineral density and propensity to fall. In the present thesis, we display that the heritability of fractures is dependent on fracture site and age. With increasing age, lifestyle becomes the dominant explanatory factor. These results indicate that focus should be on lifestyle interventions for the prevention of fractures in the elderly. Although the genetic liability to impaired balance is modest, twins with self-reported impaired balance have a substantially increased risk of osteoporotic fractures compared to their co-twin without impaired balance. Asking a patient about his or her balance might be a simple tool for future risk assessment. The genetic influence on bone phenotypes is under strong genetic influence in Swedish adult twins. These findings are in agreement with the results from previous studies in other countries, with a lower incidence of osteoporotic fractures compared to Sweden. The high heritability of bone phenotypes together with the low heritability of fractures at old age, indicates that bone mineral density has a modest influence on fracture risk at old age. In summary, based on the results in this thesis, more emphasis should be targeted to the prevention of falls, by strength and balance training in order to prevent the occurrence of low energy fractures in the elderly.
|
|
| 2. |
- Bergman, Jonathan, 1993-
(author)
-
Benefits and harms of Bisphosphonates : an observational study
- 2022
-
Doctoral thesis (other academic/artistic)abstract
- Background: Bisphosphonates are first-line treatment for osteoporosis, but osteoporosis is considered an undertreated disease. The general aim of this dissertation was to further study the benefits and harms of bisphosphonates. There were four specific research questions: (1) Do bisphosphonates reduce the risk of new fractures in older adults who have a history of fracture? (2) Do bisphosphonates reduce the risk of fracture in people taking glucocorticoids? (3) Does confounding explain why bisphosphonates are associated with lower mortality in observational studies? (4) Do bisphosphonates increase the risk of non-jaw osteonecrosis?Methods: To answer these questions, we used Swedish register data on deaths, diagnoses, and prescription medications to conduct four matched cohort studies of bisphosphonate users and nonusers. The cohorts were selected from patients registered in the Hip Fracture Register and from all residents of Sweden who were aged 50 years or older on December 31, 2005.Results: (1) Bisphosphonate users had an initially increased risk of sustaining new fractures, which appeared to be due to an underlying high risk of fracture. This increased risk diminished over time, which is consistent with a gradual treatment effect, but it is also consistent with a bias known as depletion of susceptibles. (2) Bisphosphonate users had a lower risk of fracture during glucocorticoid therapy. (3) Bisphosphonate users had a lower mortality rate from day 2 of treatment. Although such an early treatment effect cannot be ruled out, this finding is consistent with confounding. (4) Bisphosphonate users had an increased risk of developing non-jaw osteonecrosis. Conclusion: Most of the results were difficult to interpret as true benefits or harms of bisphosphonates because alternative explanations, arising from bias or confounding, were likely. The exception was the results of Study 2, where alternative explanations are more difficult to find. Therefore, Study 2 suggests that bisphosphonates reduce the risk of fractures in glucocorticoid-treated patients. Further research is needed to clarify the potential effects of bisphosphonates on mortality, non-jaw osteonecrosis, and new fractures after a previous fracture.
|
|
| 3. |
- Gillespie, Ulrika, 1971-
(author)
-
Effects of Clinical Pharmacists' Interventions : on Drug-Related Hospitalisation and Appropriateness of Prescribing in Elderly Patients
- 2012
-
Doctoral thesis (other academic/artistic)abstract
- The overall aim of this thesis was to evaluate clinical pharmacist interventions with the focus on methods aiming to improve the quality of drug therapy and increase patient safety. Adverse drug events caused by medication errors, suboptimal dosages and inappropriate prescribing are common causes of drug-related morbidity and mortality. Clinical pharmacists integrated in multi-professional health-care teams are increasingly addressing these issues. A randomised controlled trial (RCT) was conducted to investigate the effectiveness of clinical pharmacists’ interventions in reducing morbidity and use of hospital care for patients 80 years or older. The results showed that the intervention group had fewer visits to hospital and that the intervention was cost-effective. In a subsequent study based on the population in the RCT, the appropriateness of prescribing was assessed using three validated tools. The results indicated improved appropriateness of prescribing for the intervention group as a result of the intervention. The tools and the number of drugs at discharge were then tested for validity in terms of causal links between the scores at discharge and hospitalisation. No clear correlations between high scores for the tools or a high number of drugs and increased risk of hospitalisation could be detected. During the inclusion period of the RCT a survey based study was conducted where the perceived value of ward-based clinical pharmacists, from the perspective of hospital-based physicians and nurses as well as from general practitioners (GPs) was evaluated. The respondents were positive to the new collaboration to a high degree and stated increased patient safety and improvements in patients’ drug therapy as the main advantages. In the last study the frequency and severity of prescription and transcription errors, when patients enrolled in the multidose-dispensed medications (MDD) system are discharged from hospital, was investigated. The results showed that errors frequently occur when MDD patients are hospitalised.
|
|
| 4. |
- Alassaad, Anna, 1977-
(author)
-
Improving the Quality and Safety of Drug Use in Hospitalized Elderly : Assessing the Effects of Clinical Pharmacist Interventions and Identifying Patients at Risk of Drug-related Morbidity and Mortality
- 2014
-
Doctoral thesis (other academic/artistic)abstract
- Older people admitted to hospital are at high risk of rehospitalization and medication errors. We have demonstrated, in a randomized controlled trial, that a clinical pharmacist intervention reduces the incidence of revisits to hospital for patients aged 80 years or older admitted to an acute internal medicine ward. The aims of this thesis were to further study the effects of the intervention and to investigate possibilities of targeting the intervention by identifying predictors of treatment response or adverse health outcomes.The effect of the pharmacist intervention on the appropriateness of prescribing was assessed, by using three validated tools. This study showed that the quality of prescribing was improved for the patients in the intervention group but not for those in the control group. However, no association between the appropriateness of prescribing at discharge and revisits to hospital was observed.Subgroup analyses explored whether the clinical pharmacist intervention was equally effective in preventing emergency department visits in patients with few or many prescribed drugs and in those with different levels of inappropriate prescribing on admission. The intervention appeared to be most effective in patients taking fewer drugs, but the treatment effect was not altered by appropriateness of prescribing.The most relevant risk factors for rehospitalization and mortality were identified for the same study population, and a score for risk-estimation was constructed and internally validated (the 80+ score). Seven variables were selected. Impaired renal function, pulmonary disease, malignant disease, living in a nursing home, being prescribed an opioid and being prescribed a drug for peptic ulcer or gastroesophageal reflux disease were associated with an increased risk, while being prescribed an antidepressant drug (tricyclic antidepressants not included) was linked with a lower risk. These variables made up the components of the 80+ score. Pending external validation, this score has potential to aid identification of high-risk patients.The last study investigated the occurrence of prescription errors when patients with multi-dose dispensed (MDD) drugs were discharged from hospital. Twenty-five percent of the MDD orders contained at least one medication prescription error. Almost half of the errors were of moderate or major severity, with potential to cause increased health-care utilization.
|
|
| 5. |
- Gustafsson, Maria, 1971-
(author)
-
Optimizing drug therapy among people with dementia : the role of clinical pharmacists
- 2016
-
Doctoral thesis (other academic/artistic)abstract
- Background: Drugs are one of the cornerstones in the management of many diseases. In general, drugs are used for diagnosis, prevention, mitigation of symptoms, and, sometimes, to cure disease. However, drug treatment in elderly people, especially those with dementia and cognitive impairments, may involve significant risk of adverse drug events. The aim of this thesis was to identify the extent of potentially inappropriate drug treatment among people with dementia and cognitive impairment and to assess the occurrence and character of drug-related problems that lead to acute hospital admissions. Another aim was to assess the potential impact of a comprehensive medication review conducted by clinical pharmacists as part of a health care team on quality of patients’ drug therapy and drug-related hospital readmission rates.Method: Long-term use of antipsychotic/psychotropic drugs and associated factors were investigated among 344 and 278 people respectively with dementia living in specialized care units. Trends in the prescribing of potentially inappropriate drugs between 2007 and 2013, comprising 2772 and 1902 people, living in nursing homes in the county of Västerbotten, were assessed using six national quality indicators. Data on drug use, function in the activities of daily living, cognitive function and behavioral and psychological symptoms were collected using the Multi-Dimensional Dementia Assessment Scale. Further, an investigation of a separate corresponding population from 2012 was done, where potentially inappropriate drug use was measured before and after a total of 895 medication reviews. Finally, a randomized, controlled trial was carried out among people 65 years or older with dementia or cognitive impairment in internal medicine and orthopedic wards at two hospitals in northern Sweden. The proportion of hospital admissions that were drug-related were estimated, and also whether comprehensive medication reviews conducted by clinical pharmacists as part of a health care team could affect the risk of drug-related hospital readmissions.Results: Antipsychotic and other psychotropic drugs were frequently prescribed to people with dementia living in specialized care units for prolonged periods. Associations were found between behavioral and psychological symptoms and different psychotropic drugs. The extent of potentially inappropriate drug use declined between 2007 and 2013. In the separate corresponding population from 2012, the frequency of potentially inappropriate drug use was significantly reduced among people who underwent medication reviews. Hospitalizations due to drug-related problems among old people with dementia or cognitive impairment were prevalent. We found that inclusion of a clinical pharmacist in the health care team significantly reduced the risk of drug-related 30-day and 180-day readmissions. However, in a subset of patients with concomitant heart failure no effect was seen.Conclusion: Among patients with dementia or cognitive impairment long-term treatment with antipsychotic and other psychotropic drugs is common. The results indicate that these drugs are prescribed to treat behavioral and psychological symptoms among cognitively impaired individuals, despite limited evidence of their efficacy and the high risk of adverse effects. Drug-related problems, such as adverse drug reactions, constituted a major cause of hospital admissions. By reducing potentially inappropriate drug use and optimizing overall drug therapy, inclusion of clinical pharmacists in a health care team might improve the quality of patient care and reduce the risk of hospital readmissions among people with dementia.
|
|
| 6. |
- Leavy, Breiffni, 1977-
(author)
-
Fall-Related Hip Fracture : Predisposing and Precipitating Factors
- 2015
-
Doctoral thesis (other academic/artistic)abstract
- A physically inactive lifestyle is a predisposing risk factor for fall-related hip fracture. The circumstances, or precipitating factors, surrounding hip fractures are, however, not well understood, a factor of relevance for Swedish adults who have one of the highest hip fracture risks in the world. The aims of this thesis, therefore, were: to explore perceptions of physical activity (PA) among older adults, to describe the circumstances surrounding hip fracture events and the health characteristics of those who experience them.Four observational studies were conducted involving qualitative, epidemiological and mixed method designs. Participants in study I were recruited from community settings in Stockholm and Dublin (n=30). Studies II-IV (sample sizes, n=484, n=125, n=477) were based on a population-based sample of people admitted to Uppsala University hospital due to hip fracture. Study IV also incorporated the background population of Uppsala county in 2010 (n=117 494).Analysis of PA perceptions in study I revealed that PA which is functional nature is perceived as most meaningful among certain participants. The uptake of PA in later years was a means of creating a new self-identify and being active in outdoor environments was an important culture-specific motivator to PA among Swedish participants. Analysis of hip fractures patterns in studies II-III showed that: hip fractures among psychotropic drug users were twice as likely to occur during night-time hours compared to those occurring among people not receiving these drugs. Additionally, the fall-related hip fractures of community dwellers with poorest health and function tended to occur indoors during positional changes. In study IV, all categories of disease (according to the International Classification of Diseases, 10th Revision) were seen to be positively associated with hip fracture. Cardiovascular disease and previous injury (including previous fracture) posed the highest relative and absolute fracture risks.Detailed investigation of hip fracture circumstances reveal patterns in health and functional characteristics, which provide information regarding predisposing and precipitating factors for these events. This knowledge, in combination with findings regarding PA perceptions, can be used when identifying individuals at high risk for hip fracture and when tailoring fracture prevention at an individual level to those at risk.
|
|
| 7. |
- Lytsy, Birgitta, 1968-
(author)
-
Enterobacteriaceae Producing Extended-Spectrum Beta-Lactamases : Aspects of Detection, Epidemiology and Control
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- Enterobacteriaceae belong to the normal enteric flora in humans and may cause infections. Escherichia coli is the leading urinary tract pathogen with septicaemic potential, whereas Klebsiella pneumoniae causes opportunistic infections and often outbreaks in hospital settings. Beta-lactams are the first choice for treatment of infections caused by Enterobacteriaceae, and might be destroyed by extended-spectrum beta-lactamases, ESBLs. ESBLs hydrolyse all beta-lactams except cephamycin and carbapenems, and constitute a large heterogeneous group of enzymes with different origins. The phenotypic and molecular characteristics of a K. pneumoniae strain causing a major outbreak at Uppsala University Hospital between 2005 and 2008 were described. The strain was multiresistant and produced CTM-M-15, a common ESBL type in Europe. Due to the lack of obvious epidemiological links between patients, a case-control study was performed, which identified risk factors for the acquisition of the outbreak strain in urine cultures. The complex chain of transmission facilitated by patient overcrowding and the interventions applied to curb the outbreak, was revealed in the subsequent study. In the final study, the genetic background of the observed increase in ESBL-producing E. coli isolates during the K. pneumoniae outbreak was explored. The utility of six typing methods in epidemiological investigations of a local outbreak with ESBL-producing E. coli was compared. The increase of ESBL-producing E. coli isolates was not secondary to the K. pneumoniae outbreak. Twentytwo per cent belonged to the epidemic O25b-ST131 clone and only a limited number of infections were caused by nosocomial transmission. ESBL-producing Enterobacteriaceae are a challenge to clinical microbiology laboratories and infection control teams. To investigate their dissemination, typing methods need to be continuously adapted to the current situation. Proper hand disinfection and structural key problems such as over-crowding, under-staffing, lack of single rooms and bathrooms must be adressed to limit transmission.
|
|
| 8. |
- Byberg, Liisa, et al.
(author)
-
Total mortality after changes in leisure time physical activity in 50 year old men : 35 year follow-up of population based cohort
- 2009
-
In: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 338, s. b688-
-
Journal article (peer-reviewed)abstract
- Objective: To examine how change in level of physical activity after middle age influences mortality and to compare it with the effect of smoking cessation.Design: Population based cohort study with follow-up over 35 years.Setting: Municipality of Uppsala, Sweden.Participants: 2205 men aged 50 in 1970-3 who were reexamined at ages 60, 70, 77, and 82 years.Main Outcome Measure: Total (all cause) mortality.Results: The absolute mortality rate was 27.1, 23.6, and 18.4 per 1000 person years in the groups with low, medium, and high physical activity, respectively. The relative rate reduction attributable to high physical activity was 32% for low and 22% for medium physical activity. Men who increased their physical activity level between the ages of 50 and 60 continued to have a higher mortality rate during the first five years of follow-up (adjusted hazard ratio 2.64, 95% confidence interval 1.32 to 5.27, compared with unchanged high physical activity). After 10 years of follow-up their increased physical activity was associated with reduced mortality to the level of men with unchanged high physical activity (1.10, 0.87 to 1.38). The reduction in mortality associated with increased physical activity (0.51, 0.26 to 0.97, compared with unchanged low physical activity) was similar to that associated with smoking cessation (0.64, 0.53 to 0.78, compared with continued smoking).Conclusions: Increased physical activity in middle age is eventually followed by a reduction in mortality to the same level as seen among men with constantly high physical activity. This reduction is comparable with that associated with smoking cessation
|
|
| 9. |
- Green, Henrik, 1975-
(author)
-
Pharmacogenetic Studies of Paclitaxel in Ovarian Cancer : focus on interindividual differences in pharmacodynamics and pharmacokinetics
- 2007
-
Doctoral thesis (other academic/artistic)abstract
- Ovarian cancer is one of the most common female cancer diseases in the world today and in Sweden more than 800 new cases are diagnosed every year. The standard treatment consists of chemotherapy with paclitaxel in combination with carboplatin after initial cytoreductive surgery. The response to treatment and the severity of adverse drug reactions after chemotherapy varies greatly among individuals, and one of the most important factors responsible for these differences is now recognized to be the genetic variability. One of the major obstacles to successful treatment is drug resistance. Several potential mechanisms have been suggested for the resistance to paclitaxel, such as mutations in the target protein β-tubulin, single nucleotide polymorphisms (SNPs) in the gene ABCB1, which encodes the transport protein P-glycoprotein. P-glycoprotein can mediate efflux of various drugs from cancer cells as well as from the circulation into the intestinal lumen, and overexpression and/or high activity leads to drug resistance and/or increased elimination. Another reason might be the high interindividual variability of paclitaxel plasma concentrations, which has been suggested to be influenced by variability in metabolic enzymes, such as CYP2C8 and CYP3A4, and transport proteins e.g. P-glycoprotein.In the studies constituting this thesis we have investigated the possibilities of predicting the pharmacokinetics of paclitaxel as well as the tumor response and adverse drug reactions after chemotherapy in the preparation of personalized chemotherapy. We studied the correlation between the response and the presence of mutations in the dominant β-tubulin gene and SNPs in ABCB1. DNA from 40 ovarian tumors was screened for sequence variations in the β-tubulin gene without finding any, showing that β-tubulin mutations are rare and unlikely to be a clinically relevant resistance mechanism for paclitaxel. The SNPs G2677T/A and C3435T in the ABCB1 gene were determined in 53 ovarian cancer tumors from patients with poor (progressive disease or relapse within one year) or good (disease-free survival of more than one year) response to paclitaxel-carboplatin chemotherapy. Patients homozygously mutated for G2677T/A had a higher probability of responding to chemotherapy. There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment. No correlation was found for the C3435T variant.By using a newly developed quantitative LC/MS method for the simultaneous determination of paclitaxel and its hydroxymetabolites in human plasma we assessed the individual elimination of paclitaxel in 33 ovarian cancer patients. The patients were genotyped for SNPs in the ABCB1, CYP2C8 and CYP3A4 genes and their in vivo CYP3A4 enzyme activity, tumor response and toxicity, especially the neurotoxicity, were determined. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than patients with the wild type or homozygously mutated, but not compared to patients carrying the G/T alleles. A lower clearance of paclitaxel was also found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. The CYP3A4 enzyme activity in vivo affected the relative influence of CYP2C8 and CYP3A4 on the metabolism, but not the total clearance of paclitaxel. The exposure to paclitaxel was correlated to the neurotoxicity, but not to the treatment response. In conclusion, our findings suggest that the SNP G2677T/A in the ABCB1 gene, but not β-tubulin mutations, might be a predictor for paclitaxel response and that the interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.
|
|
| 10. |
- Kempen, Thomas G. H., 1988-
(author)
-
Medication reviews by clinical pharmacists in older hospitalised patients : Implementation, performance and effects
- 2021
-
Doctoral thesis (other academic/artistic)abstract
- Background Inappropriate use of medications is a leading cause of avoidable harm in health care. Medication reviews by clinical pharmacists improve medication use, but evidence on hard clinical outcomes in older hospitalised patients is scarce and implementation in practice is challenging. The aim of this thesis was to study the implementation, performance and effects of medication reviews by clinical pharmacists in older hospitalised patients.Methods A case study explored the factors involved in the implementation and sustainability of medication reviews by clinical pharmacists in Region Uppsala, Sweden. A pragmatic multicentre cluster-randomised crossover trial (MedBridge) was conducted to study the effects of hospital-based comprehensive medication reviews (CMRs) including post-discharge follow-ups on older patients’ healthcare utilisation, compared with only hospital-based reviews and usual care. The primary outcome measure was the incidence of unplanned hospital visits within 12 months. A process evaluation was conducted alongside the trial, for which different methods were applied: semi-structured interviews with patients and healthcare professionals, intervention fidelity assessment and process outcomes assessment. A practical tool to identify medication-related hospital admissions, one of the trial’s secondary outcomes, was developed and validated.Results Multiple factors involved in the implementation and sustainability of medication reviews by clinical pharmacists were identified. Examples of facilitating factors were a national focus on quality of care for the elderly and clinical pharmacy education. In total, 2637 participants (median age 81 years) were included in the MedBridge trial. The primary outcome measure did not differ between the treatment groups. Analysis of the interviews with patients and healthcare professionals resulted in seven and six themes, respectively, that were related to the performance of the trial’s interventions. A recurrent theme was the unclear role and responsibilities of the ward-based pharmacist. The intervention fidelity was high during hospital admission and lower surrounding discharge. In 77% of the intervention patients, at least one medication discrepancy or drug-related problem was solved. The developed tool, AT-HARM10, was deemed valid for use by pharmacy students to identify medication-related admissions in older patients.Conclusions This thesis suggests that, despite a high percentage of patients with medication discrepancies or drug-related problems being solved, hospital-based CMRs with and without post-discharge follow-ups, as conducted in the MedBridge trial, do not decrease the incidence of unplanned hospital visits in older patients. Future research and clinical initiatives may benefit from addressing the factors related to the implementation and performance of medication reviews that were identified in this thesis.
|
|
| 11. |
- Mitchell, Adam
(author)
-
Insights into the Effects of Type 2 Diabetes on Bone Health
- 2020
-
Doctoral thesis (other academic/artistic)abstract
- Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of hip fracture, despite a stable or even greater bone mineral density (BMD). Bone area is linked to hip fracture risk independent of BMD and smaller bone area has been reported in T2DM subjects at the radius and tibia, but information at the hip is lacking. The Mediterranean diet is associated with a lower risk of hip fracture yet the mechanisms are unclear. The diet’s effect on T2DM status may be a possible mechanism. This thesis aims to discern the effects fasting glucose levels and T2DM have on bone.In paper I, clinical cut offs of fasting glucose used to define T2DM, were used to explore the association with BMD, bone area and bone turnover markers in the Swedish mammography cohort clinical (SMCC) and the Uppsala longitudinal study of adult men (ULSAM). T2DM was associated with greater BMD yet lower bone area at the total hip when compared to those without T2DM. T2DM was also associated with lower levels of bone turnover markers.In paper II, a Mendelian randomisation (MR) study was used to assess the potential causal effects of genetically predicted fasting glucose concentrations on bone area and BMD in partici-pants from SMCC, the prospective investigation in the vasculature of Uppsala seniors (PIVUS) and ULSAM. Results suggest an increase in genetically predicted fasting glucose concentrations may be a causal risk factor for lower bone area and possibly greater BMD.In paper III, the association between T2DM status and change in bone area and BMD over 8 years, was analysed in the SMCC, PIVUS and ULSAM. Those with incident T2DM had a lesser expansion in bone area at the total hip compared to those without T2DM.In paper IV, causal inference mediation analyses were used to estimate the direct effect of Mediterranean diet on the risk of hip fracture and the possible mediating effects of T2DM and BMI in the Swedish mammography cohort (SMC) and the cohort of Swedish men (COSM). Results showed a direct effect of the Mediterranean diet on the risk of hip fracture but ruled out the effects of T2DM and BMI as major mediators.In summary, T2DM and fasting glucose were associated with lower bone area at the hip. This may provide important mechanistic evidence as to why those with T2DM have a greater risk of hip fracture. We cannot rule out mediation or counteracting effects but there is an effect of Medi-terranean diet on hip fracture that does not go through T2DM and BMI.
|
|
| 12. |
- Zayny, Ahmad
(author)
-
Vitamin D metabolism in osteoblast-like cells : effects of drugs on inactivation by CYP24A1
- 2018
-
Licentiate thesis (other academic/artistic)abstract
- Vitamin D is essential for bone function, and deficiency in active vitamin D hormone can lead to bone disorders. Long-term treatment with glucocorticoids and antiretroviral drugs used to treat HIV infection, results in osteoporosis and increased risk of fractures. Much remains unclear regarding the effects of these compounds in bone cells. In the current study, human osteosarcoma Saos-2 cells and primary human osteoblasts were found to express mRNA for the vitamin D receptor as well as activating and deactivating enzymes in vitamin D3 metabolism. These bone cells exhibited CYP24A1-mediated 24-hydroxylation, involved in deactivation of the active vitamin form. However, bioactivating vitamin D3 hydroxylase activities were not detected in either of these cells, indicating that local vitamin D bioactivation is not significant in osteoblasts.Several glucocorticoids and antiretroviral drugs, including prednisolone, efavirenz and ritonavir, down regulated CYP24A1 mRNA expression. Prednisolone and ritonavir also down regulated CYP24A1-mediated 24-hydroxylase activity in both Saos-2 and primary human osteoblasts.Also, prednisolone significantly suppressed a human CYP24A1 promoter-luciferase reporter gene in Saos-2 cells co-transfected with the glucocorticoid receptor. Thus, the results of the present study show suppression by glucocorticoids on CYP24A1 mRNA, CYP24A1-mediated metabolism and CYP24A1 promoter activity in human osteoblast-like cells. Interestingly, ritonavir markedly potentiated the induction of CYP24A1 mRNA expression by 1,25-dihydroxyvitamin D3 suggesting that ritonavir may have different regulatory effects depending on the vitamin D3 metabolite levelsAs part of this study, we examined if glucocorticoids are formed locally in Saos-2 cells. The experiments indicate formation of 11-deoxycortisol, a steroid with glucocorticoid activity, which can bind the glucocorticoid receptor. Our findings showing effects of glucocorticoids and antiretroviral drugs on CYP24A1 expression in human osteoblasts indicate a previously unknown mechanism for effects of glucocorticoids and antiretroviral drugs in human bone, where effects of these drugs may lead to altered levels of active vitamin D3.
|
|
