Vitamina D y riesgo de preeclampsia: revisión sistemática y metaanálisis / Vitamin D and risk of preeclampsia: A systematic review and meta-analysis

Resumen Introducción. Cada vez son más los hallazgos sobre la relación entre las concentraciones de vitamina D en el ser humano y diversas condiciones clínicas. Hay una gran cantidad de estudios que informan sobre dicha asociación, especialmente con complicaciones obstétricas, incluidas la preeclampsia y la diabetes mellitus de la gestación, entre otras, pero sus resultados todavía no son definitivos, por lo que se requieren estudios de intervención de calidad que confirmen la relación de la vitamina D con dichos resultados. Objetivo. Revisar la información plasmada en estudios en torno al papel de la vitamina D materna y el desarrollo de la preeclampsia. Materiales y métodos. La metodología usada siguió las recomendaciones de la guía Cochrane para la elaboración de revisiones sistemáticas y de la guía del grupo Meta-analysis of Observational Studies in Epidemiology (MOOSE) para los metaanálisis. La búsqueda incluyó estudios observacionales y ensayos clínicos controlados. Resultados. Los niveles bajos de vitamina D, medida con el examen de 25-hidroxivitamina D, son comunes en el embarazo. Los resultados de esta revisión sistemática y del metaanálisis sugieren una asociación inversa entre los niveles de vitamina D y el desarrollo de preeclampsia. Hubo heterogeneidad en los estudios en cuanto a su diseño, población y ubicación geográfica, así como a las definiciones de exposición y resultado. Los ensayos clínicos controlados aleatorizados se excluyeron del metaanálisis. Conclusión. Se encontró una asociación inversa que sugiere que, a mayores concentraciones de vitamina D, menor es la probabilidad de desarrollar preclampsia, a pesar de la heterogeneidad de la medida global en este tipo de análisis.

Abstract Introduction: Human vitamin D levels have been increasingly related to a wide range of clinical outcomes. There is a large amount of reports on its associations, especially with obstetric complications, including preeclampsia and gestational diabetes. These results are scarcely consistent and there is still a lack of quality intervention studies to confirm the role of vitamin D in those outcomes. Objective: To review the available scientific evidence on the role of maternal vitamin D in the development of preeclampsia. Materials and methods: The methodology used followed the recommendations of the Cochrane guide for the preparation of systematic reviews, and for metaanalysis, the Guide of the Metaanalysis of Observational Studies in Epidemiology group (MOOSE). The search included both observational studies and controlled clinical trials. Results: Low vitamin D levels, measured by the 25-hydroxyvitamin D test, are common in pregnancy. The results of this systematic review and metaanalysis suggest an inverse ratio between vitamin D levels and the development of preeclampsia. There was heterogeneity among the studies with regard to the design, population, geographic location, definitions of exposure, and the outcome. We excluded randomized controlled trials from this meta-analysis. Conclusion: The inverse association we found suggests that the higher the levels of vitamin D the lesser the probability of developing preeclampsia, in spite of the heterogeneity of the global measurement in this type of analysis.

Relationship between low vitamin D level and metabolic syndrome in maintenance hemodialysis patients / 中华肾脏病杂志

Objective To evaluate the relationship between low vitamin D level and metabolic syndrome (MS) in maintenance hemodialysis (MHD) patients.Methods A total of 143 patients who had received MHD from Jan 2016 to Jan 2017 in the dialysis center of our hospital were enrolled.Their clinical and laboratory data were collected.The serum 25(OH)D3 levels were measured by chemiluminescence instrument.According to the levels of 25(OH)D3,patients were divided into three groups:sufficient group (＞ 30 μg/L),insufficient group (15-30 μg/L) and deficient group (＜ 15 μg/L) to explore how the 25(OH)D3 were associated with MS and abnormal metabolic parameters,including central obesity,raised triglycerides (TG),reduced high-density lipoprotein cholesterol (HDL-C),raised systolic blood pressure (SBP),raised diastolic blood pressure (DBP) and increased fasting blood glucose (FBG).The risk factors of MS and abnormal metabolic factors were analyzed by multivariate logistic regression model.Results Among the 143 MHD patients,the median of serum 25(OH)D3 was 24.30(12.90,29.50) μg/L and the prevalence of MS was 45.45％(65 cases).Among 3 groups the prevalence of MS,the abdominal circumference and the serum TG showed statistical differences,and they increased with the severity of 25(OH)D3 deficiency (all P ＜ 0.05).The body mass indexes of patients in the insufficient and deficient groups were elevated compared with that in the sufficient group (all P ＜ 0.05).SBP,TG and FBG in deficient group were significantly higher but HDL-C was lower than those in the other two groups (all P ＜ 0.05).The more abnormal metabolism existed,the lower 25(OH)D3 levels patients had (H=61.316,P＜0.001).Multivariate logistic regression analysis showed that in MHD patients low 25(OH)D3 negatively correlated with MS (OR=0.889,95％CI 0.846-0.934,P ＜ 0.001) and abnormal metabolic factors central obesity (OR=0.913,95％CI 0.874-0.953,P ＜ 0.001),raised TG (OR=0.932,95％ CI 0.894-0.971,P=0.001),reduced HDL-C (OR=0.901,95％ CI 0.845-0.959,P=0.001),raised SBP (OR=0.898,95％CI 0.847-0.953,P＜ 0.001) and raised FBG (OR=0.956,95％CI 0.920-0.994,P=0.024).Conclusions The prevalence of MS is high in MHD patients and low levels of 25(OH)D3 may be an independent risk factor for MS and abnormal metabolic factors.

The effect of active vitamin D on monocyte chemoattratant protein-1 expression from patients with system lupus erythematosus / 中华风湿病学杂志

Objective In order to explore the effect of 25-(OH)D3 on monocyte chemoattratant protein (MCP)-1 expression from patients with system lupus erythematosus (SLE),we detected the level of active vitamin D and the expression of MCP-1 mRNA in patients with SLE,and analyzed the correlation between them.Methods The level of serum 25-(OH)D3 and mRNA expression of MCP-1 in 154 SLE patients and 31 healthy individuals were detected by enzyme-linked immuno sorbent assay (ELISA) and real time quanti-tative pol ymerase chain reaction (PCR) respectively.We also analyzed the correlation between serum 25-(OH)D3 level and the expression of MCP-1 mRNA,then analyzed the function of 25(OH)D3 on the regula-tion of MCP-1 mRNA expression in vitro.The differences between the two groups were tested by t-test and x2 test,multiple data were tested by one-way ANOVA and the correlation was analyzed by Pearson's correlation,all data were analyzed by statistical product and service solutions (SPSS) 17.0 software.Results The serum 25(OH)D3 levels in SLE group (20±11) ng/ml was significantly lower than normal control group (29±11) ng/ml (t=4.198,P＜0.01),and the ratio of the serum levels of vitamin D deficiency in SLE group were significantly higher than that of normal control group [55.8％(86/154) vs 22.6％(7/31),x2=11.421,P=0.001].The expression level of MCP-1 mRNA in PBMCs from the normal control group was significantly lower than the SLE group (1.14±0.27 vs 1.44± 0.31,t=3.277,P=0.001),serum 25(OH)D3 level and MCP-1 mRNA expression in patients with SLE PBMCs were significantly negatively correlated (r=-0.289,P＜0.01).Further study found that 25-(OH)D3 inhibited MCP-1 mRNA expression in PBMCs from SLE patients depending on the concentration.Conclusion The decreased 25-(OH)D3 level and up-regulated MCP-1 mRNA expression suggestthat MCP-1 may play an important role in SLE pathological process.

Maintenance Dose of Vitamin D: How Much Is Enough?

BACKGROUND: It is still unclear the ideal vitamin D dosage once the deficiency and insufficiency is treated. Once deficiency was corrected we prospectively treated patients with 2,000 IU of vitamin D3 to check whether this dosage is enough to keep them above the 30 ng/mL of 25-hydroxy-vitamin D (25[OH]D). METHODS: One hundred and thirty-five Saudi Arabian men and women treatment naïve for the vitamin D deficiency and insufficiency were part of this study. History and clinical examination were done to rule out any metabolic bone disease. Weight and height was taken to calculate the body mass index (BMI). Patients who were vitamin D deficient (≥30 ng/mL), a standard treatment of 50,000 IU of vitamin D3 weekly for 3 months, a blood test for the vitamin D levels at the end of 3 months, maintenance dose of 2,000 IU of vitamin D3 for 3 months and a third blood sample after 3 months. RESULTS: The data for 128 patients was available for analysis. The average age was 44.95±12.97 years with the mean BMI of 29.60±2.59 kg/m2. The baseline 25(OH)D level was 13.16±3.30 ng/mL. The increase in the level of 25(OH)D on 50,000 IU weekly was significant from 13.16±3.3 ng/mL to 36.97±4.67 ng/mL (P < 0.001) and then 2,000 IU daily for next 3 months, the level of 25(OH)D dropped top 20.38±5.42 ng/mL (P < 0.001). CONCLUSIONS: Our study indicates that the maintenance dose of 2,000 IU of vitamin D is not enough for patients to keep the 25(OH)D levels above 30 ng/mL.

Relationship between serum 25-hydroxycholecalciferol deficiency and the risk of peritoneal dialysis associated peritonitis / 中华肾脏病杂志

Objective To investigate the relationship between serum 25-hydroxycholecalciferol [25(OH)D3] deficiency and the risk of peritoneal dialysis associated peritonitis.Methods Baseline clinical data (before the peritoneal dialysis catheter insertion) of peritoneal dialysis patients treated with CAPD in the First Affiliated Hospital of Guangxi Medical University from May 1,2013 to February 1,2016 were retrospective analyzed.All the patients were followed-up until July 31,2016.According to the baseline serum 25(OH)D3 levels,patients were divided into deficiency group (25(OH)D3 ＜ 15 ng/ml) and non deficiency group (25(OH)D3 ≥ 15 ng/ml),the baseline clinical data of the two groups were also analyzed.Kaplan-Meier method was used to compare the time-to-peritonitis of two groups.Cox proportional hazard model was used to analyze the relationship between the 25(OH)D3 deficiency and the risk of peritonitis.ROC curve was used to analyze the predictive value of the baseline serum 25(OH)D3 for the risk of PDAP in peritoneal dialysis patients.Results Compared with the 25(OH)D3 non deficiency group,25(OH)D3 deficiency group had a significant increase incidence of peritonitis,high diastolic blood pressure and mean arterial pressure,but serum albumin,total serum protein decreased significantly (P ＜ 0.05).Kaplan-Meier survival analysis showed that,compared with 25(OH)D3 non deficiency group,the time-to-peritonitis episode of patients with 25(OH)D3 deficiency were shorter (P ＜ 0.05).Cox proportional hazard model showed that after adjusting for age,sex,hemoglobin,serum albumin,C-reactive protein,total Kt/V,eGFR,diabetes or not,25(OH)D3 deficiency is the independent risk factor of peritoneal dialysis associated peritonitis (HR 5.247,95％CI 1.180-23.340,P ＜ 0.05).ROC curve showed the area under the curve that baseline serum 25(OH)D3 deficiency predict the occurrence of PDAP was 0.714,and the best cut-off point of baseline serum 25(OH)D3 was 11.35 ng/ml (sensitivity 75％,specificity 63％).Conclusions Peritoneal dialysis associated peritonitis occurred earlier in peritoneal dialysis patients whose baseline serum 25(OH)D3 deficiency.Baseline serum 25(OH)D3 deficiency is the independent risk factor of peritoneal dialysis associated peritonitis,which may predict the incidence of peritoneal dialysis associated peritonitis.

Detection bias evaluation of ten commercial total 25-hydroxyvitamin D immunoassays / 中华检验医学杂志

Obejective To evaluate the accuracies of ten commercial total 25-hydroxyvitamin D [25(OH) D] immnoassays.Methods NIST 25 (OH) D reference material SRM 972a,which consisted of four vials of frozen serum with different concentration levels of different 25 (OH) D types,and two human serumsamples provided by our lab (BIMT),which had different concentration levels of 25 (OH) D3,were analyzed by ten total 25-hydroxyvitamin D immnoassays from Biomerieux,Mindray,Maccura,Chemclin,Abbott (2),Siemens,SNIBE (2),Roche,and by isotope-dilution liquid chromatography-tandem mass spectrometry(ID-LC/MS/MS) founded by BIMT.For the measurements of SRM 972a,the biases between tested values and certified values were calculated as a evaluating indicator,meanwhile the test biases between immnoassays and ID-LC/MS/MS were used as a evaluating indicator for the measurements of BIMT 25(OH) D3 serum samples.Test bias lower than 10％ was deemed acceptible.Results The ID-LC/MS/MS exhibited low biases at (1.6％-2.8％) in the measurements of all levels of SRM 972a.8 immnoassays showed low biases at(1.5％-3.5％) in the measurements of level 1 of SRM 972a,which had a high 25(OH) D3 concentration level,but only 2 immnoassays gave low biases at (3.6％-3.7％)in the measurements of high 25 (OH)D2 concentration sample (level 3).While,5 immnoassays gave low biases at (-0.3％-9.0％) in the measurements of high 3-epi-25 (OH) D3 concentrationsample (level 4).It seems that,when SRM 972a were analyzed,only one of the ten commercial total 25 (OH)D immnoassays were in good accuracy and analytical specificity agrements with ID-LC/MS/MS.When two human serum25(OH) D3samples from BIMT were tested,most immunoassays were overall in relative good agreement with ID-LC/MS/MS at high 25 (OH) D3concentration level.Conclusion The test biases in the total 25 (OH) D measurements are differences between differentimmnoassays and ID-LC/MS/MS,and the specificities of current commercial total 25 (OH) D immnoassays should be improved,especially the performance on the equivalent recognition of 25 (OH) D2 and 25 (OH) D3.

Determination of calcifediol in microbial transformation broth of VD3 by reversed-phase high performance liquid chromatography / 中国药学杂志

OBJECTIVE: To determine the content of calcifediol in microbial transformation broth of VD3 quickly and accurately. METHODS: The separation was performed on an Elite Hypersil C18 column (4.6 mm × 250 mm, 5 μm) with acetonitrile-water (85:15) as the mobile phase eluted at a flow rate of 2.0 mL · min-1. The column temperature was maintained at 50℃. External standard method was adopted using the peak area at 265 nm for determination. RESULTS: A good linear relationship was obtained in the range of 10.1 -2 020 μg · mL-1 (r =0.999 9), the limit of quantitation was 0.6 ng, the limit of detection was 0.3 ng, and the average recovery rate was 101.06% (RSD 1.44%, n=9). CONCLUSION: The established RP-HPLC method could meet the request of content determination of calcifediol in VD3 microbial transformation broth in industrial production.

Correlation of serum vitamin D level with pulmonary function related factors in adult asthma / 天津医药

Objectives To explore the correlation of level of serum 25-hydroxyvitamin D with pulmonary function in adult with asthma. Methods Patients were divided into Asthmatic group(n=62)and Control group (n=28). The Asthmatic group was further divided into Mild Group (n=6), Moderate Group (n=13) and Severe Group (n=43). Serum levels of 25-hy?droxyvitamin D [25(OH)D], denoted as 25(OH) Vit D was detected by ELISA. Pulmonary function indicators,including FVC (forced vital capacity) , FEV1 (forced expiratory volume in 1 second) , FEV1%predicted , and FEV1/FVC%were deter?mined by a pulmonary function testing device. General profiles such as medical history, age and height as well as serum VitD levels were compared between subgroups of the asthmatic groups and between two genders. Serum levels of 25 (OH) VitD were compared between asthmatic group and control group while its correlation with FEV1%predicted were calculated in all three sub asthmatic groups. Results There was no significant difference in medical history, age, height and the 25(OH) VitD levels between male and female participants. Serum 25(OH) Vit D level was significantly lower in the asthmatic patient group [(29.69±20.45) nmol/L] compared to that in control group [(75.16±4.06) nmol/L] (P<0.05). It was significantly lower in severe sub group than those in the mild and moderate sub groups. The differences were both statistically significant ( P<0.05). There were positive correlations between serum 25(OH) Vit D levels and FEV1%predicted ( P<0.05) in all sub asth?matic groups. Conclusion Vitamin D deficiency is highly prevalent in asthmatic patients, and there is a strong correlation between 25(OH) Vit D asthma severity as well as between lung function.

Serum level of vitamin D3 in cutaneous melanoma / Nível sérico de vitamina D3 em portadores de melanoma cutâneo

Objective To compare the level of vitamin D3 in cutaneous melanoma patients, with or without disease activity, with reference values and with patients from a general hospital. Methods The serum levels of vitamin D3 were measured in cutaneous melanoma patients, aged 20 to 88 years, both genders, from January 2010 to December 2013. The samples from the general group were processed at Hospital Israelita Albert Einstein (control group). Data analysis was performed using the Statistics software. Results A total of 100 patients were studied, 54 of them men, with mean age of 54.67 years, and 95 Caucasian. Out of these 100 patients, 17 had active disease. The average levels of vitamin D3 in the melanoma patients were lower than the level considered sufficient, but above the average of the control group. Both groups (with or without active disease) of patients showed a similar distribution of vitamin D3 deficiency. Conclusion Vitamin D3 levels in melanoma patients were higher than those of general patients and lower than the reference level. If the reference values are appropriate, a large part of the population had insufficient levels of vitamin D, including those with melanoma, or else, this standard needs to be reevaluated. No difference in vitamin D3 levels was found among melanoma patients with or without active disease. More comprehensive research is needed to assess the relation between vitamin D and melanoma. .

Objetivo Comparar o nível de vitamina D3 em portadores de melanoma, em atividade de doença ou não, com os valores de referência e com pacientes de um hospital geral. Métodos Os níveis séricos de vitamina D3 foram dosados em portadores de melanoma cutâneo entre 22 a 80 anos, de ambos os sexos, de janeiro de 2010 a dezembro de 2013. As amostras do grupo dos pacientes gerais foram processadas no Hospital Israelita Albert Einstein (grupo controle). A análise dos dados foi realizada utilizando o software Statistica. Resultados Foram estudados 100 pacientes, sendo 54 homens, com média de idade 54,67 anos, e 95 brancos. Desses 100 pacientes, 17 apresentavam doença em atividade. A média dos níveis de vitamina D3 nos 100 pacientes foi inferior ao nível considerado suficiente, porém acima da média do grupo controle. A deficiência de vitamina D3 apresentou distribuição semelhante nos dois grupos com melanoma (em atividade de doença ou não). Conclusão Os níveis de vitamina D3 nos pacientes com melanoma foram superiores aos dos pacientes gerais e inferiores aos de referência. Se os valores de referência estão adequados, grande parte da população apresenta níveis insuficientes de vitamina D3, incluindo os portadores de melanoma, ou tal padrão precisa ser reavaliado. Não houve diferença dos níveis de vitamina D3 entre portadores de melanoma com ou sem atividade. Estudos relacionando vitamina D e melanoma devem ser aprofundados. .

The study of relationship between serum levels of 25-hydroxyvitamin D3 and total IgE in children with bronchial asthma / 中国医师进修杂志

Objective To study the effect of the serum levels of 25-hydroxyvitamin D3 [25-(OH)D3] and total IgE (TIgE) in pathogenesis of the children bronchial asthma.Methods Twenty-two children with bronchial asthma (bronchial asthma group) and 20 healthy children (control group) were selected.The serum levels of 25-(OH)D3 and TIgE in the children of 2 groups were detected.Results The level of serum 25-(OH)D3 in bronchial asthma group was significantly lower than that in control group [(23.64 ± 3.89)μ g/L vs.(35.82 ± 4.37) μ g/L],there was statistical difference (P ＜ 0.05).The level of serum TIgE in bronchial asthma group was significantly higher than that in control group [(208.62 ± 32.59) kU/L vs.(73.84 ± 18.86) kU/L],there was statistical difference (P ＜ 0.05).There was negative correlation between the level of serum 25-(OH)D3 and TIgE in bronchial asthma group (r =-0.832,P ＜ 0.01),but there was no correlation between the level of serum 25-(OH)D3 and TIgE in control group (r =-0.038,P ＞0.05).Conclusions The lack of 25-(OH)D3 may be associated with allergy and childhood bronchial asthma.By monitor the levels of 25-(OH)D3 and TIgE may assess condition of childhood bronchial asthma.

Influence of basic osteoporosis intervention on 25-hydroxy vitamin D level, lower limb muscle strength and its balance function among Chinese elderly people / 中华老年医学杂志

Objective To observe influence of basic osteoporosis intervention on the 25-hydroxy vitamin D[25(OH)D] levels,low limb muscle strength and its balance function among Chinese elderly people.Methods Cross sectional study and statistics analysis were performed among total 1026 elderly (≥65years) patients from 16 hospitals throughout China.Daily taking amount of dairy products,calcium,vitamin D supplement,sunlight and physical exercise were recorded.Serum 25 (OH) D level was measured.Limb muscle strength and balance tests were performed.Results Daily intake of dairy products was insufficient in more than 42.0％ (430 cases) participating patients.The average sunlight time of participating patients was (1.2 ± 0.8) h per day.The average physical exercise time was (1.2 ± 0.7) h per day.37.7 ％ (387 cases) participating patients took supplemental calcium and vitamin D.36.8％ (278 cases)participating patients took supplemental calcium.The 25 (OH) D level was less than 50 nmol/L in 77.2％ (792 cases) participating patients,while 50～75 nmol/Lin 16.7％(171 cases).48.7％ (474/973),64.6％(624/966)and 63.6％ (614/966) patients were in high fall risk according to the timed up and go test(TUG),chair rising test(CRT) and tandem gait test(TGT),which showed that the levels of 25 (OH) D deficiency were positively correlated with the elderly fall risk.Conclusions Daily intake of dairy products,sunlight,calcium and ordinary vitamin D supplement are insufficient among Chinese elderly people.Decreases of muscle strength and balance function among elderly people are related to 25 (OH) D levels.Exercise,not Vitamin D supplement,can reduce fall risk through improving muscle strength and balance function in elderly people.

The influence of serum 25(OH)D levels on abnormal glucose metabolism induced by glucocorticoid in renal glomerular disease patients / 中华肾脏病杂志

Objective To explore the levels of serum 25(OH)D in glomerular disease patients and investigate its influence on the impaired glucose metabolism after treated with glucocorticoid. Methods A total of 61 patients with glomerular disease confirmed by clinical diagnosis and renal biopsy were included in the case group before receiving steroid therapy. 16 cases were selected as control at the same period. Before and six weeks after the treatment of glucocorticoid, all subjects took oral glucose tolerance test (OGT). According to the results of OGT, patients were divided into normal glucose regulation (NGR) group, impaired glucose regulation (IGR) group and steroid diabetes mellitus (SDM) group. Serum 25(OH)D levels were detected with enzyme?linked immunosorbent assay (ELISA), and other clinical data including albumin(Alb), Scr and urine protein were collected. Results (1) Before treated with glucocorticoid, the serum 25(OH)D levels in the control group [(64.09±13.53) nmol/L]were significantly higher than that in NGR group [(50.81 ± 12.44) nmol/L], while the latter was significantly higher than that in IGR group [(42.71 ± 8.09) nmol/L, all P5.6% increased the risk of developing steroid diabetes 5.586 and 5.197 times, respectively. Age increased 10 years or insulin resistance index increased one, the risk of occurred SDM increased 2.443 and 2.755 times, respectively. Conclusions Most glomerular disease patients are serum 25 (OH)D deficiency or insufficiency. Low level of serum 25(OH)D is one of the main risk factors of steroid diabetes in patients with glomerular disease when treated with glucocorticoid.

Clinical effect of exercise therapy on the patients with osteoporosis / 中华老年医学杂志

Objective To evaluate the clinical effect of exercise therapy on patients with osteoporosis according to osteoporosis quality of life scale(OQOLS)and the changes in biochemical markers of bone metabolism.Methods Totally 94 patients with primary osteoporosis were randomly divided into 2 groups:the intervention group [exercise therapy (Wu Xing Jian Gu Cao) with calcium/vitamin D supplementation for 90 days] and the control group (only calcium/vitamin D supplementation for 90 days].OQOLS and the changes in biochemical markers of bone metabolism were observed before and after treatment.Results Compared with before treatment,25-hydroxy vitamin D[25-(OH) D]levels were increased in control group (33 cases) and intervention group (29 cases) after treatment [(61.2± 11.1) mmol/L vs.(48.1±26.2)mmol/L,both P＜0.001],and the enhanced level was higher in the intervention group than in the control group (P＜0.05).Compared with before treatment,bone alkaline phosphatase (BALP) was decreased in control and intervention group after treatment (both P＜0.05).There were significant differences in OQOLS in both groups between before and after treatment except for the function of physical activities in intervention group (P＜0.05).Conclusions The basic and exercise therapy can both increase [25-(OH) D] level,reduce BALP,and have clinical effects on bone metabolism,while exercise therapy has an improvement in osteoporosis quality of life in patients with osteoporosis.