Does the VDR gene polymorphism influence the efficacy of denosumab therapy in postmenopausal osteoporosis?

Introduction: One of the challenges of personalized medicine is a departure from traditional pharmacology toward individualized, genotype-based therapies. Postmenopausal osteoporosis is a prevalent condition requiring intensive treatment, whose effects are measurable only after a long time, and the goal is bone fracture prevention. This study aimed to determine the influence of VDR gene variation on anti-osteoporotic one-year treatment with denosumab in 63 Polish women with postmenopausal osteoporosis. Materials and methods: The correlation between bone mineral density (BMD) of the lumbar vertebral column (L1-L4) and femoral neck, and genotype distributions for the ApaI, BsmI, FokI, and TaqI variants of the VDR gene was analyzed. Bone fractures during denosumab therapy were also investigated. Results: In the case of the Bsml polymorphism, female patients with BB and Bb genotypes had statistically significantly higher values of BMD and T-score/Z-score indicators, which persisted after a year of denosumab treatment. Our results indicated that the Bsml polymorphism contributes to better bone status, and, consequently, to more efficient biological therapy. The study did not reveal significant differences between changes (delta) in BMD and genotypes for the analyzed VDR gene loci. In the entire study group, one bone fracture was observed in one patient throughout the yearlong period of denosumab therapy. Conclusions: BB and Bb genotypes of the Bsml polymorphism of the VDR gene determine higher DXA parameter values both before and after one-year denosumab therapy in postmenopausal women with osteoporosis.

Analysis of the tumor necrosis factor superfamily member 11 gene polymorphism with bone mineral density and bone fracture frequency in patients with postmenopausal osteoporosis.

PURPOSE: We aimed to examine the polymorphism of the promoter and exon 5 of the TNFSF11 gene and their impact on bone mineral density (BMD) and the frequency of bone fractures. TNFSF11 encodes the receptor activator of the NF-kB ligand (RANKL), a key regulator of bone metabolism and osteoporosis drug targets. BMD is an essential measure in diagnosing osteoporosis and assessing the risk of fractures. In vivo, RANKL expression research suggests that promoter TNFSF11 variants influence BMD. Moreover, exon 5 polymorphism of a linear epitope sequence for a denosumab could be related to the effectiveness of biological therapy. PATIENTS AND METHODS: The study included 114 postmenopausal osteoporosis patients. BMD was measured in the lumbar spine and the femoral neck. Genetic analysis was performed using Sanger sequencing. Genotypes data for 263 female European population group were obtained from the 1000Genomes database. RESULTS: We identified six promoter polymorphisms (rs9525641, rs9533155, rs9533156, rs11839112, rs28926171, rs183599708) and one silent TNFSF11 variant in exon 5 (rs9562415). Three of the sequence variants detected (rs9525641, rs9533155, rs9533156) proved to be polymorphic, whereas the others four occurred at a frequency below 2%. The statistical analysis demonstrated no significant differences between polymorphisms and BMD, and bone fractures. However, variant rs9533156 was relevant with the lumbar spine T-score (p = 0.0273), and no association with BMD was of borderline significance (p = 0.0529). CONCLUSIONS: Variant rs9533156 may contribute to the genetic regulation of BMD in Polish postmenopausal osteoporosis, while the exon 5 sequence of the TNFSF11 gene is very conservative.

Bone Metabolism and the c.-223C > T Polymorphism in the 5'UTR Region of the Osteoprotegerin Gene in Patients with Inflammatory Bowel Disease.

Osteoporosis is more frequent in inflammatory bowel disease (IBD) patients. A reduction in bone mineral mass in these individuals is caused not only by inflammatory processes in the bowel, because osteoporosis occurs already in very young IBD patients and in newly diagnosed individuals who have not yet undergone any pharmacological treatment. One of individual determinants of the bone turnover parameters is osteoprotegerin (OPG) encoded by the TNFRSF11B gene. The c.-223C > T polymorphism in this gene has been extensively studied in post-menopausal osteoporosis patients. However, no such studies exist for osteoporosis related to IBD. The aim of our study was to determine whether the c.-223C > T (rs2073617) polymorphism in the 5'UTR region of the gene encoding osteoprotegerin is a functional polymorphism which may change the gene expression and resulting OPG levels, and so be associated with osteopenia and osteoporosis, and impaired bone metabolism in Crohn's disease and ulcerative colitis patients. Our study included 198 IBD patients and 41 healthy controls. Lumbar spine and femoral neck bone mineral density, T-score, Z-score as well as OPG, RANKL, vitamin D, calcium and interleukin 4 and 10 concentrations were determined for all study subjects. Genotyping of the TNFRSF11B polymorphic site was performed by restriction fragment length polymorphism technique. Statistical analyses were conducted using Statistica software. Odds ratios, 95 % confidence intervals, and P values were calculated using the HWE calculator. Our results did not allow determining an unequivocal association between the polymorphic variants of the TNFRSF11B 5'UTR region and a susceptibility to osteoporosis in IBD patients. We have shown, however, that the c.-223T allele was twice as more frequent in Crohn's disease (CD) patients than among controls (OR = 1.99, P value = 0.009). Interestingly, average osteoprotegerin levels in CD patients did not significantly differ from those in controls, whereas in ulcerative colitis patients, OPG levels were significantly lower. We have concluded that low OPG levels may be associated with osteoporosis in ulcerative colitis, but it is not correlated with the c.-223C > T polymorphism in the TNFRSF11B gene. In CD patients, in turn, we observed increased RANKL levels. Our observations confirm different pathogeneses of Crohn's disease and ulcerative colitis as well as different molecular backgrounds of osteoporosis associated with these two diseases.

Association analysis of the COL1A1 polymorphism with bone mineral density and prevalent fractures in Polish postmenopausal women with osteoporosis.

INTRODUCTION: Polymorphism in the promoter region of collagen type 1α (COL1A1) +1245G/T (Sp1, rs1800012) was in some studies shown to be relevant for bone mineral density (BMD) and low-energy fracture prediction. The aim of the study was to confirm this finding in a group of postmenopausal women diagnosed with osteoporosis. MATERIAL AND METHODS: We investigated 311 Caucasian women (mean age: 65.2 ±9.39 years) either after low-energy fractures (regardless of the location) or meeting World Health Organization (WHO) criteria for osteoporosis. All patients underwent clinical examination in order to exclude secondary osteoporosis; hip and lumbar spine DEXA was performed (Lunar). The three genotypes of Sp1 polymorphism were determined by RFLP (restriction fragment length polymorphism). RESULTS: Distribution of COL1A1 genotypes (SS/Ss/ss) agreed with Hardy-Weinberg equilibrium. No relation between COL1A1 genotypes and hip/L1-L4 BMD was found. Fractures were reported in 26.3% of women. Prevalence of low-energy fractures, regardless of the type, was 50.0% in ss genotype carriers, 26.4% in SS homozygotes and 23.7% in Ss heterozygotes. There was no statistically significant recessive or dominant effect of any Sp1 genotype on fracture prevalence (p = 0.613). CONCLUSIONS: We failed to observe that COL1A1 Sp 1 genotypes contribute to BMD determination or are associated with prevalent low-energy fractures in a Polish cohort of postmenopausal osteoporotic women.

The role of counselling and other factors in compliance of postmenopausal osteoporotic patients to alendronate 70 therapy.

INTRODUCTION: The aim of the study was to assess the role of patient counselling, nurse assistance and effects of biochemical examinations in adherence of women with postmenopausal osteoporosis to alendronate 70 administration over 12 months of therapy. MATERIAL AND METHODS: Compliance and persistence to alendronate 70 therapy were assessed in a prospective study of 123 postmenopausal women, followed up for one year. The patients were divided into 4 groups (controls, counselled group, biochemical group and nurse assisted group) with monitoring every 6 months; in the nurse assisted group, additional phone contacts were made after 3 and 9 months of treatment. After 12 months, compliance and persistence were analysed. The medication possession ratio (MPR) was regarded as optimal when its value exceeded 80%. RESULTS: The compliance to alendronate 70 therapy was 54.03% in the control group and the mean persistence with medication was 197 days. The MPR above 80% was observed in 37.5%, and, after 1 year, 43.75% of patients were found persistent with the therapy. In the remaining groups, both compliance and persistence were higher but not statistically significantly, compared to the control group. Neither patient's age, education, diet, nor physical activity influenced the compliance with prescribed therapy. The most common reason to discontinue therapy was either its side effects or smoking. CONCLUSIONS: The obtained results suggest that better adherence with medical recommendations is observed in patients who receive additional attention, e.g. counselling, biochemical tests or nursing care. The critical elements for therapy discontinuation were side effects and smoking.

Prognostic factors in patients surgically treated after hip fracture.

INTRODUCTION: By the impact of demographic changes and as the result of the 'incorrect' lifestyles pursued in developed societies, osteoporosis has become a serious social problem. Hip fracture is the most serious complication of osteoporosis and is associated with high mortality rates or permanent health impairment. The goal of this study was an evaluation of the impact of selected socio-economic factors and of the time period from fracture to surgical intervention on the patient's prognosis. MATERIAL AND METHODS: A group of 148 patients (114 women and 34 men) participated in the study, their age varying between 48 and 93 years, all of them after surgical treatment of hip fracture. A questionnaire study was carried out, encompassing all the participants. RESULTS: During a year-long follow up, thirty-four (34) patients, i.e. 23% of the whole group, passed away. Further comparisons were performed between two groups: Group A - 114 patients, who survived the follow up period, and Group B - those who died. The mean age of patients was 76.3 and 82.6 years in Groups A and B, respectively (p 〈 0.05). In Group A, 79.8% of the patients declared full self-dependence prior to fracture episode vs. 44.1% of the patients in Group B (p 〈 0.05). Regular physical activity - in various forms - was undertaken by 39.5% of the patients in Group A and 11.8% of those in Group B (p 〈 0.05). Active ways of spending outdoor time were reported by 32.5% of the patients in Group A vs. 14.7% in Group B (p 〈 0.05). Fracture unfavourably influenced the material situation of affected patients. No relationship was found between the time period from fracture to surgery and the patient's prognosis. CONCLUSIONS: 1. Despite the currently available surgical treatment methods, hip fracture is still laden with a high risk of fatality. 2. High physical activity, especially outdoors, self-dependence and having a partner positively influence patient's prognosis after hip fracture. 3. Hip fracture negatively changes the material situation of patients. 4. The length of time from hip fracture to operation has no effect on the survival rate.

Vitamin D receptor gene polymorphisms, bone mineral density and fractures in postmenopausal women with osteoporosis.

The goal of the study was to investigate the possibility of an association between polymorphisms and single alleles of BsmI, ApaI, TaqI of the vitamin D receptor (VDR) gene with bone mineral density (BMD) and prevalence of vertebral/non-vertebral fractures in a group of postmenopausal Polish women with osteoporosis. The study group comprised of 501 postmenopausal females with osteoporosis (mean age 66.4 ± 8.9), who were diagnosed on the basis of either the WHO criteria or self-reported history of low-energy fractures. The three polymorphisms were determined by PCR (polymerase chain reaction) and RFLP (restriction fragment length polymorphism). BMD at the lumbar spine and femoral neck was assessed by dual energy X-ray absorptiometry (DXA). 285 fractures were reported in the whole group (168 vertebral and 117 non-vertebral). Incidence of non-vertebral fractures was significantly higher in the carriers of single alleles a of ApaI, b of BsmI and T of TaqI VDR gene polymorphisms (p = 0.021, 0.032, 0.020, respectively). No significant associations between allelic variants of the studied polymorphisms and BMD or fracture incidence were found. (1).The presence of single alleles a,b and T of ApaI, BsmI, TaqI VDR gene polymorphisms respectively, might serve as an indicator of non-vertebral fractures. (2). Lack of association between the VDR gene polymorphisms and BMD suggests that VDR contributes to low-energy fractures also through other ways.

Influence of social competence of physicians on patient compliance with osteoporosis medications--a study on Polish postmenopausal women.

OBJECTIVE: The aim of the study was to examine the impact of social competence of physicians on the effectiveness of patient compliance and persistence with therapy. MATERIAL AND METHODS: The study included physicians and their patients, previously diagnosed with osteoporosis, and eligible to receive pharmacological treatment. The physicians were evaluated with the social competence questionnaire involving three dimensions: social exposure, intimacy and assertiveness, as well as in the combined scale. All patients in the study group were prescribed the same medication: alendronate once a week. Compliance and persistence of the patients were juxtaposed with social interaction skills of physicians during 7 scheduled appointments at 2-month intervals. RESULTS: Doctor's effectiveness in situations demanding close interpersonal contact was higher in the group with good compliance--group A (p < 0.001), as well as in the situations of social exposure, (p < 0.001). On the other hand, their assertiveness was higher in the group with poor compliance--group B (p < 0.001). Co-morbid conditions (group A: 76%, group B: 74%), as well as earlier fractures (40.43% vs. 36.78%) were comparable in both groups. Disease acceptance and suggested methods of treatment were more often accepted by patients from group A than group B (56% vs. 33%, respectively). CONCLUSIONS: (1) Disease acceptance is essential for effective treatment. (2) Social skills of physicians influence patient adherence to therapy recommendations. (3) Close interpersonal contact between physicians and their patients eliminates the feeling of fear and

A discussion of the intervention thresholds in osteoporosis treatment in Poland.

INTRODUCTION: Epidemiological prognoses regarding the global spread of post-menopausal osteoporosis can prove somewhat nebulous. But it is clear that low-energy fractures and their consequences will become an increasingly serious health problem. Therefore it is crucial to implement prognostic procedures which could more effectively predict the incidence of osteoporosis and its complications. MATERIAL AND METHODS: The study involved 378 female patients aged 40-86 years for whom clinical risk factors of osteoporotic fracture were analysed. Densitometry (DPX) was performed at femoral neck. The 10-year risk of fracture was assessed according to the British model of FRAX calculator. RESULTS: The study group was divided into two, depending on the history of low-energy fractures. Previous osteoporotic fractures were confirmed in 128 patients. In this group, the mean bone mineral density (BMD) values (0.717 g/cm(2)) were lower than in the group without fracture history (0.735 g/cm(2)). In 33.3% of patients aged 50-59 years and 17% of women aged 60-79 who required medical treatment for their clinical status (previous fracture), the FRAX value did not meet the criterion of pharmacotherapy administration. Considering BMD in the calculation of FRAX produced an even higher underestimation of the fracture risk. Of women aged 40-49, 25% were qualified for pharmacotherapy of osteoporosis. In that particular age category, BMD did not affect the FRAX value. BMD measurement had a higher discriminatory value among patients aged 50-79, increasing the number of patients requiring therapy by more than 50%. CONCLUSIONS: 1. The FRAX calculator does not always consider the history of low-energy fractures as a criterion sufficient for therapy implementation. 2. Designing a FRAX calculator specifically for the Polish population would be advisable.

Correlation of vitamin D receptor gene (VDR) polymorphism with osteoporotic changes in Polish postmenopausal women.

OBJECTIVE: Recently the significance of genetic traits, influencing hormonal and environmental factors, in susceptibility to osteopenia and osteoporosis development has been indicated. Much attention to the polymorphic variants of vitamin D receptor (VDR) gene was paid. The restriction polymorphisms in VDR gene could be involved in the modulation of vitamin D action and modulate the level of bone mineral density (BMD) and the risk to develop osteopenia and osteoporosis. MATERIALS AND METHODS: Total 321 postmenopausal women (mean age 63.26 +/- 8.90 years), including women with osteoporosis (163 patients) and osteopenia (95) have been compared to 63 women with normal t-score value. For detection of VDR polymorphisms PCR/RFLP (polymerase chain reaction/restriction fragment length polymorphism) assay have been used. RESULTS: The frequency of BsmI, ApaI, and TaqI polymorphic variants of VDR gene detected in investigated groups was not statistically different. The slight, not significant tendency to prevalence of a allele (ApaI polymorphism) in the controls comparing to women with osteoporosis and osteopenia have been noted. Higher prevalence of homozygous TT genotype (TaqI polymorphism) the in the both groups with lower BMD value (47.9 : 49.5 vs. 34.9% in the controls) and higher prevalence of T allele in these both groups (65.9 : 68.4 vs. 57.9) was been also observed. CONCLUSIONS: The presence of T allele of TaqI polymorphism could predict the higher risk to develop osteoporosis in postmenopausal woman; consequently t allele could have protective effect. The presence of A allele (ApaI polymprphism) seems to be weakly connected with osteoporosis susceptibility.

Association analysis of vitamin D receptor gene polymorphisms with bone mineral density in young women with Graves' disease.

UNLABELLED: Graves' (GD) hyperthyroidism induces accelerated bone turnover that leads to decreased bone mineral density (BMD). The role of the VDR gene in predisposition to primary osteoporosis has been recognized. Recent studies show associations between the VDR gene polymorphisms and susceptibility to autoimmune diseases. Here we analyzed if VDR gene polymorphisms: BsmI, ApaI, TaqI, and FokI may predispose women with Graves' hyperthyroidism to BMD reduction or to disease development. The subjects were 75 premenopausal female Polish patients with GD and 163 healthy women. The genotyping was performed by the use of the restriction fragment length polymorphism analysis (RFLP). We studied the association of the VDR polymorphisms and their haplotypes with patients' BMD and also SNPs and haplotypes association with Graves' disease. We found a strong linkage disequilibrium for the BsmI, ApaI, and TaqI polymorphims that formed three most frequent haplotypes in Graves' women: baT (47.9%), BAt (34.9%), and bAT (16.4%). We did not show statistically significant association of analyzed VDR polymorphisms or haplotypes with decreased bone mineral density in Graves' patients. However, the presence of F allele had a weak tendency to be associated with Graves' disease (with OR=1.93; 95% CI: 0.97-3.84; p=0.058). IN CONCLUSION: VDR gene polymorphisms do not predict the risk of decreased BMD in Polish women with Graves'. It may be speculated that the F allele carriers of the VDR-FokI polymorphism are predisposed to Graves' disease development.

Association analysis of the polymorphisms of the VDR gene with bone mineral density and the occurrence of fractures.

Associations of the FokI, BsmI, ApaI, and TaqI polymorphisms of the vitamin D receptor (VDR) gene with the bone mineral density (BMD) of the lumbar part of the spinal column (BMD LS) and the neck of the femur (BMD FN), and with the occurrence of fractures, were studied using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis on DNA isolated from peripheral blood of 239 women and 40 men from the region of western Poland. Three polymorphisms of the 3' end of the VDR gene (BsmI, ApaI, TaqI) indicated a strong linkage disequilibrium. Association analysis of the VDR gene FokI polymorphism with BMD LS showed a dose effect of allele f. The association of the bAT haplotype of the BsmI, ApaI, and TaqI polymorphisms of the VDR gene with BMD FN was statistically significant. The association of the ApaI polymorphism with the occurrence of fractures was observed. Associations were also observed between the occurrence of fractures and the baT haplotypes of the VDR gene.

[Quality of life in patients with hip bone fractures]. / Jakosc zycia chorych po zlamaniu szyjki kosci udowej.

UNLABELLED: The aim of the study was to evaluate quality of life in patients who received surgical treatment of hip fracture. MATERIAL AND METHODS: Fifty patients (mean age: 77,5) including 37 women and 13 men participated in the study. All patients filled in a questionnaire constructed specially for the study. Patients were investigated three times: first time during hospitalization after surgery, second time within one month, and the last time after one year since surgery. Patients were not diagnosed as osteoporotic, before fracture had occurred. The diagnosis of osteoporosis was done on the basis of risk factors analysis and occurrence of low-energy fracture. RESULTS: Eight percent of patients assesed their economical status as very good before the hip fracture has occurred. There were no such assessments after the hip fracture. Before hip fracture 28% of patients' assessed their economical status as low, after hip fracture there were 50% of low economical status assessments. Twenty two percent of patients need continuous care after one year since hip fracture in comparison to 16% of patients before hip fracture. Twenty eight percent of patients who suffered from hip fracture assessed their health condition as bad, in comparison to 16% of such assessments before hip fracture. Eight percent of patients stated that their quality of life is low, in comparison to 40% of such assessments after one year since hip fracture. All patients declared that pain ailments increased during last year. Mortality rate in investigated group, despite immediate treatment, was 40%. In investigated group 40% of patients died within one year since hip fracture, despite immediate treatment. In group of patients who died within one year 54% assessed their quality of life as low. CONCLUSION: Quality of life assessment is important indicator of overall health condition and treatment efficiency.

Polymorphism of VDR gene--the most effective molecular marker of osteoporotic bone fractures risk within postmenopausal women from Wielkopolska region of Poland.

The major public health problem which will arise is a frequency of osteoporosis. The first manifestations of this disease are often bone fractures. Identification and evaluation of individual bone fracture risk will be the most effective way of solving the problem. Genetic determination of osteoporosis is unquestionable. The aim of this study is to detect which variants of genotypes lead to illness. We investigated 187 patients with osteoporosis (161 women, 26 men) and 19 healthy subjects. Polymorphisms of the following genes were investigated: OPG, VDR, ESR1, TGFB1 COL1A1, and BMP2. The statistically significant relationship between BMD value and T allele of Taq I VDR gene were found. Genotypes: aa, bb, TT of VDR gene occur more frequently in polish osteoporotic population in Wielkopolska region within patients with higher risk of bone fractures.