| 1. |
- Zheng, Hou-Feng, et al.
(författare)
-
Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture
- 2015
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-
-
Tidskriftsartikel (refereegranskat)abstract
- The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF <= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants(1-8), as well as rare, population specific, coding variants(9). Here we identify novel non-coding genetic variants with large effects on BMD (n(total) = 53,236) and fracture (n(total) = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564(T), MAF51.6%, replication effect size510.20 s.d., P-meta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size +10.41 s.d., P-meta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
|
|
| 2. |
|
|
| 3. |
- Langdahl, Bente L., et al.
(författare)
-
A 24-Month Study Evaluating the Efficacy and Safety of Denosumab for the Treatment of Men With Low Bone Mineral Density : Results From the ADAMO Trial
- 2015
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 100:4, s. 1335-1342
-
Tidskriftsartikel (refereegranskat)abstract
- Context: One in 4 men in the United States aged >50 years will have an osteoporosis-related fracture. Fewer data are available on osteoporosis treatment in men than in women. Objective: The purpose of this study was to evaluate denosumab therapy in men with low bone mineral density (BMD). Design: This was a phase 3 study with 2 treatment periods: a previously reported 12-month double-blind, placebo-controlled phase and a 12-month open-label phase. Setting: This was a multicenter study conducted in North America and Europe. Participants: A total of 228 men entered the open-label phase and 219 completed the study. Intervention: Men from the original denosumab (long-term) and placebo (crossover) groups received 60 mg of denosumab sc every 6 months. Main Outcome Measures: BMD, serum collagen type I C-telopeptide, and safety were measured. Results: During the open-label phase, continued BMD increases occurred with long-term denosumab treatment (2.2% lumbar spine, 0.9% total hip, 1.3% femoral neck, 1.3% trochanter, and 0.2% 1/3 radius), resulting in cumulative 24-month gains from baseline of 8.0%, 3.4%, 3.4%, 4.6%, and 0.7%, respectively (all P < .01). The crossover group showed BMD gains after 12 months of denosumab treatment similar to those of the long-term denosumab group during the first treatment year. Significant reductions in serum collagen type I C-teleopeptide were observed after denosumab administration. Adverse event rates were similar between groups, and no new safety signals were identified. Conclusions: In men with low BMD, denosumab treatment for a second year continued to increase BMD, maintained reductions in bone resorption, and was well tolerated. BMD increased in men initiating denosumab during the second year. These effects were similar to those previously seen in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation therapy.
|
|
| 4. |
- Langdahl, Bente L., et al.
(författare)
-
Fracture Rate, Quality of Life and Back Pain in Patients with Osteoporosis Treated with Teriparatide : 24-Month Results from the Extended Forsteo Observational Study (ExFOS)
- 2016
-
Ingår i: Calcified Tissue International. - : Springer Science and Business Media LLC. - 0171-967X .- 1432-0827. ; 99:3, s. 259-271
-
Tidskriftsartikel (refereegranskat)abstract
- We describe the pre-planned interim analysis of fracture outcomes, health-related quality of life (HRQoL) and back pain in patients with severe osteoporosis treated with teriparatide for up to 24 months in the Extended Forsteo (Forsteo(A (R)) is a registered trade name of Eli Lilly and Company) Observational Study (ExFOS), a prospective, multinational, observational study. Data on incident clinical fractures, HRQoL (EQ-5D questionnaire) and back pain [100 mm visual analogue scale (VAS)] were collected. The number of patients with fractures was summarised in 6-month intervals and fracture rate over each 6-month period was assessed using logistic regression for repeated measures. Changes from baseline in EQ-5D and back pain VAS were analysed using mixed models for repeated measures. Of 1454 patients in the active treatment cohort, 90.6 % were female and 14.4 % were taking glucocorticoids. During teriparatide treatment (median duration 23.7 months), 103 patients (7.1 %) sustained a total of 122 incident clinical fractures (21 % vertebral, 79 % non-vertebral). A 49 % decrease in the odds of fractures and a 75 % decrease in the odds of clinical vertebral fractures were observed in the > 18- to 24-month period versus the first 6-month period (both p < 0.05). EQ-5D scores and back pain VAS scores were significantly improved from baseline at each post-baseline observation during teriparatide treatment. In conclusion, patients with severe osteoporosis showed a significant reduction in the incident fracture rate during 24 months of teriparatide treatment in routine clinical practice, accompanied by a significant improvement in HRQoL and reduction in back pain. Results should be interpreted in the context of the non-controlled design of this observational study.
|
|
| 5. |
- Napoli, Nicola, et al.
(författare)
-
Effects of Teriparatide in Patients with Osteoporosis in Clinical Practice : 42-Month Results During and After Discontinuation of Treatment from the European Extended Forsteo (R) Observational Study (ExFOS)
- 2018
-
Ingår i: Calcified Tissue International. - : SPRINGER. - 0171-967X .- 1432-0827. ; 103:4, s. 359-371
-
Tidskriftsartikel (refereegranskat)abstract
- This study aimed to describe clinical outcomes in patients prescribed teriparatide and followed up for 18months after stopping the drug in real-life conditions. The Extended Forsteo (R) Observational Study analysed incident clinical fractures in 6-month intervals using logistic regression with repeated measures. Changes in back pain (visual analogue scale) and health-related quality of life (HRQoL; EQ-5D questionnaire) were analysed using mixed models for repeated measures. Patients were analysed if they had a post-baseline visit, regardless of whether and for how long they took teriparatide. Of 1531 patients analysed (90.7% female, mean age: 70.3years), 76 (5.0%) never took teriparatide. Median treatment duration was 23.6months. The adjusted odds of clinical fracture decreased by 47% in the >12- to 18-month treatment period (p=0.013) compared with the first 6-month period, with no statistically significant reduction in the >18- to 24-month interval. The clinical fracture rate remained stable during the 18 months' post-teriparatide, when approximately 98% of patients took osteoporosis medication (51% bisphosphonates). Clinical vertebral fractures were reduced at every time period compared with the first 6months. Adjusted mean back pain scores decreased and EQ-5D scores increased significantly at each post-baseline observation. In a real-life clinical setting, the risk of clinical fractures declined during 24months of teriparatide treatment. This reduction was maintained 18months after stopping teriparatide. In parallel, patients reported significant improvements in back pain and HRQoL. The results should be interpreted in the context of the non-controlled design of this observational study.
|
|
