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1.  Variation in the MC4R Gene Is Associated with Bone Phenotypes in Elderly Swedish Women 
PLoS ONE  2014;9(2):e88565.
Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r2 = 0.2–0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs. CC: BUA: 100 vs. 103 vs. 103; p = 0.002); (SOS: 1521 vs. 1526 vs. 1524; p = 0.008); (Stiffness index: 69 vs. 73 vs. 74; p = 0.0006) after adjustment for confounders. They also had low folate (18 vs. 17 vs. 16; p = 0.03) and vitamin D (93 vs. 91 vs. 90; p = 0.03) and high Hcy levels (13.7 vs 14.4 vs. 14.5; p = 0.06). Fracture incidence was lower among women with the C-allele, (52% vs. 58%; p = 0.067). Variation in MC4R was not associated with BMD or body composition in either OPRA or PEAK-25. SNPs close to FTO and INSIG2 were not associated with any bone phenotypes in either cohort and FTO SNPs were only associated with body composition in PEAK-25 (p≤0.001). Our results suggest that genetic variation close to MC4R is associated with quantitative ultrasound and risk of fracture.
doi:10.1371/journal.pone.0088565
PMCID: PMC3916440  PMID: 24516669
2.  Polymorphisms in the Inflammatory Genes CIITA, CLEC16A and IFNG Influence BMD, Bone Loss and Fracture in Elderly Women 
PLoS ONE  2012;7(10):e47964.
Osteoclast activity and the fine balance between bone formation and resorption is affected by inflammatory factors such as cytokines and T lymphocyte activity, mediated by major histocompatibility complex (MHC) molecules, in turn regulated by the MHC class II transactivator (MHC2TA). We investigated the effect of functional polymorphisms in the MHC2TA gene (CIITA), and two additional genes; C-type lectin domain 16A (CLEC16A), in linkage disequilibrium with CIITA and Interferon-γ (IFNG), an inducer of CIITA; on bone density, bone resorption markers, bone loss and fracture risk in 75 year-old women followed for up to 10 years (OPRA n = 1003) and in young adult women (PEAK-25 n = 999). CIITA was associated with BMD at age 75 (lumbar spine p = 0.011; femoral neck (FN) p = 0.049) and age 80 (total body p = 0.015; total hip p = 0.042; FN p = 0.028). Carriers of the CIITA rs3087456(G) allele had 1.8–3.4% higher BMD and displayed increased rate of bone loss between age 75 and 80 (FN p = 0.013; total hip p = 0.030; total body p = 3.8E−5). Despite increasing bone loss, the rs3087456(G) allele was protective against incident fracture overall (p = 0.002), osteoporotic fracture and hip fracture. Carriers of CLEC16A and IFNG variant alleles had lower BMD (p<0.05) and ultrasound parameters and a lower risk of incident fracture (CLEC16A, p = 0.011). In 25-year old women, none of the genes were associated with BMD. In conclusion, variation in inflammatory genes CIITA, CLEC-16A and INFG appear to contribute to bone phenotypes in elderly women and suggest a role for low-grade inflammation and MHC class II expression for osteoporosis pathogenesis.
doi:10.1371/journal.pone.0047964
PMCID: PMC3485004  PMID: 23133532
3.  Higher risk of reoperation for bipolar and uncemented hemiarthroplasty 
Acta Orthopaedica  2012;83(5):459-466.
Background and purpose
Hemiarthroplasty as treatment for femoral neck fractures has increased markedly in Sweden during the last decade. In this prospective observational study, we wanted to identify risk factors for reoperation in modular hemiarthroplasties and to evaluate mortality in this patient group.
Patients and methods
We assessed 23,509 procedures from the Swedish Hip Arthroplasty Register using the most common surgical approaches with modular uni- or bipolar hemiarthroplasties related to fractures in the period 2005–2010. Completeness of registration (individual procedures) was 89–96%. The median age was 85 years and the median follow-up time was 18 months.
Results
3.8% underwent reoperation (any further hip surgery), most often because of implant dislocation or infection. The risk of reoperation (Cox regression) was higher for uncemented stems (hazard ratio (HR) = 1.5), mainly because of periprosthetic femoral fractures. Bipolar implants had a higher risk of reoperation irrespective of cause (HR = 1.3), because of dislocation (1.4), because of infection (1.3), and because of periprosthetic fracture (1.7). The risk of reoperation due to acetabular erosion was lower (0.30) than for unipolar implants, but reoperation for this complication was rare (1.7 per thousand). Procedures resulting from failed internal fixation had a more than doubled risk; the risk was also higher for males and for younger patients. The surgical approach had no influence on the risk of reoperation generally, but the anterolateral transgluteal approach was associated with a lower risk of reoperation due to dislocation (HR = 0.7). At 1 year, the mortality was 24%. Men had a higher risk of death than women (1.8).
Interpretation
We recommend cemented hemiarthroplasties and the anterolateral transgluteal approach. We also suggest that unipolar implants should be used, at least for the oldest and frailest patients.
doi:10.3109/17453674.2012.727076
PMCID: PMC3488171  PMID: 22998529
4.  Large-Scale Analysis of Association Between LRP5 and LRP6 Variants and Osteoporosis 
Jama  2008;299(11):1277-1290.
Context
Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.
Objective
To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.
Design and Setting
Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.
Main Outcome Measures
Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.
Results
The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n =25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P=3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P=2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P =3.8 × 10−5) and 8 mg/cm2 (P=5.0×10−6) for the Met667 and Val1330 alleles, respectively (n=25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08–1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01–1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05–1.24 per allele [7876 fractures among 31 435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01–1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.
Conclusions
Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P<10−7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
doi:10.1001/jama.299.11.1277
PMCID: PMC3282142  PMID: 18349089
5.  Changes in implant choice and surgical technique for hemiarthroplasty 
Acta Orthopaedica  2012;83(1):7-13.
Background and purpose
Treatment of displaced femoral neck fractures in Sweden has shifted towards more arthroplasties, especially hemiarthroplasties. We describe the hemiarthroplasty population in Sweden 2005 through 2009.
Methods
Since 2005, the Swedish Hip Arthroplasty Register has registered hemiarthroplasties on a national basis. We assessed hemiarthroplasty procedures in the Register 2005–2009 regarding patient details, implants, and surgical techniques. Completeness of recordings was calculated compared to the Swedish National Patient Register.
Results
Completeness increased from 89% to 96% during the study period. 21,346 hemiarthroplasty procedures were assessed. The relative number of patients with femoral neck fracture as diagnosis increased from 91% to 94%; the proportion of men increased from 27% to 30%. The median age increased from 83 to 84 years in men and from 84 to 85 years in women. Patients classified as having evident cognitive impairment increased from 19% to 22%. More men than women were ASA 4. The proportion of monoblock-type implants (Austin-Moore and Thompson) decreased from 18% to 0.9%. Modular implants increased generally, but in 2009 bipolar implants decreased in favor of unipolar implants. Lubinus and Exeter stems, and Mega Caput and Vario Cup implant heads were most common. The use of uncemented implants decreased from 10% to 3%. Use of the anterolateral approach increased from 47% to 56%.
Interpretation
Important changes in surgical technique and implant choice occurred during the observation period. We interpret these changes as being reflections of the continuing effort by Swedish orthopedic surgeons to improve the quality of treatment, because the changes are consistent with recent findings in the Swedish Hip Arthroplasty Register and in other scientific studies.
doi:10.3109/17453674.2011.641104
PMCID: PMC3278650  PMID: 22112151
6.  Polymorphisms in the macrophage migration inhibitory factor gene and bone loss in postmenopausal women 
Bone  2010;47(2):424-429.
Osteoporosis is a severe condition in postmenopausal women and a common cause of fracture. Osteoporosis is a complex disease with a strong genetic impact, but susceptibility is determined by many genes with modest effects and environmental factors. Only a handful of genes consistently associated with osteoporosis have been identified so far.
Inflammation affects bone metabolism by interfering with the interplay between bone resorption and formation, and many inflammatory mediators are involved in natural bone remodeling. The cytokine macrophage migration inhibitory factor (MIF) has been shown to affect bone density in rodents, and polymorphisms in the human MIF promoter are associated with inflammatory disorders such as rheumatoid arthritis. We investigated the association of polymorphisms in the MIF gene with bone mineral density (BMD) and bone loss in 1002 elderly women using MIF promoter polymorphisms MIF-CATT5-8 and rs755622(G/C) located -794 and -173 bp upstream of the transcriptional start site. Bone loss was estimated both by the change in BMD over 5 years and by the levels of bone resorption markers in serum measured at four occasions during a 5 year period.
The MIF-CATT7/rs755622(C) haplotype was associated with increased rate of bone loss during 5 years at the femoral neck (p<0.05) and total hip (p<0.05). In addition, the MIF-CATT7/rs755622(C) haplotype carriers had higher levels of the bone turnover marker serum C-terminal cross-linking telopeptide of type I collagen (S-CTX-I, p<0.01) during the 5 year follow-up period. There was no association between MIF-CATT7/rs755622(C) and baseline BMD at femoral neck, total hip or lumbar spine.
We conclude that MIF promoter polymorphisms have modest effects on bone remodeling and are associated with the rate of bone loss in elderly women.
doi:10.1016/j.bone.2010.05.009
PMCID: PMC3126921  PMID: 20471506
Osteoporosis; Genetics; Inflammation; Bone remodeling; Osteoimmunology
7.  Preventing fractures in elderly people 
BMJ : British Medical Journal  2003;327(7406):89-95.
Preventing fractures in elderly people is a priority, especially as it has been predicted that in 20 years almost a quarter of people in Europe will be aged over 65. This article describes the factors contributing to fracture, interventions to prevent fracture, and the various treatments.
PMCID: PMC1126451  PMID: 12855529

Results 1-8 (8)