Context:
The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years.
Objective:
...The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure.
Design, Setting, and Participants:
This was a multicenter, international, open-label study of 4550 women.
Intervention:
Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover).
Main Outcome Measures:
Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported.
Results:
Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture.
Conclusion:
Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.
The Klotho (KL) gene is involved in phosphate homeostasis. Polymorphisms in this gene have been reported to be associated with the risk of cardiovascular disease. Here we used computational tools to ...predict the damage-associated single nucleotide polymorphisms (SNPs) in the human KL gene. We further investigated the association of SNPs in the KL gene and mortality in the Swedish multicenter prospective Osteoporotic Fractures in Men (MrOS) cohort. This study included 2921 men (aged 69-81 years) with mean 4.49 ± 1.03 years follow-up. 18 SNPs in the KL gene were genotyped using Sequenom. These SNPs were identified by in silico tools for the coding and noncoding genome to predict the damaging SNPs. After quality analyses, SNPs were analyzed for mortality risk using two steps approach on logistic regression model screening and then Cox regression model confirmation. Two non-synonymous SNPs rs9536314 and rs9527025 were found to be potentially damaging SNPs that affect KL protein stability and expression. However, these two SNPs were not statistically significantly associated with all-cause mortality (crude Hazard ratio HR 1.72, 95% confidence interval CI 0.96-3.07 in rs9536314; crude HR 1.82, 95% CI 0.998-3.33 in rs9527025) or cardiovascular mortality (crude HR 1.52, 95% CI 0.56-4.14 in rs9536314; crude HR 1.54, 95% CI 0.55-4.33 in rs9527025) in additive model using Cox regression analysis. In conclusion, these two potentially damaging SNPs (rs9536314 and rs9527025) in the KL gene were not associated with all-cause mortality or cardiovascular mortality in MrOs cohort. Larger scales studies and meta-analysis are needed to confirm the correlation between polymorphisms of the KL gene and mortality.
The purpose of this study is to determine the prevalence and morbidity of neck pain with or without cervical rhizopathy, upper extremity motor deficit and/or thoracolumbar pain in elderly men.
We ...conducted a cross-sectional questionnaire study of 3,000 community-dwelling older men with a mean age of 75.4 ± 3.2 years (range 69-81) to determine if they had experienced neck pain with or without cervical rhizopathy/upper extremity motor deficit/thoracolumbar pain (yes/no) during the preceding 12 months, and if so, morbidity with the condition (no/minor/moderate/severe).
Among the participants, 865 (29%) reported they had experienced neck and 1,619 (54%) thoracolumbar pain. Among the men with neck pain, 59% had experienced only neck pain, 17% neck pain and cervical rhizopathy and 24% neck pain, rhizopathy and motor deficit. For men with only neck pain, the morbidity was severe in 13%, for men with neck pain and rhizopathy it was 24%, and for men with pain, rhizopathy and motor deficit it was 46% (p < 0.001). Among the men with neck pain, 23% had experienced only neck pain and no thoracolumbar pain; the remaining 77% had both neck and thoracolumbar pain. The morbidity was severe in 10% of the men with neck pain but no thoracolumbar pain and 30% in men with neck and thoracolumbar pain (p < 0.001).
Neck pain in elderly men is common but symptoms and morbidity vary. For men who only have neck pain, 1/8 rated their morbidity as severe, while almost half who also had cervical rhizopathy and motor deficit and almost 1/3 of those who also had thoracolumbar pain reported severe morbidity.
Context: The risk of many conditions, including prostate cancer, breast cancer, and osteoporosis, is associated with serum levels of sex steroids.
Objective: The aim of the study was to identify ...genetic variations in sex steroid-related genes that are associated with serum levels of estradiol (E2) and/or testosterone in men.
Design: Genotyping of 604 single nucleotide polymorphisms in 50 sex steroid-related candidate genes was performed in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study (n = 1041 men; age, 18.9 ± 0.6 yr). Replications of significant associations were performed in the Osteoporotic Fractures in Men (MrOS) Sweden study (n = 2568 men; age, 75.5 ± 3.2 yr) and in the MrOS US study (n = 1922 men; age, 73.5 ± 5.8 yr). Serum E2, testosterone, and estrone (E1) levels were analyzed using gas chromatography/mass spectrometry.
Results: The screening in the GOOD cohort identified the single nucleotide polymorphism rs2470152 in intron 1 of the CYP19 gene, which codes for aromatase, responsible for the final step of the biosynthesis of E2 and E1, to be most significantly associated with serum E2 levels (P = 2 × 10−6). This association was confirmed both in the MrOS Sweden study (P = 9 × 10−7) and in the MrOS US study (P = 1 × 10−4). When analyzed in all subjects (n = 5531), rs2470152 was clearly associated with both E2 (P = 2 × 10−14) and E1 (P = 8 × 10−19) levels. In addition, this polymorphism was modestly associated with lumbar spine BMD (P < 0.01) and prevalent self-reported fractures (P < 0.05).
Conclusions: rs2470152 of the CYP19 gene is clearly associated with serum E2 and E1 levels in men.
The single nucleotide polymorphisms rs2470152 of the CYP19 gene are strongly associated with serum estradiol 2 and estradol 1 levels in men.
OBJECTIVE—Disturbances in mineral metabolism define an increased cardiovascular risk in patients with chronic kidney disease. Fibroblast growth factor-23 (FGF23) is a circulating regulator of ...phosphate and vitamin D metabolism and has recently been implicated as a putative pathogenic factor in cardiovascular disease. Because other members of the FGF family play a role in lipid and glucose metabolism, we hypothesized that FGF23 would associate with metabolic factors that predispose to an increased cardiovascular risk. The goal of this study was to investigate the relationship between FGF23 and metabolic cardiovascular risk factors in the community.
METHODS AND RESULTS—Relationships between serum FGF23 and body mass index (BMI), waist circumference, waist-to-hip ratio, serum lipids, and fat mass were examined in 2 community-based, cross-sectional cohorts of elderly whites (Osteoporotic Fractures in Men Study964 men aged 75±3.2; Prospective Investigation of the Vasculature in Uppsala Seniors study946 men and women aged 70). In both cohorts, FGF23 associated negatively with high-density lipoprotein and apolipoprotein A1 (7% to 21% decrease per 1-SD increase in log FGF23; P<0.01) and positively with triglycerides (11% to 14% per 1-SD increase in log FGF23; P<0.01). A 1-SD increase in log FGF23 was associated with a 7% to 20% increase in BMI, waist circumference, and waist-to-hip ratio and a 7% to 18% increase in trunk and total body fat mass (P<0.01) as determined by whole-body dual x-ray absorptiometry. FGF23 levels were higher in subjects with the metabolic syndrome compared with those without (46.4 versus 41.2 pg/mL; P<0.05) and associated with an increased risk of having the metabolic syndrome (OR per 1-SD increase in log FGF23, 1.21; 95% CI, 1.04 to 1.40; P<0.05).
CONCLUSION—We report for the first time on associations between circulating FGF23, fat mass, and adverse lipid metabolism resembling the metabolic syndrome, potentially representing a novel pathway(s) linking high FGF23 to an increased cardiovascular risk.
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