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1.  Thyroid Hormone Levels Within Reference Range Are Associated with Heart Rate, Cardiac Structure, and Function in Middle-Aged Men and Women 
Thyroid  2013;23(8):947-954.
Background
Triiodothyronine (T3) has many effects on the heart, and marked changes in cardiac function and structure occur in patients with (subclinical) thyroid disease. We investigated whether between-subject variation in thyroid hormone levels within the euthyroid range is also associated with heart rate and echocardiographic heart function and structure.
Methods
Subjects were selected from the Asklepios study (n=2524), a population-representative random sample of patients aged between 35 and 55 years, free from overt cardiovascular disease at baseline. Analyses were restricted to 2078 subjects (1013 women and 1065 men), not using antihypertensive or thyroid medication nor having antithyroperoxidase antibody levels above clinical cut-off or thyrotropin (TSH) levels outside the reference range. All subjects were phenotyped in-depth and underwent comprehensive echocardiography, including diastolic evaluation. Thyroid function parameters were determined by automated electrochemiluminescence.
Results
Heart rate was robustly positively associated with (quartiles of) free T3 (FT3) and T3, both in subjects with TSH levels within reference (0.27–4.2 μU/L) and in narrow TSH range (0.5–2.5 μU/L; p<0.0001). FT3 and T3 were negatively associated with left ventricular (LV) end-diastolic volume but positively associated with relative wall thickness. Total T3 (TT3) was associated with enhanced ventricular contraction (as assessed by tissue Doppler imaging). Free thyroxine, FT3, and TT3 were positively associated with late ventricular filling, and TT3 was associated with early ventricular filling.
Conclusion
We have demonstrated a strong positive association between thyroid hormone levels within the euthyroid range and heart rate, and more subtle effects on cardiac function and structure. More specifically, we suggest a smaller LV cavity size (with increased relative wall thickness), an enhanced atrial and ventricular contraction, and LV relaxation with higher circulating thyroid hormones. These results illustrate that variation in thyroid hormone levels, even within the reference range, exerts effects on the heart.
doi:10.1089/thy.2012.0471
PMCID: PMC3752520  PMID: 23339744
2.  Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease 
Medici, Marco | Porcu, Eleonora | Pistis, Giorgio | Teumer, Alexander | Brown, Suzanne J. | Jensen, Richard A. | Rawal, Rajesh | Roef, Greet L. | Plantinga, Theo S. | Vermeulen, Sita H. | Lahti, Jari | Simmonds, Matthew J. | Husemoen, Lise Lotte N. | Freathy, Rachel M. | Shields, Beverley M. | Pietzner, Diana | Nagy, Rebecca | Broer, Linda | Chaker, Layal | Korevaar, Tim I. M. | Plia, Maria Grazia | Sala, Cinzia | Völker, Uwe | Richards, J. Brent | Sweep, Fred C. | Gieger, Christian | Corre, Tanguy | Kajantie, Eero | Thuesen, Betina | Taes, Youri E. | Visser, W. Edward | Hattersley, Andrew T. | Kratzsch, Jürgen | Hamilton, Alexander | Li, Wei | Homuth, Georg | Lobina, Monia | Mariotti, Stefano | Soranzo, Nicole | Cocca, Massimiliano | Nauck, Matthias | Spielhagen, Christin | Ross, Alec | Arnold, Alice | van de Bunt, Martijn | Liyanarachchi, Sandya | Heier, Margit | Grabe, Hans Jörgen | Masciullo, Corrado | Galesloot, Tessel E. | Lim, Ee M. | Reischl, Eva | Leedman, Peter J. | Lai, Sandra | Delitala, Alessandro | Bremner, Alexandra P. | Philips, David I. W. | Beilby, John P. | Mulas, Antonella | Vocale, Matteo | Abecasis, Goncalo | Forsen, Tom | James, Alan | Widen, Elisabeth | Hui, Jennie | Prokisch, Holger | Rietzschel, Ernst E. | Palotie, Aarno | Feddema, Peter | Fletcher, Stephen J. | Schramm, Katharina | Rotter, Jerome I. | Kluttig, Alexander | Radke, Dörte | Traglia, Michela | Surdulescu, Gabriela L. | He, Huiling | Franklyn, Jayne A. | Tiller, Daniel | Vaidya, Bijay | de Meyer, Tim | Jørgensen, Torben | Eriksson, Johan G. | O'Leary, Peter C. | Wichmann, Eric | Hermus, Ad R. | Psaty, Bruce M. | Ittermann, Till | Hofman, Albert | Bosi, Emanuele | Schlessinger, David | Wallaschofski, Henri | Pirastu, Nicola | Aulchenko, Yurii S. | de la Chapelle, Albert | Netea-Maier, Romana T. | Gough, Stephen C. L. | Meyer zu Schwabedissen, Henriette | Frayling, Timothy M. | Kaufman, Jean-Marc | Linneberg, Allan | Räikkönen, Katri | Smit, Johannes W. A. | Kiemeney, Lambertus A. | Rivadeneira, Fernando | Uitterlinden, André G. | Walsh, John P. | Meisinger, Christa | den Heijer, Martin | Visser, Theo J. | Spector, Timothy D. | Wilson, Scott G. | Völzke, Henry | Cappola, Anne | Toniolo, Daniela | Sanna, Serena | Naitza, Silvia | Peeters, Robin P.
PLoS Genetics  2014;10(2):e1004123.
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10−8) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68–2.81, P = 8.1×10−8), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26–1.82, P = 2.9×10−6), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66–0.89, P = 6.5×10−4). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22–1.54, P = 1.2×10−7 and OR: 1.25, 95% CI 1.12–1.39, P = 6.2×10−5). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18–2.10, P = 1.9×10−3). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
Author Summary
Individuals with thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune thyroid diseases (AITD), which are common in the general population and associated with increased cardiovascular, metabolic and psychiatric morbidity and mortality. As the causative genes of TPOAbs and AITD remain largely unknown, we performed a genome-wide scan for TPOAbs in 18,297 individuals, with replication in 8,990 individuals. Significant associations were detected with variants at TPO, ATXN2, BACH2, MAGI3, and KALRN. Individuals carrying multiple risk variants also had a higher risk of increased thyroid-stimulating hormone levels (including subclinical and overt hypothyroidism), and a decreased risk of goiter. The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, and the MAGI3 variant was also associated with an increased risk of hypothyroidism. This first genome-wide scan for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. These results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which individuals are particularly at risk of developing clinical thyroid dysfunction.
doi:10.1371/journal.pgen.1004123
PMCID: PMC3937134  PMID: 24586183
3.  Quality of Life in Sarcopenia and Frailty 
Calcified tissue international  2013;93(2):101-120.
The reduced muscle mass and impaired muscle performance that defines sarcopenia in older individuals is associated with increased risk of physical limitation and a variety of chronic diseases. It may also contribute to clinical frailty.
A gradual erosion of quality of life (QoL) has been evidenced in these individuals, although much of this research has been done using generic QoL instruments, particularly the SF-36, which may not be ideal in older populations with significant comorbidities.
This review and report of an expert meeting, presents the current definitions of these geriatric syndromes (sarcopenia and frailty). It then briefly summarises QoL concepts and specificities in older populations, examines the relevant domains of QoL and what is known concerning QoL decline with these conditions. It calls for a clearer definition of the construct of disability and argues that a disease-specific QoL instrument for sarcopenia/frailty would be an asset for future research and discusses whether there are available and validated components that could be used to this end and whether the psychometric properties of these instruments are sufficiently tested. It calls also for an approach using utility weighting to provide some cost estimates and suggests that a time trade off study could be appropriate.
doi:10.1007/s00223-013-9758-y
PMCID: PMC3747610  PMID: 23828275
Age; aging; muscle weakness; quality of life; malnutrition
4.  Genetic Variations in the Androgen Receptor Are Associated with Steroid Concentrations and Anthropometrics but Not with Muscle Mass in Healthy Young Men 
PLoS ONE  2014;9(1):e86235.
Objective
The relationship between serum testosterone (T) levels, muscle mass and muscle force in eugonadal men is incompletely understood. As polymorphisms in the androgen receptor (AR) gene cause differences in androgen sensitivity, no straightforward correlation can be observed between the interindividual variation in T levels and different phenotypes. Therefore, we aim to investigate the relationship between genetic variations in the AR, circulating androgens and muscle mass and function in young healthy male siblings.
Design
677 men (25–45 years) were recruited in a cross-sectional, population-based sibling pair study.
Methods
Relations between genetic variation in the AR gene (CAGn, GGNn, SNPs), sex steroid levels (by LC-MS/MS), body composition (by DXA), muscle cross-sectional area (CSA) (by pQCT), muscle force (isokinetic peak torque, grip strength) and anthropometrics were studied using linear mixed-effect modelling.
Results
Muscle mass and force were highly heritable and related to age, physical activity, body composition and anthropometrics. Total T (TT) and free T (FT) levels were positively related to muscle CSA, whereas estradiol (E2) and free E2 (FE2) concentrations were negatively associated with muscle force. Subjects with longer CAG repeat length had higher circulating TT, FT, and higher E2 and FE2 concentrations. Weak associations with TT and FT were found for the rs5965433 and rs5919392 SNP in the AR, whereas no association between GGN repeat polymorphism and T concentrations were found. Arm span and 2D:4D finger length ratio were inversely associated, whereas muscle mass and force were not associated with the number of CAG repeats.
Conclusions
Age, physical activity, body composition, sex steroid levels and anthropometrics are determinants of muscle mass and function in young men. Although the number of CAG repeats of the AR are related to sex steroid levels and anthropometrics, we have no evidence that these variations in the AR gene also affect muscle mass or function.
doi:10.1371/journal.pone.0086235
PMCID: PMC3900506  PMID: 24465978
5.  Health technology assessment in osteoporosis 
We review the various aspects of health technology assessment in osteoporosis, including epidemiology and burden of disease, and assessment of the cost-effectiveness of recent advances in the treatment of osteoporosis and the prevention of fracture, in the context of the allocation of healthcare resources by decision-makers in osteoporosis. This article was prepared on the basis of a symposium held by the Belgian Bone Club and the discussions surrounding that meeting, and is based on a review and critical appraisal of the literature. Epidemiological studies confirm the immense burden of osteoporotic fractures for patients and society with lifetime risks of any fracture of the hip, spine and forearm of around 40% for women and 13% for men. The economic impact is also large, for example, Europe’s six largest countries spent €31 billion on osteoporotic fractures in 2010. Moreover, the burden is expected to increase in the future with demographic changes and increasing life expectancy. Recent advances in the management of osteoporosis include novel treatments, better fracture risk assessment notably via fracture risk algorithms, and improved adherence to medication. Economic evaluation can inform decision-makers in healthcare on the cost-effectiveness of the various interventions. Cost-effectiveness analyses suggest that the recent advances in the prevention and treatment of osteoporosis may constitute an efficient basis for the allocation of scarce healthcare resources. In summary, health technology assessment is increasingly used in the field of osteoporosis and could be very useful to help decision-makers efficiently allocate healthcare resources.
doi:10.1007/s00223-013-9724-8
PMCID: PMC3696176  PMID: 23515633
Burden of disease; cost-effectiveness; economic evaluation; health technology assessment; osteoporosis
6.  Health Technology Assessment in Osteoporosis 
We review the various aspects of health technology assessment in osteoporosis, including epidemiology and burden of disease, and assessment of the cost-effectiveness of recent advances in the treatment of osteoporosis and the prevention of fracture, in the context of the allocation of health-care resources by decision makers in osteoporosis. This article was prepared on the basis of a symposium held by the Belgian Bone Club and the discussions surrounding that meeting and is based on a review and critical appraisal of the literature. Epidemiological studies confirm the immense burden of osteoporotic fractures for patients and society, with lifetime risks of any fracture of the hip, spine, and forearm of around 40 % for women and 13 % for men. The economic impact is also large; for example, Europe’s six largest countries spent €31 billion on osteoporotic fractures in 2010. Moreover, the burden is expected to increase in the future with demographic changes and increasing life expectancy. Recent advances in the management of osteoporosis include novel treatments, better fracture-risk assessment notably via fracture risk algorithms, and improved adherence to medication. Economic evaluation can inform decision makers in health care on the cost-effectiveness of the various interventions. Cost-effectiveness analyses suggest that the recent advances in the prevention and treatment of osteoporosis may constitute an efficient basis for the allocation of scarce health-care resources. In summary, health technology assessment is increasingly used in the field of osteoporosis and could be very useful to help decision makers efficiently allocate health-care resources.
doi:10.1007/s00223-013-9724-8
PMCID: PMC3696176  PMID: 23515633
Burden of disease; Cost-effectiveness; Economic evaluation; Health technology assessment; Osteoporosis
7.  Towards a diagnostic and therapeutic consensus in male osteoporosis 
Summary
Consensus views on osteoporosis in men are reported
Background
Workshop within a meeting on osteoporosis in men to identify areas of consensus amongst a panel (the authors) and the participants of the meeting.
Methods
Public debate with an expert panel on preselected topics
Results and conclusions
Consensus views reached on diagnostic criteria for osteoporosis in men and defined aspects of the pathophysiology and treatment of osteoporosis in men
doi:10.1007/s00198-011-1632-z
PMCID: PMC3555694  PMID: 21509585
Bone mineral density; Bone quality; Fracture risk; Gonadal hormone status; Obesity; Testosterone; Treatment; T-score
8.  Glucose Intolerance and the Amount of Visceral Adipose Tissue Contribute to an Increase in Circulating Triglyceride Concentrations in Caucasian Obese Females 
PLoS ONE  2012;7(9):e45145.
Context
Lipotoxicity is a risk factor for developing obesity-related metabolic complications, including non-alcoholic fatty liver disease, type 2 diabetes (DM2), cardiovascular disease and stroke. Yet, the mechanisms underlying the development of lipotoxicity itself remain poorly understood. Here, we investigated whether glucose intolerance aggravates lipotoxicity by evaluating the association between triglyceride (TG) concentrations and glucose tolerance status in a cross-sectional study on obese Caucasian women at risk for DM2.
Methods
913 obese females unknown to have diabetes were recruited (mean age: 41.2±SD 12.3; median BMI: 36.2, IQR 32.9–40.2). Visceral (VAT) and subcutaneous abdominal adipose tissue volumes were quantified with computed tomography. Glucose, insulin, and triglyceride concentrations were determined in fasting state and following a 75 gram oral glucose tolerance test.
Results
Based on fasting and 2 h post-load glucose levels, 27% of the women had impaired glucose tolerance (IGT), and 8% had newly diagnosed DM2. Fasting TG concentrations were similar between the IGT- and DM2-groups, and increased as compared to women with normal glucose tolerance (NGT). Even when adjusting for age, hip circumference and VAT, fasting TG concentrations remained elevated as compared to NGT. Mixed modelling analysis of post-load responses showed that TG concentrations declined more slowly in the DM2-group as compared to IGT and NGT. However, when adjusting for VAT the difference in decline between the glucose tolerance groups disappeared.
Conclusions
Glucose intolerance associates with elevated fasting TG concentrations in obese Caucasian women. We propose that glucose intolerance and increased VAT reduce lipid disposal mechanisms and may accelerate lipotoxicity.
doi:10.1371/journal.pone.0045145
PMCID: PMC3460993  PMID: 23028811
9.  Bivariate association analysis in selected samples: application to a GWAS of two bone mineral density phenotypes in males with high or low BMD 
Our specific aims were to evaluate the power of bivariate analysis and to compare its performance with traditional univariate analysis in samples of unrelated subjects under varying sampling selection designs. Bivariate association analysis was based on the seemingly unrelated regression (SUR) model that allows different genetic models for different traits. We conducted extensive simulations for the case of two correlated quantitative phenotypes, with the quantitative trait locus making equal or unequal contributions to each phenotype. Our simulation results confirmed that the power of bivariate analysis is affected by the size, direction and source of the phenotypic correlations between traits. They also showed that the optimal sampling scheme depends on the size and direction of the induced genetic correlation. In addition, we demonstrated the efficacy of SUR-based bivariate test by applying it to a real Genome-Wide Association Study (GWAS) of Bone Mineral Density (BMD) values measured at the lumbar spine (LS) and at the femoral neck (FN) in a sample of unrelated males with low BMD (LS Z-scores ≤−2) and with high BMD (LS and FN Z-scores >0.5). A substantial amount of top hits in bivariate analysis did not reach nominal significance in any of the two single-trait analyses. Altogether, our studies suggest that bivariate analysis is of practical significance for GWAS of correlated phenotypes.
doi:10.1038/ejhg.2011.22
PMCID: PMC3110051  PMID: 21427758
bivariate association; GWAS; BMD; osteoporosis
10.  Osteoporosis in Men 
Journal of Osteoporosis  2012;2012:675984.
doi:10.1155/2012/675984
PMCID: PMC3337618  PMID: 22570804
11.  Fetal Microchimeric Cells in Blood of Women with an Autoimmune Thyroid Disease 
PLoS ONE  2011;6(12):e29646.
Context
Hashimoto's thyroiditis (HT) and Graves' disease (GD), two autoimmune thyroid diseases (AITD), occur more frequently in women than in men and show an increased incidence in the years following parturition. Persisting fetal cells could play a role in the development of these diseases.
Objective
Aim of this study was to detect and characterize fetal cells in blood of postpartum women with and without an AITD.
Participants
Eleven patients with an AITD and ten healthy volunteers, all given birth to a son maximum 5 years before analysis, and three women who never had been pregnant, were included. None of them had any other disease of the thyroid which could interfere with the results obtained.
Methods
Fluorescence in situ hybridization (FISH) and repeated FISH were used to count the number of male fetal cells. Furthermore, the fetal cells were further characterized.
Results
In patients with HT, 7 to 11 fetal cells per 1.000.000 maternal cells were detected, compared to 14 to 29 fetal cells in patients with GD (p = 0,0061). In patients with HT, mainly fetal CD8+ T cells were found, while in patients with GD, fetal B and CD4+ T cells were detected. In healthy volunteers with son, 0 to 5 fetal cells were observed, which was significantly less than the number observed in patients (p<0,05). In women who never had been pregnant, no male cells were detected.
Conclusion
This study shows a clear association between fetal microchimeric cells and autoimmune thyroid diseases.
doi:10.1371/journal.pone.0029646
PMCID: PMC3246474  PMID: 22216337
12.  Mediators of physical activity change in a behavioral modification program for type 2 diabetes patients 
Background
Many studies have reported significant behavioral impact of physical activity interventions. However, few have examined changes in potential mediators of change preceding behavioral changes, resulting in a lack of information concerning how the intervention worked. Our purpose was to examine mediation effects of changes in psychosocial variables on changes in physical activity in type 2 diabetes patients.
Methods
Ninety-two patients (62 ± 9 years, 30, 0 ± 2.5 kg/m2, 69% males) participated in a randomized controlled trial. The 24-week intervention was based on social-cognitive constructs and consisted of a face-to-face session, telephone follow-ups, and the use of a pedometer. Social-cognitive variables and physical activity (device-based and self-reported) were collected at baseline, after the 24-week intervention and at one year post-baseline. PA was measured by pedometer, accelerometer and questionnaire.
Results
Post-intervention physical activity changes were mediated by coping with relapse, changes in social norm, and social modeling from family members (p ≤ 0.05). One-year physical activity changes were mediated by coping with relapse, changes in social support from family and self-efficacy towards physical activity barriers (p ≤ 0.05)
Conclusions
For patients with type 2 diabetes, initiatives to increase their physical activity could usefully focus on strategies for resuming regular patterns of activity, on engaging family social support and on building confidence about dealing with actual and perceived barriers to activity.
Trial Registration
NCT00903500, ClinicalTrials.gov.
doi:10.1186/1479-5868-8-105
PMCID: PMC3191467  PMID: 21958233
13.  Sex Steroids Affect Triglyceride Handling, Glucose-Dependent Insulinotropic Polypeptide, and Insulin Sensitivity 
Diabetes Care  2010;33(8):1831-1833.
OBJECTIVE
To evaluate metabolic effects of sex steroids in nonfasting and fasting conditions, independent from changes in body composition.
RESEARCH DESIGN AND METHODS
A randomized clinical trial was performed to create contrasting sex steroid levels in healthy young men: by letrozole (aromatase inhibitor) to lower estradiol (E2) and increase testosterone (group T, n = 10) versus letrozole plus E2 patches to lower T and raise E2 (group E, n = 10). Mixed meals and hyperinsulinemic-euglycemic clamps were performed before and after a 1-week treatment period.
RESULTS
Following intervention, the postprandial triglyceride response displayed a diverging response with a decline in group T and an increase in group E; the postprandial glucose-dependent insulinotropic polypeptide (GIP) response increased in group T. Insulin sensitivity increased in group T but remained unaltered in group E.
CONCLUSIONS
In healthy young men, short-term changes in sex steroids affect postprandial triglyceride and GIP response and insulin sensitivity.
doi:10.2337/dc10-0515
PMCID: PMC2909071  PMID: 20484128
14.  Adverse Reactions and Drug–Drug Interactions in the Management of Women with Postmenopausal Osteoporosis 
Calcified Tissue International  2011;89(2):91-104.
The pharmacological management of disease should involve consideration of the balance between the beneficial effects of treatment on outcome and the probability of adverse effects. The aim of this review is to explore the risk of adverse drug reactions and drug–drug interactions with treatments for postmenopausal osteoporosis. We reviewed evidence for adverse reactions from regulatory documents, randomized controlled trials, pharmacovigilance surveys, and case series. Bisphosphonates are associated with gastrointestinal effects, musculoskeletal pain, and acute-phase reactions, as well as, very rarely, atrial fibrillation, atypical fracture, delayed fracture healing, osteonecrosis of the jaw, hypersensitivity reactions, and renal impairment. Cutaneous effects and osteonecrosis of the jaw are of concern for denosumab (both very rare), though there are no pharmacovigilance data for this agent yet. The selective estrogen receptor modulators are associated with hot flushes, leg cramps, and, very rarely, venous thromboembolism and stroke. Strontium ranelate has been linked to hypersensitivity reactions and venous thromboembolism (both very rare) and teriparatide with headache, nausea, dizziness, and limb pain. The solidity of the evidence base depends on the frequency of the reaction, and causality is not always easy to establish for the very rare adverse reactions. Drug–drug interactions are rare. Osteoporosis treatments are generally safe and well tolerated, though they are associated with a few very rare serious adverse reactions. While these are a cause for concern, the risk should be weighed against the benefits of treatment itself, i.e., the prevention of osteoporotic fracture.
doi:10.1007/s00223-011-9499-8
PMCID: PMC3135835  PMID: 21637997
Osteoporosis; Adverse drug reaction; Drug–drug interaction; Bisphosphonate; Denosumab; SERM; Strontium ranelate; Teriparatide
15.  Cutaneous Side Effects of Antiosteoporosis Treatments 
Cutaneous adverse reactions are reported for many therapeutic agents and, in general, are observed in between 0% and 8% of treated patients depending on the drug. Antiosteoporotic agents are considered to be safe in terms of cutaneous effects, however there have been a number of case reports of cutaneous adverse reactions which warrant consideration. This was the subject of a working group meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis in April 2009, which focused on the impact of cutaneous adverse reactions and drug-induced hypersensitivity in the management of postmenopausal osteoporosis. This position paper was drafted following these discussions and includes a flowchart for their recognition. Cutaneous adverse reactions observed with antiosteoporotic agents were reviewed and included information from case reports, regulatory documents and pharmacovigilance. These reactions ranged from benign effects including exanthematous or maculopapular eruption (drug rash), photosensitivity and urticaria, to the severe and potentially life-threatening reactions of angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), Stevens Johnson syndrome and toxic epidermal necrolysis. A review of the available evidence demonstrates that cutaneous adverse reactions occur with all commonly used antiosteoporotic treatments. Notably, there are reports of Stevens Johnson syndrome and toxic epidermal necrolysis for bisphosphonates, and of DRESS and toxic epidermal necrolysis for strontium ranelate. These severe reactions remain very rare (<1 in 10,000 cases). In general, with proper management and early recognition, including immediate and permanent withdrawal of the culprit agent, accompanied by hospitalization, rehydration and systemic corticosteroids if necessary, the prognosis is positive.
doi:10.1177/1759720X10387202
PMCID: PMC3383534  PMID: 22870464
antiosteoporosis treatments; cutaneous adverse reactions; hypersensitivity reactions; osteoporosis
16.  Serum Dioxin-like Activity Is Associated with Reproductive Parameters in Young Men from the General Flemish Population 
Environmental Health Perspectives  2006;114(11):1670-1676.
Background
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and some related environmental contaminants are aryl hydrocarbon receptor (AhR) ligands that exert reproductive and developmental toxicity in laboratory animals. In humans, fertility-related effects are less documented.
Objective
The aim of this study was to investigate the relationship between dioxin-like biological activity in serum and parameters of reproductive status in men from the general population 5 months after a polychlorinated biphenyl and dioxin food-contamination episode in Belgium.
Design
In the framework of the cross-sectional Flemish Environment and Health Study (FLEHS), we recruited 101 men 20–40 years of age and evaluated sperm parameters, measured sex hormones, and gathered information on a number of lifestyle factors. In addition, we determined the AhR-mediated enzymatic response elicited by individual serum samples and expressed it as TCDD equivalent concentrations (CALUX-TEQs) using an established transactivation assay.
Results
Age (p = 0.04) and the frequency of fish (p = 0.02) and egg (p = 0.001) consumption were independent positive determinants of serum dioxin-like activity. After correcting for possible confounders, we found that a 2-fold increase in CALUX-TEQ > 16 pg/L was associated with a 7.1% and 6.8% (both p = 0.04) decrease in total and free testosterone, respectively. We also observed a more pronounced drop in semen volume of 16.0% (p = 0.03), whereas sperm concentration rose by 25.2% (p = 0.07). No relationship was found with total sperm count or sperm morphology.
Conclusions
These data suggest an interaction of dioxin-like compounds with the secretory function of the seminal vesicles or prostate, possibly indirectly through an effect on testosterone secretion, at levels not affecting spermatogenesis as such.
doi:10.1289/ehp.9224
PMCID: PMC1665408  PMID: 17107851
dioxin; DR-CALUX; egg consumption; hormones; male fertility; semen volume; sperm concentration; TCDD; testosterone

Results 1-16 (16)