Completeness of RET testing in patients with medullary thyroid carcinoma in Denmark 1997-2013: a nationwide study.

BACKGROUND: The completeness of REarranged during Transfection (RET) testing in patients with medullary thyroid carcinoma (MTC) was recently reported as 60%. However, the completeness on a population level is unknown. Similarly, it is unknown if the first Danish guidelines from 2002, recommending RET testing in all MTC patients, improved completeness in Denmark. We conducted a nationwide retrospective cohort study aiming to evaluate the completeness of RET testing in the Danish MTC cohort. Additionally, we aimed to assess the completeness before and after publication of the first Danish guidelines and characterize MTC patients who had not been tested. METHODS: The study included 200 patients identified from the nationwide Danish MTC cohort 1997-2013. To identify RET tested MTC patients before December 31, 2014, the MTC cohort was cross-checked with the nationwide Danish RET cohort 1994-2014. To characterize MTC patients who had not been RET tested, we reviewed their medical records and compared them with MTC patients who had been tested. RESULTS: Completeness of RET testing in the overall MTC cohort was 87% (95% CI: 0.81-0.91; 173/200). In the adjusted MTC cohort, after excluding patients diagnosed with hereditary MTC by screening, completeness was 83% (95% CI: 0.76-0.88; 131/158). Completeness was 88% (95% CI: 0.75-0.95; 42/48) and 81% (95% CI: 0.72-0.88) (89/110) before and after publication of the first Danish guidelines, respectively. Patients not RET tested had a higher median age at diagnosis compared to those RET tested. Median time to death was shorter in those not tested relative to those tested. CONCLUSION: The completeness of RET testing in MTC patients in Denmark seems to be higher than reported in other cohorts. No improvement in completeness was detected after publication of the first Danish guidelines. In addition, data indicate that advanced age and low life expectancy at MTC diagnosis may serve as prognostic indicators to identify patients having a higher likelihood of missing the compulsory RET test.

Survival and Long-Term Biochemical Cure in Medullary Thyroid Carcinoma in Denmark 1997-2014: A Nationwide Study.

BACKGROUND: Survival of medullary thyroid carcinoma (MTC) subgroups in relation to the general population is poorly described. Data on the factors predicting long-term biochemical cure in MTC patients are nonexistent at a population level. A nationwide retrospective cohort study of MTC in Denmark from 1997 to 2014 was conducted, aiming to detect subgroups with survival similar to that of the general population and to identify prognostic factors for disease-specific survival and long-term biochemical cure. METHODS: The study included 220 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. As a representative sample of the general population, a reference population matched 50:1 to the MTC cohort was used. RESULTS: Patients diagnosed with hereditary MTC by screening (hazard ratio [HR] = 1.5 [confidence interval (CI) 0.5-4.3]), patients without regional metastases (HR = 1.4 [CI 0.9-2.3]), and patients with stage I (HR = 1.3 [CI 0.6-3.1]), stage II (HR = 1.1 [CI 0.6-2.3]), and III (HR = 1.3 [CI 0.4-4.2]) disease had an overall survival similar to the reference population. On multivariate analysis, the presence of distant metastases (HR = 12.3 [CI 6.0-25.0]) predicted worse disease-specific survival, while the absence of regional lymph node metastases (odds ratio = 40.1 [CI 12.0-133.7]) was the only independent prognostic factor for long-term biochemical cure. CONCLUSIONS: Patients with hereditary MTC diagnosed by screening, patients without regional metastases, and patients with stages I, II, and III disease may have similar survival as the general population. The presence of distant metastases predicted worse disease-specific survival, while the absence of regional metastases predicted long-term biochemical cure.

Replication of newly proposed TNM staging system for medullary thyroid carcinoma: a nationwide study.

A recent study proposed new TNM groupings for better survival discrimination among stage groups for medullary thyroid carcinoma (MTC) and validated these groupings in a population-based cohort in the United States. However, it is unknown how well the groupings perform in populations outside the United States. Consequently, we conducted the first population-based study aiming to evaluate if the recently proposed TNM groupings provide better survival discrimination than the current American Joint Committee on Cancer (AJCC) TNM staging system (seventh and eighth edition) in a nationwide MTC cohort outside the United States. This retrospective cohort study included 191 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. In multivariate analysis, hazard ratios for overall survival under the current AJCC TNM staging system vs the proposed TNM groupings with stage I as reference were 1.32 (95% CI: 0.38-4.57) vs 3.04 (95% CI: 1.38-6.67) for stage II, 2.06 (95% CI: 0.45-9.39) vs 3.59 (95% CI: 1.61-8.03) for stage III and 5.87 (95% CI: 2.02-17.01) vs 59.26 (20.53-171.02) for stage IV. The newly proposed TNM groupings appear to provide better survival discrimination in the nationwide Danish MTC cohort than the current AJCC TNM staging. Adaption of the proposed TNM groupings by the current AJCC TNM staging system may potentially improve accurateness in survival discrimination. However, before such an adaption further population-based studies securing external validity are needed.

Incidence and prevalence of multiple endocrine neoplasia 2A in Denmark 1901-2014: a nationwide study.

BACKGROUND: The incidence and prevalence of multiple endocrine neoplasia 2A (MEN2A) have only been reported once in a nationwide setting. However, it is unclear whether the figures are representative of other populations, as the major component of the syndrome, hereditary medullary thyroid carcinoma (MTC), has been reported as rare in the same country. We conducted a nationwide retrospective cohort study of MEN2A in Denmark from 1901 to 2014, aiming to describe the incidence and prevalence. METHODS: This study included 250 unique MEN2A patients born or resident in Denmark before December 31, 2014. Patients were identified through the Danish REarranged during Transfection (RET) cohort, linkage of MEN2A pedigrees, the Danish MTC cohort, a nationwide collaboration of MEN2 centers, cross-checking of other relevant cohorts, and a systematic literature search. RESULTS: The incidence from 1971 to 2000 was 28 (95% CI: 21-37) per million live births per year. Incidence for the specific mutations or for the overall MEN2A group did not change significantly from 1901 to 2014 (P>0.05). Point prevalence at January 1, 2015, was 24 per million (95% CI: 20-28). CONCLUSION: The incidence and prevalence of MEN2A in Denmark seem higher than those reported in other countries. This is likely explained by the Danish C611Y founder effect. Also, our data indicate no significant change in MEN2A incidence during the last century.

Incidence and prevalence of sporadic and hereditary MTC in Denmark 1960-2014: a nationwide study.

Recent studies have shown a significant increase in the temporal trend of medullary thyroid carcinoma (MTC) incidence. However, it remains unknown to which extent sporadic medullary thyroid carcinoma (SMTC) and hereditary MTC (HMTC) affect the MTC incidence over time. We conducted a nationwide retrospective study using previously described RET and MTC cohorts combined with review of medical records, pedigree comparison and relevant nationwide registries. The study included 474 MTC patients diagnosed in Denmark between 1960 and 2014. In the nationwide period from 1997 to 2014, we recorded a mean age-standardized incidence of all MTC, SMTC and HMTC of 0.19, 0.13 and 0.06 per 100,000 per year, respectively. The average annual percentage change in incidence for all MTC, SMTC and HMTC were 1.0 (P = 0.542), 2.8 (P = 0.125) and -3.1 (P = 0.324), respectively. The corresponding figures for point prevalence at January 1, 2015 were 3.8, 2.5 and 1.3 per 100,000, respectively. The average annual percentage change in prevalence from 1998 to 2015 for all MTC, SMTC and HMTC was 2.8 (P < 0.001), 3.8 (P < 0.001) and 1.5 (P = 0.010), respectively. We found no significant change in the incidence of all MTC, SMTC and HMTC possibly due to our small sample size. However, due to an increasing trend in the incidence of all MTC and opposing trends of SMTC (increasing) and HMTC (decreasing) incidence, it seems plausible that an increase for all MTC seen by others may be driven by the SMTC group rather than the HMTC group.

Founder Effect of the RETC611Y Mutation in Multiple Endocrine Neoplasia 2A in Denmark: A Nationwide Study.

BACKGROUND: Multiple endocrine neoplasia (MEN) 2A and 2B are caused by REarranged during Transfection (RET) germline mutations. In a recent nationwide study, an unusually high prevalence (33%) of families with the C611Y mutation was reported, and it was hypothesized that this might be due to a founder effect. The first nationwide study of haplotypes in MEN2A families was conducted, with the aim of investigating the relatedness and occurrence of de novo mutations among Danish families carrying similar mutations. METHODS: The study included 21 apparently unrelated MEN2A families identified from a nationwide Danish RET cohort from 1994 to 2014. Twelve, two, two, three, and two families carried the C611Y, C618F, C618Y, C620R, and C634R mutations, respectively. Single nucleotide polymorphism chip data and identity by descent analysis were used to assess relatedness. RESULTS: A common founder mutation was found among all 12 C611Y families and between both C618Y families. No relatedness was identified in the remaining families. CONCLUSION: The data suggest that all families with the C611Y germline mutation in Denmark originate from a recent common ancestor, probably explaining the unusually high prevalence of this mutation. Additionally, the results indicate that the C611Y mutation rarely arises de novo, thus underlining the need for thorough multigenerational genetic work up in carriers of this mutation.

Bone structural changes after gastric bypass surgery evaluated by HR-pQCT: a two-year longitudinal study.

OBJECTIVE, DESIGN AND METHODS: Roux-en-Y gastric bypass (RYGB) has proved successful in attaining sustained weight loss but may lead to metabolic bone disease. To assess impact on bone mass and structure, we measured a real bone mineral density at the hip and spine by dual-energy X-ray absorptiometry, and volumetric BMD (vBMD) and bone microarchitecture at the distal radius and tibia by high-resolution peripheral quantitative CT in 25 morbidly obese subjects (15 females, 10 males) at 0, 12 and 24 months after RYGB. Bone turnover markers (BTMs), calciotropic and gut hormones and adipokines were measured at the same time points. RESULTS: After a 24.1% mean weight loss from baseline to month 12 (P < 0.001), body weight plateaued from month 12 to 24 (-0.9%, P = 0.50). However, cortical and trabecular vBMD and microarchitecture deteriorated through the 24 months, such that there was a 5 and 7% reduction in estimated bone strength at the radius and tibia respectively (both P < 0.001). The declines observed in the first 12 months were matched or exceeded by declines in the 12- to 24-month period. While a significant increase in BTMs and decrease in leptin and insulin were seen at 24 months, these changes were maximal at month 12 and stabilized from month 12 to 24. CONCLUSIONS: Despite weight stabilization and maintenance of metabolic parameters, bone loss and deterioration in bone strength continued and were substantial in the second year. The clinical importance of these changes in terms of increased risk of developing osteoporosis and fragility fractures remain an important concern.

Distribution of RET Mutations in Multiple Endocrine Neoplasia 2 in Denmark 1994-2014: A Nationwide Study.

BACKGROUND: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations. METHODS: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8-11 and 13-16. Mutations were defined according to the ARUP database July 1, 2016. RESULTS: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation. CONCLUSIONS: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark.

Bone Structural Changes and Estimated Strength After Gastric Bypass Surgery Evaluated by HR-pQCT.

Roux-en-Y gastric bypass surgery (RYGB) is an effective treatment of morbid obesity, with positive effects on obesity-related complications. The treatment is associated with bone loss, which in turn might increase fracture risk. The aim of this study was to evaluate changes in bone mineral density (BMD) and bone architecture assessed using dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT), 6 and 12 months after RYGB, and correlate them to changes in selected biochemical markers. A prospective cohort study included 25 morbidly obese patients (10 males, 15 females). Patients were examined with DXA of the hip and spine, HR-pQCT of radius and tibia, and blood sampling before and 6 and 12 months after RYGB. Patients lost in average 33.5 ± 12.1 kg (25.8 ± 8.5 %) in 12 months. In tibia, we found significant loss of total, cortical and trabecular volumetric BMD after 12 months (all p < 0.001). Microarchitectural changes involved lower trabecular number, increased trabecular separation, and network inhomogeneity along with thinning of the cortex. Estimated bone failure load was decreased after 12 months (p = 0.005). We found only minor changes in radius. Results demonstrate significant alterations of bone microarchitecture suggesting an accelerated endosteal resorption along with disintegration of the trabecular structure which resulted in a loss of estimated bone strength in tibia. Such changes may underlie the recently reported increased risk of fracture in bariatric patients after surgery. We only observed bone structural changes in the weight-bearing bone, which indicates that mechanical un-loading is the primary mediator.

Multidisciplinary Management of Mastocytosis: Nordic Expert Group Consensus.

Mastocytosis is a heterogeneous group of diseases defined by an increased number and accumulation of mast cells, and often also by signs and symptoms of mast cell activation. Disease subtypes range from indolent to rare aggressive forms. Mastocytosis affects people of all ages and has been considered rare; however, it is probably underdiagnosed with potential severe implications. Diagnosis can be challenging and symptoms may be complex and involve multiple organ-systems. In general it is advised that patients should be referred to centres with experience in the disease offering an individualized, multidisciplinary approach. We present here consensus recommendations from a Nordic expert group for the diagnosis and general management of patients with mastocytosis.

Does adding an appended oncology module to the Global Trigger Tool increase its value?

OBJECTIVE: To determine any additional value in the evaluation of safety levels by adding an appended oncology module to the Institute for Healthcare Improvement's Global Trigger Tool (GTT). DESIGN: Comparison of two independent retrospective chart reviews: one review team using the general GTT method and one using the general GTT method plus the appended oncology module on the same inpatient charts. SETTING: The Department of Clinical Oncology at a Danish University Hospital (1000 beds). PARTICIPANTS: All inpatients admitted to the hospital in 2010, n = 3692, biweekly sample of 10 admission charts resulting in a double review of 240 charts. MAIN OUTCOME MEASURES: Total number of identified adverse events (AEs), distribution of identified AEs in the harm categories of the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP), AEs per 100 admissions and AEs per 1000 admission days. RESULTS: No significant (95% confidence interval) difference was found between review teams using the general GTT versus the general GTT plus the appended oncology module on the total number of identified AEs, AEs per 100 admissions, AEs per 1000 admission days or in the overall distribution of identified AEs in the five NCC MERP harm categories. CONCLUSIONS: The study showed that adding the appended oncology module to the GTT did not increase its value regarding the evaluation of safety levels. This finding could be due to the measurement error of the GTT. Further studies evaluating the measurement properties and the specific additional modules to the general GTT are needed.

Familial hypocalciuric hypercalcemia and calcium sensing receptor.

Familial hypocalciuric hypercalcemia (FHH) is a lifelong, benign autosomal dominant disease characterized by hypercalcemia, normal to increased parathyroid hormone level, and a relatively low renal calcium excretion. Inactivation of the calcium-sensing receptor in heterozygous patients results in FHH, while in homozygous patients as well as in compound heterozygous or dominant negative heterozygous patients, it may result in neonatal severe hyperparathyroidism (NSHPT). Parathyroid surgery is not indicated in FHH and does not lower plasma calcium unless total parathyroidectomy is performed, in which case hypocalcemia ensues. There is currently no definitive medical treatment available, although pamidronate can be used to stabilize these patients before parathyroidectomy. Some NSHPT patients are asymptomatic subsequently in their lives. In this paper, clinical characteristics of this relatively rare disorder are presented.

Osteoporosis and prostate cancer: a cross-sectional study of Danish men with prostate cancer before androgen deprivation therapy.

OBJECTIVE: The aim of this study was to analyse the prevalence of osteoporosis and risk factors of osteoporotic fractures before androgen deprivation in Danish men. Treatment and prognosis of prostate cancer necessitate management of long-term consequences of androgen deprivation therapy (ADT), including accelerated bone loss resulting in osteoporosis. Osteoporotic fractures are associated with excess morbidity and mortality. MATERIAL AND METHODS: Patients with prostate cancer awaiting initiation of ADT were consecutively included. Half of the patients had localized disease and were referred for curative intended radiation, and the remaining patients had disseminated disease. Blood samples were collected, a questionnaire was administered and a dual-energy X-ray absorptiometry (DXA) scan was performed before initiating ADT. The patients were included between January 2010 and March 2012. The study was approved by the local ethics committee. None of the patients had received prior androgen deprivation or osteoporosis treatment. RESULTS: In total, 105 individuals were included. The mean age of the participants was 70 years (range 53-91 years, SD 6.3). The median prostate-specific antigen level was 30.5 g/l (1-5714 g/l). The average Gleason score was 7.8 (range 5-10, SD 1.1). Fifty patients had localized prostate cancer and the other 55 patients had disseminated disease. The prevalence of osteoporosis was 10% and the prevalence of osteopenia was 58% before ADT. There was no significant difference between the two subgroups concerning osteoporosis. Smoking use was the only factor that was significantly associated with an increased prevalence of osteoporosis in the study population. CONCLUSION: Two-thirds of patients with prostate cancer awaiting ADT had osteoporosis or reduced bone mass. Further awareness regarding osteoporosis and bone health in prostate cancer is needed. It is suggested that patients with prostate cancer undergo a DXA scan before starting ADT.

Variation in the Kozak sequence of WNT16 results in an increased translation and is associated with osteoporosis related parameters.

The importance of WNT16 in the regulation of bone metabolism was recently confirmed by several genome-wide association studies and by a Wnt16 (Wnt16(-/-)) knockout mouse model. The aim of this study was thus to replicate and further elucidate the effect of common genetic variation in WNT16 on osteoporosis related parameters. Hereto, we performed a WNT16 candidate gene association study in a population of healthy Caucasian men from the Odense Androgen Study (OAS). Using HapMap, five tagSNPs and one multimarker test were selected for genotyping to cover most of the common genetic variation in and around WNT16 (MAF>5%). This study confirmed previously reported associations for rs3801387 and rs2707466 with bone mineral density (BMD) at several sites. Furthermore, we additionally demonstrated that rs2908007 is strongly associated with BMD at several sites in the young, elderly and complete OAS population. The observed effect of these three associated SNPs on the respective phenotypes is comparable and we can conclude that the presence of the minor allele results in an increase in BMD. Additionally, we performed re-sequencing of WNT16 on two cohorts selected from the young OAS cohort, based on their extreme BMD values. On this basis, rs55710688 was selected for an in vitro translation experiment since it is located in the Kozak sequence of WNT16a. We observed an increased translation efficiency and thus a higher amount of WNT16a for the Kozak sequence that was significantly more prevalent in the high BMD cohort. This observation is in line with the results of the Wnt16(-/-) mice. Finally, a WNT luciferase reporter assay was performed and showed no activation of the ß-catenin dependent pathway by Wnt16. We did detect a dose-dependent inhibitory effect of Wnt16 on WNT1 activation of this canonical WNT pathway. Increased translation of WNT16 can thus lead to an increased inhibitory action of WNT16 on canonical WNT signaling. This statement is in contrast with the known activating effect of canonical WNT signaling on bone formation and suggests a stimulatory effect on bone metabolism via noncanonical WNT signaling. More research is required to not only confirm this hypothesis, but also to further elucidate the role of non-canonical WNT pathways in bone metabolism and the general mechanisms of interplay between the different WNT signaling pathways.

KIT D816V mutation burden does not correlate to clinical manifestations of indolent systemic mastocytosis.

BACKGROUND: Clinical manifestations of indolent systemic mastocytosis (ISM) comprise mediator-related symptoms, anaphylaxis, and osteoporosis. A new sensitive method for KIT D816V mutation detection allows quantification of the level of mutation-positive cells. OBJECTIVE: To investigate whether the fraction of KIT D816V positive cells in peripheral blood (PB) or bone marrow (BM) aspirate in adult patients with ISM correlates with clinical manifestations of the disease. METHODS: We included 48 adult patients with ISM (28 females/20 males) from our center in whom the KIT D816V mutation level in both BM aspirate and PB was analyzed. For each patient, the severity of mediator-related symptoms (skin, gastrointestinal, musculoskeletal, and neuropsychiatric) and episodes of anaphylaxis were evaluated by interview and medical record files. Bone mineral density was determined by using dual-energy x-ray absorptiometry. RESULTS: Median fraction (range) of KIT D816V positive cells was 0.6 (0.01%-90%) in BM and 0.3 (0.003%-49%) in PB. Mutation level did not differ between patients with none/mild symptoms and patients with moderate/severe symptoms, patients with and without anaphylaxis, or patients with osteoporosis/osteopenia and normal bone mineral density. No significant differences in clinical profile were detected in patients with different levels of mutation except for an indication of longer disease duration and age in patients with highest mutation levels. CONCLUSION: To our knowledge, this is the first report on the clinical impact of the fraction of KIT D816V mutation positive cells in ISM, which in the present study does not seem to correlate with clinical manifestations of the disease.

Assessment of the global trigger tool to measure, monitor and evaluate patient safety in cancer patients: reliability concerns are raised.

BACKGROUND: Countries around the world are currently aiming to improve patient safety by means of the Institute for Healthcare Improvement global trigger tool (GTT), which is considered a valid tool for evaluating and measuring patient safety within organisations. So far, only few data on the measurement properties and utility of the GTT have been published. AIMS: To determine and evaluate the effect of interrater variation between review teams on the standard outcome measures of the GTT and to assess and quantify measurement error of the GTT. METHODS: Retrospective chart reviews were conducted on identical charts by two independent review teams in 2010 at a department of oncology in a university hospital. Standard GTT outcome measurements were obtained and compared between teams using statistical process control (SPC) charts. A Bland-Altman plot assessed measurement error and limits of agreement. RESULTS: Only 31% of adverse events (AE) were identified by both teams, and further differences in categorisation of identical events was found. Moderate interrater agreement (κ=0.45) between teams gave rise to different conclusions on the patient safety process when monitoring using SPC charts. The Bland-Altman plot suggests little systematic error but large random error. CONCLUSIONS: Review teams may identify different AE and reach different conclusions on the safety process when using the GTT on identical charts. Tracking true change in the safety level is difficult due to measurement error of the GTT. The results do not encourage further use of the GTT until additional evaluation studies on the measurement properties of the GTT have been conducted.

Genetic association study of WNT10B polymorphisms with BMD and adiposity parameters in Danish and Belgian males.

Because of the importance of the Wnt pathway in the development and maintenance of both adipose and bone tissue, we wanted to evaluate the involvement of WNT10B, a Wnt pathway activator, in adipogenesis and osteoblastogenesis in humans. Genetic association between WNT10B polymorphisms and adiposity parameters as well as bone mineral density (BMD) measurements was analysed in two independent populations. The first is a population of 1,228 Danish men (702 aged 20-29 years; 532 aged 60-74 years) from the Odense Androgen Study (OAS), which was designed as a cross-sectional, population-based study. The second population, called SIBLOS, includes 922 Belgian men (34 ± 5 years old) and contains siblings selected from over 500 families. Four tagSNPs (rs833840, rs833841, rs10875902 and rs4018511) that capture variation of ten SNPs (MAF > 5 %) in a 15.2 kb region spanning the WNT10B gene and its flanking regions were genotyped. Although no association with body mass index was found, we found all tagSNPs to be associated with BMD parameters (BMD whole body, total hip and femoral neck) and height in the OAS population. The association of rs10875902 was most prominent (nominal p = 0.012) and confirmed a previously shown negative effect on BMD. No significant associations were observed in the SIBLOS population. In the present study, no association between WNT10B polymorphisms and adiposity parameters was found. However, our results clearly illustrate a role for WNT10B variants in determining human BMD. The effect of WNT10B polymorphisms on height should be evaluated in additional populations.

Resistin polymorphisms show associations with obesity, but not with bone parameters in men: results from the Odense Androgen Study.

Resistin is an obesity-related adipokine which has also been implicated in bone metabolism. Therefore, we designed a study to investigate the possible role of resistin gene variation in both obesity and bone mineral density. We included 1,155 individuals from the Odense Androgen Study (663 young subjects and 492 older subjects), a population-based, prospective, observational study on the inter-relationship between endocrine status, body composition, muscle function, and bone metabolism in men, in an association study with resistin (RETN) polymorphisms. Three RETN variants (rs1862513, rs3745367 and rs3745369) were genotyped with TaqMan Pre-Designed Genotyping assays. Linear regression was performed to investigate the possible association of these variants with several obesity- and bone-related parameters. After genotyping 1,155 Danish men, 663 young subjects and 492 older subjects, we found that rs3745367 was associated with several obesity-related measures in both the young and elderly cohort. Rs3745369 was only associated with obesity-phenotypes in the elderly cohort. When studying the combined cohorts, we could confirm the associations of rs3745367 with several obesity-related parameters. We were unable to identify any association between RETN polymorphisms and bone-related measurements. Together, these results illustrate resistin's role in the development of obesity. Rs3745367 gives the most consistent results in the current study and these should be confirmed in other populations. Research into its possible functional effect might also be required. A role for RETN variants in determining bone mineral density seems unlikely from our results.

Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: cohort analysis using a national prescription database.

Ocular inflammatory reactions have been described in patients on bisphosphonate treatment. We estimated the incidence rate of ocular inflammation at 3 and 12 months in patients treated for osteoporosis using a register-based cohort linked to prescription data (hospitals and private practice) and hospital data. From January 1, 1997 to December 31, 2007, a total of 88,202 patients beginning osteoporosis therapy were identified. Of those patients, 82,404 (93%) began oral bisphosphonates and 5798 (7%) nonbisphosphonates. Within the first year of treatment, 4769 (5.4%) of patients on osteoporosis therapy filled one or more prescriptions for topical eye steroids (TES). TES treatment rates (per 1000 patient-years) in the first year of osteoporosis treatment were 44 (95% confidence interval [CI] 42 to 46) for alendronate, 40 (95% CI 38 to 43) for etidronate, 45 (95% CI 35 to 57) for risedronate, 32 (95% CI 27 to 37) for raloxifene, and 64 (95% CI 49 to 83) for strontium ranelate. After adjustment for age, Charlson index, and the number of comedications, pulmonary disease in men was associated with an increased use of TES (odds ratio [OR] = 1.48; 95% CI 1.17 to 1.86; p = 0.001). In women, malignant disease (OR = 1.27; 95% CI 1.02 to 1.60; p = 0.04) and pulmonary disease (OR = 1.32; 95% CI 1.07 to 1.62; p = 0.01) were significant predictors at 3 months and rheumatic diseases at 12 months (OR = 1.20; 95% CI 1.10 to 1.31; p < 0.001). There was no significant difference between the different drug classes (bisphosphonates versus nonbisphosphonates, alendronate versus nonalendronate-bisphosphonates) for risk of ocular inflammation, with age and the number of comedications being the only significant predictors. Hospital-treated uveitis (48 patients, or 0.05%) showed a similar trend. In conclusion, after initiation of treatment for osteoporosis, the risk of inflammatory eye reactions requiring TES is relatively low and not significantly different between bisphosphonate and nonbisphosphonate users. Patients with a rheumatic or pulmonary disease are at increased risk.