Baseline bone turnover marker levels can predict change in bone mineral density during antiresorptive treatment in osteoporotic patients: the Copenhagen bone turnover marker study.

Anti-resorptive osteoporosis treatment might be more effective in patients with high bone turnover. In this registry study including clinical data, high pre-treatment bone turnover measured with biochemical markers was correlated with higher bone mineral density increases. Bone turnover markers may be useful tools to identify patients benefitting most from anti-resorptive treatment. INTRODUCTION: In randomized, controlled trials of bisphosphonates, high pre-treatment levels of bone turnover markers (BTM) were associated with a larger increase in bone mineral density (BMD). The purpose of this study was to examine this correlation in a real-world setting. METHODS: In this registry-based cohort study of osteoporosis patients (n = 158) receiving antiresorptive therapy, the association between pre-treatment levels of plasma C-telopeptide of type I Collagen (CTX) and/or N-terminal propeptide of type I procollagen (PINP) and change in bone mineral density (BMD) at lumbar spine, total hip, and femoral neck upon treatment was examined. Patients were grouped according to their pre-treatment BTM levels, defined as values above and below the geometric mean for premenopausal women. RESULTS: Pre-treatment CTX correlated with annual increase in total hip BMD, where patients with CTX above the geometric mean experienced a larger annual increase in BMD (p = 0.008) than patients with CTX below the geometric mean. The numerical pre-treatment level of CTX showed a similar correlation at all three skeletal sites (total hip (p = 0.03), femoral neck (p = 0.04), and lumbar spine (p = 0.0003)). A similar association was found for PINP where pre-treatment levels of PINP above the geometric mean correlated with a larger annual increase in BMD for total hip (p = 0.02) and lumbar spine (p = 0.006). CONCLUSION: Measurement of pre-treatment BTM levels predicts osteoporosis patients' response to antiresorptive treatment. Patients with high pre-treatment levels of CTX and/or PINP benefit more from antiresorptive treatment with larger increases in BMD than patients with lower pre-treatment levels.

Effect of metformin and insulin vs. placebo and insulin on whole body composition in overweight patients with type 2 diabetes: a randomized placebo-controlled trial.

Some studies indicate potential beneficial effects of metformin on body composition and bone. This trial compared metformin + insulin vs placebo + insulin. Metformin treatment had a small but positive effect on bone quality in the peripheral skeleton, reduced weight gain, and resulted in a more beneficial body composition compared with placebo in insulin-treated patients with type 2 diabetes. INTRODUCTION: Glucose-lowering medications affect body composition. We assessed the long-term effects of metformin compared with placebo on whole body bone and body composition measures in patients with type 2 diabetes mellitus. METHODS: This was a sub-study of the Copenhagen Insulin and Metformin Therapy trial, which was a double-blinded randomized placebo-controlled trial assessing 18-month treatment with metformin compared with placebo, in combination with different insulin regimens in patients with type 2 diabetes mellitus (T2DM). The sub-study evaluates the effects on bone mineral content (BMC), density (BMD), and body composition from whole body dual-energy X-ray absorptiometry (DXA) scans which were assessed at baseline and after 18 months. RESULTS: Metformin had a small, but positive, (p < 0.05) effect on subtotal, appendicular, and legs BMC and BMD compared with placebo. After adjustment for sex, age, vitamin D, smoking, BMI, T2DM duration, HbA1c, and insulin dose, the effects on appendicular BMC and BMD persisted (p < 0.05 for both). The changes in appendicular BMC and BMD corresponded approximately to a 0.7% and 0.5% increase in the metformin group and 0.4% and 0.4% decrease in the placebo group, respectively. These effects were mostly driven by an increase in BMC and BMD in the legs and a loss of BMC and BMD in the arms. During 18 months, all participants increased in weight, fat mass (FM), FM%, and lean mass (LM), but decreased in LM%. The metformin group increased less in weight (subtotal weight (weight-head) - 2.4 [- 3.5, - 1.4] kg, p value < 0.001) and FM (- 1.5 [- 2.3, - 0.8] kg, p value < 0.001) and decreased less in LM% (0.6 [0.2, 1.1] %, p value < 0.001) compared with the placebo group. CONCLUSION: Metformin treatment had a small positive effect on BMC and BMD in the peripheral skeleton and reduced weight gain compared with placebo in insulin-treated patients with T2DM.

The effect of metformin versus placebo in combination with insulin analogues on bone mineral density and trabecular bone score in patients with type 2 diabetes mellitus: a randomized placebo-controlled trial.

Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS) in patients with type 2 diabetes. Metformin had no significant effect on BMD in the spine and hip or TBS compared with a placebo. INTRODUCTION: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of fractures despite a high bone mass. Some antihyperglycemic medications have been found to affect bone metabolism. We assessed the long-term effects of metformin compared with placebo on bone mineral density (BMD) and trabecular bone score (TBS). METHODS: This was a sub-study of a multicenter, randomized, 18-month placebo-controlled, double-blinded trial with metformin vs. placebo in combination with different insulin regimens (the Copenhagen Insulin and Metformin Therapy trial) in patients with T2DM. BMD in the spine and hip and TBS in the spine were assessed by dual-energy X-ray absorptiometry at baseline and after 18 months follow-up. RESULTS: Four hundred seven patients were included in this sub-study. There were no between-group differences in BMD or TBS. From baseline to 18 months, TBS decreased significantly in both groups (metformin group, - 0.041 [- 0.055, - 0.027]; placebo group - 0.046 [- 0.058, - 0.034]; both p < 0.001). BMD in the spine and total hip did not change significantly from baseline to 18 months. After adjustments for gender, age, vitamin D, smoking, BMI, duration of T2DM, HbA1c, and insulin dose, the TBS between-group differences increased but remained non-significant. HbA1c was negatively associated with TBS (p = 0.009) as was longer duration of diabetes, with the femoral neck BMD (p = 0.003). Body mass index had a positive effect on the hip and femoral neck BMD (p < 0.001, p = 0.045, respectively). CONCLUSIONS: Eighteen months of treatment with metformin had no significant effect on BMD in the spine and hip or TBS in patients with T2DM compared with a placebo. TBS decreased significantly in both groups. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00657943).

Predicting mortality and incident immobility in older Belgian men by characteristics related to sarcopenia and frailty.

There is an increasing awareness of sarcopenia in older people. We applied machine learning principles to predict mortality and incident immobility in older Belgian men through sarcopenia and frailty characteristics. Mortality could be predicted with good accuracy. Serum 25-hydroxyvitamin D and bone mineral density scores were the most important predictors. INTRODUCTION: Machine learning principles were used to predict 5-year mortality and 3-year incident severe immobility in a population of older men by frailty and sarcopenia characteristics. METHODS: Using prospective data from 1997 on 264 older Belgian men (n = 152 predictors), 29 statistical models were developed and tuned on 75% of data points then validated on the remaining 25%. The model with the highest test area under the curve (AUC) was chosen as the best. From these, ranked predictor importance was extracted. RESULTS: Five-year mortality could be predicted with good accuracy (test AUC of .85 [.73; .97], sensitivity 78%, specificity 89% at a probability cut-off of 22.3%) using a Bayesian generalized linear model. Three-year incident severe immobility could be predicted with fair accuracy (test AUC .74 [.57; .91], sensitivity 67%, specificity 78% at a probability cut-off of 14.2%) using a multivariate adaptive regression splines model. Serum 25-hydroxyvitamin D levels and hip bone mineral density scores were the most important predictors of mortality, while biochemical androgen markers and Short-Form 36 Physical Domain questions were the most important predictors of immobility. Sarcopenia assessed by lean mass estimates was relevant to mortality prediction but not immobility prediction. CONCLUSIONS: Using advanced statistical models and a machine learning approach 5-year mortality can be predicted with good accuracy using a Bayesian generalized linear model and 3-year incident severe immobility with fair accuracy using a multivariate adaptive regression splines model.

A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone.

Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/ß-catenin pathway were more frequently mutated and negative regulators of Wnt/ß-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01). Conclusions: Wnt/ß-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

Surgically treated osteonecrosis and osteomyelitis of the jaw and oral cavity in patients highly adherent to alendronate treatment: a nationwide user-only cohort study including over 60,000 alendronate users.

Osteonecrosis of the jaw (ONJ) is rare (2.53/10,000 person-years) among alendronate users, but long-term and compliant use are associated with an increased risk of surgically treated ONJ. Risk of surgically treated ONJ is higher in patients with rheumatoid diseases and use of proton pump inhibitors. INTRODUCTION: ONJ is a rare event in users of oral bisphosphonates. Our aims were to evaluate if the risk of surgically treated ONJ increases with longer or more compliant treatment with alendronate for osteoporosis and to identify risk factors for surgically treated ONJ. METHODS: Open nationwide register-based cohort study containing one nested case-control study. Patients were treatment-naïve incident users of alendronate 1996-2007 in Denmark, both genders, aged 50-94 at the time of beginning treatment (N = 61,990). Participants were followed to 31 December 2013. RESULTS: Over a mean of 6.8 years, 107 patients received surgery for ONJ or related conditions corresponding to an incidence rate of 2.53 (95% confidence interval (CI) 2.08 to 3.05) per 10,000 patient years. Recent use was associated with an adjusted odds ratio (OR) 4.13 (95% CI 1.94 to 8.79) compared to past use. Similarly, adherent users (medication possession ratio (MPR) >50%) were at two to threefold increased risk of ONJ compared to low adherence (MPR <50%), and long-term (>5 years) use was related with higher risk (adjusted OR 2.31 (95% CI (1.14 to 4.67)) than shorter-term use. History of rheumatoid disorders and use of proton pump inhibitors were independently associated with surgically treated ONJ. CONCLUSIONS: Our data suggest that recent, long-term, and compliant uses of alendronate are associated with an increased risk of surgically treated ONJ. Nevertheless, the rates remain low, even in long-term adherent users. ONJ risk appears higher in patients with conditions likely to indirectly affect the oral mucosa.

A Single-Institution Experience in Percutaneous Image-Guided Biopsy of Malignant Pleural Mesothelioma.

PURPOSE: Mesothelioma has been considered a difficult pathologic diagnosis to achieve via image-guided core needle biopsy. The purpose of this study was to assess the diagnostic sensitivity of percutaneous image-guided biopsy for diagnosis of pleural mesothelioma. MATERIALS AND METHODS: Retrospective review was performed to identify patients with a confirmed diagnosis of pleural mesothelioma and who underwent image-guided needle biopsy between January 1, 2002, and January 1, 2016. Thirty-two patients with pleural mesothelioma were identified and included for analysis in 33 image-guided biopsy procedures. Patient, procedural, and pathologic characteristics were recorded. Complications were characterized via standardized nomenclature [Common Terminology for Clinically Adverse Events (CTCAE)]. RESULTS: Percutaneous image-guided biopsy was associated with an overall sensitivity of 81%. No CTCAE clinically significant complications were observed. No image-guided procedures were complicated by pneumothorax or necessitated chest tube placement. No patients had tumor seeding of the biopsy tract. CONCLUSION: Percutaneous image-guided biopsy can achieve high sensitivity for pathologic diagnosis of pleural mesothelioma with a low procedural complication rate, potentially obviating need for surgical biopsy.

Clinical fracture risk evaluated by hierarchical agglomerative clustering.

Clustering analysis can identify subgroups of patients based on similarities of traits. From data on 10,775 subjects, we document nine patient clusters of different fracture risks. Differences emerged after age 60 and treatment compliance differed by hip and lumbar spine bone mineral density profiles. INTRODUCTION: The purposes of this study were to establish and quantify patient clusters of high, average and low fracture risk using an unsupervised machine learning algorithm. METHODS: Regional and national Danish patient data on dual-energy X-ray absorptiometry (DXA) scans, medication reimbursement, primary healthcare sector use and comorbidity of female subjects were combined. Standardized variable means, Euclidean distances and Ward's D2 method of hierarchical agglomerative clustering (HAC), were used to form the clustering object. K number of clusters was selected with the lowest cluster containing less than 250 subjects. Clusters were identified as high, average or low fracture risk based on bone mineral density (BMD) characteristics. Cluster-based descriptive statistics and relative Z-scores for variable means were computed. RESULTS: Ten thousand seven hundred seventy-five women were included in this study. Nine (k = 9) clusters were identified. Four clusters (n = 2886) were identified based on low to very low BMD with differences in comorbidity, anthropometrics and future bisphosphonate compliance. Two clusters of younger subjects (n = 1058, mean ages 30 and 51 years) were identified as low fracture risk with high to very high BMD. A mean age of 60 years was the earliest that allowed for separation of high-risk clusters. DXA scan results could identify high-risk subjects with different antiresorptive treatment compliance levels based on similarities and differences in lumbar spine and hip region BMD. CONCLUSIONS: Unsupervised HAC presents a novel technology to improve patient characteristics in bone disease beyond traditional T-score-based diagnosis. Technological and validation limitations need to be overcome to improve its use in internal medicine. Current DXA scan indication guidelines could be further improved by clustering algorithms.

Long-term leukopenia in a lung transplanted patient with cystic fibrosis treated with zoledronic acid: a case report.

Cystic fibrosis (CF) is a serious autosomal recessive genetic disorder associated with chronic lung disease, malabsorption, malnutrition, pancreatic insufficiency and premature respiratory failure. Recent advances in medical science and technology have increased the lifespan of patients with CF, albeit with long-term consequences of the disease, such as osteoporosis, becoming of increasing significance. The medical treatment of osteoporosis in patients with CF or after organ transplantation is still being explored, and no clear guidelines regarding the best choice of bisphosphonate exist. We report a case of a young woman with CF, lung transplantation and low bone mass developing long-term leukopenia after treatment with zoledronic acid. The leukopenia, with a strong affection of the neutrocytes, lasted for 4 months and the condition only went into remission after granulocyte-colony stimulating factor (G-CSF) treatment. It is important to be aware of symptomatic leukopenia in immunosuppressive patients after treatment with zoledronic acid.

Treatment of osteoporosis after alendronate or risedronate.

Alendronate (ALN) and risedronate (RIS) are ideal as first-choice therapy options in the treatment of postmenopausal osteoporosis. What to do for patients who do not respond adequately to bisphosphonates has not been conclusively determined, but transitioning to other therapies should be considered. The aim of this article is to describe potential alternatives for patients switching from ALN or RIS to other therapies for osteoporosis. A systematic search of PubMed was conducted to find papers that evaluate the effects of switching therapies on fractures, bone mineral density (BMD), or bone turnover markers. Results from 11 studies that prospectively assessed treatment after ALN or RIS in women with postmenopausal osteoporosis were reviewed. All studies are of short duration (all 24 months or less) and assess the topic of transitioning therapy from ALN or RIS. None of the studies had the statistical power to assess fracture-reduction efficacy. Transitioning from ALN to zoledronic acid maintains therapeutic effects for 12 months. Switching to strontium ranelate, denosumab, or teriparatide causes further increases in BMD. Specifically, transitioning to teriparatide could be used for a limited time for select patients but needs to be followed up with anti-resorptive treatment to prevent a loss of the bone gained. There are only few studies-of short duration-that assess the topic of transitioning therapy from ALN or RIS, although this is a very frequent occurrence in clinical practice. This is especially true if the patient has not reached his/her therapy goal. Further long-term studies are needed.

Optimal age of commencing and discontinuing thiazide therapy to protect against fractures.

UNLABELLED: A study of national Danish patient data with regard to thiazide diuretics vs. non-treatment. We find that after age 83 years, thiazides increase the 10-year risk of major fractures. We also find that thiazides can be stopped after 63 years old to possibly protect against fracture occurrence. INTRODUCTION: The purpose of this study was to retrospectively examine the optimal age for commencing and discontinuing thiazide therapy to protect from osteoporotic fractures. METHODS: A population-based, retrospective matched cohort study was done using national data of 2.93 million Danish subjects. Ten-year crude and adjusted age-grouped hazard ratios (HRs) of fracture occurrence were stratified by age of commencing thiazides compared to non-exposure. Separate analyses were done on Anatomical Therapeutic Chemical Classification System (ATC) codes C03AA and C03AA + C03AB compiled. Ten-year crude HRs of fracture occurrence for discontinuing vs. continuing thiazides were estimated and stratified by age for the two groups. RESULTS: For C03AB alone (97.1 % of thiazide prescriptions), adjusted 10-year HRs of fracture occurrence were significantly increased for thiazide commencement after age 83 years and comparable to non-exposure for commencement between ages 50 and 83 years. For C03AA + C03AB, 10-year adjusted HRs of fracture occurrence were significantly increased from ages 73 years and upwards. Crude 10-year HRs of fracture occurrence were significantly decreased for discontinuing vs. continuing thiazides at or after age 63 years for C03AB and age 77 years for C03AA + C03AB. CONCLUSIONS: No significantly protective effect of thiazides was found on fracture occurrence compared to non-users, but evidence that thiazides increase the 10-year adjusted HR risk of fractures if prescribed after the age of 83 years for C03AB and 73 years for C03AA + C03AB. Discontinuing thiazides at or after age 63 years for C03AB or 77 years for C03AA & C03AB significantly decreases the 10-year risk of fractures compared to continuing thiazides. Further prospective studies are warranted.

Continuous and long-term treatment is more important than dosage for the protective effect of thiazide use on bone metabolism and fracture risk.

BACKGROUND: Data from observational studies have suggested that thiazide diuretics protect against fractures. Few studies have investigated time frames from initiation of treatment to fracture occurrence. OBJECTIVE: To evaluate the time to spinal, hip, femur, wrist and upper extremity fracture occurrence before and after thiazide exposure. METHODS: A matched retrospective cohort study of patient information from national Danish patient databases was conducted. Patients with reimbursed prescriptions for noncompounded thiazide diuretics with potassium supplementation (Anatomical Therapeutic Chemical classification system code C03AB) between 1996 and 2011 were matched with nonexposed control subjects by date of birth and gender. Weekly odds ratios (ORs) of fracture occurrence and total incidence rates (IRs) and incidence rate ratios (IRRs) of fracture risk were calculated for the periods before treatment initiation, weeks 1-42 and weeks 43-780. RESULTS: A total of 1,602,141 'thiazide exposure periods' (46,8271 individuals) and 1,530,233 'nonexposure periods' (655,399 individuals) were included in the analysis. Thiazide use was associated with factors of increased de novo fracture risk. Weekly adjusted fracture risk between exposure and nonexposure was increased prior to commencing thiazide therapy, further increasing from weeks 1-42 weeks and then decreasing gradually from weeks 43-780. There was a decreasing trend in total age-adjusted risk during these periods: IRR [95% confidence interval 1.44 [1.42; 1.47], 1.27 [1.24; 1.29] and 1.14 [1.11; 1.18], respectively. Prescription patterns showed several treatment breaks amongst thiazide users. CONCLUSIONS: It appears that thiazides reduce the background risk of fracture that is increased prior to commencing therapy. Long duration and continuity of thiazide exposure seems to be important to obtain this protective effect on fracture risk, but we have found in this study that this approach is not always used in clinical practice.

Hyponatremia and osteoporosis: insights from the Danish National Patient Registry.

UNLABELLED: The association between hyponatremia and osteoporosis was evaluated in humans. A significant association was found between low sodium levels, lower bone mineralization in the hip, and with several common conditions. Hyponatremia could be used as a marker of osteoporosis and systemic disease. INTRODUCTION: The objective of this study was to evaluate the association between hyponatremia and osteoporosis in humans through a cross-sectional study. METHODS: Patient information was gathered from regional and national Danish patient databases, both in- and outpatient settings, from 2004 to 2011. Patients with dual-energy x-ray absorptiometry (DXA) scans performed within this time were included if accompanied [Na+] was measured within 14 days prior or past the scan date. A total of 1575 patients were included. RESULTS: A total of 104 patients were hyponatremic (6.6 %). Total hip and lumbar spine bone mineral content (BMC) and densities (BMD) and T-scores were all significantly lower with hyponatremia. The odds ratio (OR) of osteoporosis significantly increased among hyponatremic patients at both total hip (unadjusted OR = 2.17, 95% CI = [1.40-3.34], p < .05) and lumbar spine (unadjusted OR = 1.83, 95% CI = [1.20-2.80], p < .05) regions. Dose-response found between increasing [Na+] and increasing total hip BMC (slope .174, adjusted p < .05), BMD (slope .004, adjusted p < .05), and T-score (slope .034, adjusted p < .05). Systemic disease was more prevalent in hyponatremia. CONCLUSION: The presence of hyponatremia increases the risk of concurrent osteoporosis at both the total hip and lumbar spine in humans. Hyponatremia could be used a screening tool and marker of secondary osteoporosis.

Subsequent fracture rates in a nationwide population-based cohort study with a 10-year perspective.

SUMMARY: Fractures after the age of 50 are frequently observed in Denmark, and many of these may be osteoporotic. This study examined the incidence of all and subsequent fractures in a 10-year period from 2001 to 2011. The incidence of subsequent fractures was high, especially following hip fracture. INTRODUCTION: The purpose of this study is to examine patterns of subsequent fractures and mortality rates over a 10-year period in patients already suffering from fracture. METHODS: The study was designed as a nationwide, register-based follow-up study. Patients were included if diagnosed with an index fracture (ICD-10 codes: S22.x, S32.x, S42.x, S52.x, S62.x, S72.x, S82.x, S92.x, T02.x, T08.x, T10.x and T12.x) between January 1st, 2001 and December 31st, 2001 and if older than 50 years at time of fracture. The patients were investigated for future subsequent fractures from January 1st, 2002 to December 31st, 2011. RESULTS: In this study, we demonstrated that patients with fractures (especially hip fractures) have a high risk of subsequent fractures, especially hip fracture. Other fractures, which are not commonly considered as osteoporotic fractures, such as lower leg, were frequently observed in the 10 years following index fracture. The cumulative incidence proportion (CIP) of subsequent fractures during the 10-year follow-up period was high for all recurrent fractures (9-46 %). Subsequent hip fracture, regardless of index fracture, had the highest CIP across the study period, ranging from 9 to 40 %. Appendicular fractures were often followed by a recurrent fracture, or subsequent fractures at a more proximal location in the same limb, i.e. forearm fractures were followed by humerus fractures. These results have not been previously demonstrated to this extent, and according to our knowledge, no previous studies have estimated cumulative 10-year subsequent fracture incidences for any non-hip fractures. CONCLUSION: Patients suffering a fracture (and especially a hip fracture) have a high incidence of subsequent fracture. Fractures after the age of 50 may be considered an early warning of increased risk for future fractures in many patients.

External auditory canal and middle ear cholesteatoma and osteonecrosis in bisphosphonate-treated osteoporosis patients: a Danish national register-based cohort study and literature review.

UNLABELLED: Long-term treatment with bisphosphonates against osteoporosis may cause atypical femur fractures and osteonecrosis of the jaw. Eight cases of bisphosphonate-associated osteonecrosis of the external auditory canal area are published. Based on Danish national registers, we report a time- and dose-dependent increased risk of cholesteatoma in osteoporosis patients treated with bisphosphonates. INTRODUCTION: In the recent years, there has been a focus on possible rare side effects of bisphosphonates (BPs). Eight cases of BP-associated osteonecrosis of the external auditory canal have been reported in the world literature. Our aim was to describe the incidence of external auditory canal and middle ear diseases in Danish patients exposed to BPs in the treatment of osteoporosis. METHODS: This register-based nationwide cohort study was conducted on the Danish population of approximately 5.6 million individuals. Patients who were prescribed BP for treatment of osteoporosis from 2003 to 2010 (n = 131,794) were included in the study and compared with the age- and gender-matched controls, unexposed to BP. RESULTS: The overall incidence of cholesteatoma in the ear was low. Only 350 events were seen in 527,176 cases and controls over 2,826,120.73 observation years. Totally, 119 events of cholesteatoma in the ear were recorded after initiation of BP therapy, 34 in the external auditory canal and 85 in the middle ear. Cholesteatoma in the external auditory canal was more frequent in the exposed than in the unexposed group (p < 0.0001). We found a significant dose-event relationship between incidence of cholesteatoma and dose of alendronate (p < 0.0001) and etidronate (p < 0.0001). Furthermore, we found an association between duration of treatment with alendronate and etidronate and risk of cholesteatoma in the external auditory ear canal (log rank, p = 0.002). No cases of bone destruction were observed during the 7-year observation period in either group. CONCLUSION: The use of oral BP is associated with an increased risk of cholesteatoma of the external auditory canal. The risk is small and associated with duration and dosage of BP.

A functional amino acid substitution in the glucose-dependent insulinotropic polypeptide receptor (GIPR) gene is associated with lower bone mineral density and increased fracture risk.

CONTEXT: Food ingestion decreases bone resorption, and glucose-dependent insulinotropic polypeptide (GIP) may mediate this effect. Mice overexpressing GIP have increased osteoblast activity and are rescued from age-related bone loss, whereas GIPR knockout mice have decreased cortical bone mass and compromised bone quality. Carriers of the functional variant GIPR Glu354Gln (rs1800437) have higher plasma glucose 2 hours after glucose ingestion, suggesting that the variant encoding GIPR 354Gln decreases the effect of GIP. OBJECTIVE: The objective of the study was to investigate the effect of GIPR Glu354Gln on bone mineral density (BMD) and fracture risk. DESIGN: This was a prospective, comprehensive, cohort study (number NCT00252408). PARTICIPANTS: A total of 1686 perimenopausal women were included. MAIN OUTCOME MEASURES: Dual-energy X-ray absorptiometry was performed at baseline and after 10 years. Incident fractures were recorded during the follow-up and were obtained from the Danish National Patient Registry, giving a total follow-up time of a minimum 16 years. RESULTS: After 10 years, women with the minor frequency C allele of rs1800437 (354Gln) had significantly lower BMD at the femoral neck compared with carriers of the major G-allele (CC: 0.755 ± 0.015 g/cm(2) vs CG: 747 ± 0.005 g/cm(2); GG: 0.766 ± 0.004 g/cm(2), P < .001). Correspondingly, total hip BMD was significantly lower among C allele carriers (CC: 0.881 ± 0.016 g/cm(2); CG: 0.884 ± 0.005 g/cm(2); and GG: 0.906 ± 0.004 g/cm(2), P < .001). Finally, women homozygous for the variant C allele had an increased risk (hazard ratio 1.6, confidence interval 1.0-2.6, P < .05) of nonvertebral fractures. CONCLUSION: This study demonstrates an association between a functional GIPR polymorphism Glu354Gln (rs1800437) and BMD and fracture risk. These findings further establish GIP to be involved in the regulation of bone density.

Characteristics of patients who suffer major osteoporotic fractures despite adhering to alendronate treatment: a National Prescription registry study.

UNLABELLED: Antiresorptive treatment reduces the risk of fractures, but most patients remain at elevated risk. We used health registers to identify predictors of new major osteoporotic fractures in patients adhering to alendronate. Risk factors showed a different pattern than in the general population and included dementia, ulcer disease, and Parkinson's disease. INTRODUCTION: Antiresorptives reduce the excess risk of fractures in patients with osteoporosis, but most patients remain at elevated risk. In some countries, patients must sustain fractures while on bisphosphonate (BP) treatment to qualify for more expensive treatment. It is unclear if patients who fracture on BP can be viewed as a distinct subgroup. METHODS: The National Prescription registry was used to identify 38,088 new alendronate users. The outcome was major osteoporotic fractures 6+ months after filling the first prescription in patients with a medication possession ratio > 80 %. RESULTS: One thousand and seventy-two (5.5 %) patients sustained major osteoporotic fractures. The risk increased with age and was lower in men. The most important risk factor was the number of comedications (hazard ratio (HR) 1.04, 95 % CI 1.03-1.06, for each drug). Dementia (HR 1.81, 95 % CI 1.18-2.78), prior fracture (one: HR 1.17, 95 % CI 1.02-1.34; multiple: HR 1.34, 95 % CI 1.08-1.67), and ulcer disease (HR 1.45, 95 % CI 1.04-2.03) also increased the risk. Diabetes did not influence fracture risk, nor did rheumatic disorders. The risk was lower in glucocorticoid users (HR 0.78, 95 % CI 0.65-0.93). CONCLUSION: Risk factors while adhering to BP show a somewhat different pattern than that of the general population and FRAX. Ulcer disease and dementia may impair the ability to use the medications correctly. Though this is an observational study and associations may not be causal, it may be prudent to include dementia, ulcer disease, and Parkinson's disease to capture the risk of fractures on treatment. Lower risk in patients treated with glucocorticoids and in men probably reflects a lower treatment threshold related to guidelines.

Time trends for alendronate prescription practices in women with chronic obstructive pulmonary disease and women exposed to systemic glucocorticoids.

UNLABELLED: Chronic obstructive pulmonary disease (COPD) and systemic glucocorticoid exposure are well-known risk factors of osteoporosis. We evaluated alendronate prescription practices related to COPD and exposure to systemic corticosteroids from 1996 to 2008 and showed an increasing targeting of alendronate treatment in patients with COPD and patients with systemic corticosteroid exposure. INTRODUCTION: COPD and systemic glucocorticoid exposure are well-known risk factors of osteoporosis and fragility fracture, but osteoporosis is often underdiagnosed and undertreated in these patients. This study aims to evaluate alendronate prescription practices related to COPD and/or to exposure to systemic glucocorticoids among Danish women. METHODS: A total of 388,314 female subjects >50 years old, 64,719 of whom initiated treatment with alendronate, and 323,595 age- and gender-matched controls were retrospectively identified between 1996 and 2008 from national health registers. Multivariate logistic regression was used for examining prescription practices, specifically if these risk factors (COPD or glucocorticoid exposure) increased or decreased the likelihood of beginning alendronate therapy. RESULTS: A diagnosis of COPD was associated with an increased likelihood of using alendronate (odds ratio (OR) 1.4, 95 % confidence interval (CI) 1.4-1.5, p < 0.001). Further, a diagnosis of COPD was associated with an increasing tendency of initiating alendronate treatment in the study period (OR 1.3 (95 % CI 1.1-1.5, years 1996-1999) to 1.5 (95 % CI 1.4-1.6, years 2006-2008), p < 0.01). Exposure to systemic glucocorticoids was associated with a significantly increasing (OR 3.6, 95 % CI 3.3-3.9 to OR 5.5, 95 % CI 5.3-5.8) probability of receiving alendronate treatment in the same observation period. CONCLUSION: This nationwide register-based study on alendronate prescription practices in Denmark shows an increasing targeting of alendronate treatment in patients with COPD and an even stronger trend for patients with systemic glucocorticoid exposure, perhaps indicating increased awareness of well-known and associated conditions.

Analysis of the association between bisphosphonate treatment survival in Danish hip fracture patients-a nationwide register-based open cohort study.

UNLABELLED: Bisphosphonate (BP) users have decreased mortality, but this could be due to channeling bias. National healthcare data on hip fracture showed lower mortality in patients who were treated prior to fracture or began treatment after fracture. Reduced mortality after only one prescription filled points to the importance of patient factors. INTRODUCTION: Use of bisphosphonates has been found to be associated with decreased mortality even when adjusted for sex, frailty, bone mineral density and comorbidity, but BP may chiefly be initiated in patients with osteoporosis whose life expectancy is judged to be good. Our aim was to investigate the association between BP initiated before or after a hip fracture with mortality, and any modifying effects of comorbid conditions and recurrent fracture. METHODS: This register-based cohort study used prescription and mortality information for Danish patients born ≤1945 experiencing a hip fracture between 1/Jan/1999 and 31/Dec/ 2002 (N = 42,076). Patients who began BP after hip fracture were compared with hip fracture patients who remained alive at the time when their matched index case began treatment. RESULTS: Patients who used BP prior to their hip fracture (4.6 %) had significantly lower 3-month mortality (adjusted odds ratio, OR, 0.68; 0.59-0.77). Patients who began BP after the fracture (2.6 %) had significantly decreased mortality, both for patients who filled only one prescription (adjusted hazard ratio, HR 0.84; 0.73-0.95) and for patients who filled multiple prescriptions HR 0.73 (0.61-0.88). There was a significant interaction by gender with no significant risk reduction in men. CONCLUSION: This national dataset shows significantly and substantially improved survival in women who receive BP before or after their hip fracture. However, the observation of a reduction in mortality in patients who filled only one prescription for a BP suggests that patient factors may account for a considerable part of the survival advantage observed with BPs.