Drug utilization analysis of osteoporosis medications in seven European electronic health databases.

We studied the characteristics of patients prescribed osteoporosis medication and patterns of use in European databases. Patients were mostly female, older, had hypertension. There was suboptimal persistence particularly for oral medications. Our findings would be useful to healthcare providers to focus their resources on improving persistence to specific osteoporosis treatments. PURPOSE: To characterise the patients prescribed osteoporosis therapy and describe the drug utilization patterns. METHODS: We investigated the treatment patterns of bisphosphonates, denosumab, teriparatide, and selective estrogen receptor modulators (SERMs) in seven European databases in the United Kingdom, Italy, the Netherlands, Denmark, Spain, and Germany. In this cohort study, we included adults aged ≥ 18 years, with ≥ 1 year of registration in the respective databases, who were new users of the osteoporosis medications. The study period was between 01 January 2018 to 31 January 2022. RESULTS: Overall, patients were most commonly initiated on alendronate. Persistence decreased over time across all medications and databases, ranging from 52-73% at 6 months to 29-53% at 12 months for alendronate. For other oral bisphosphonates, the proportion of persistent users was 50-66% at 6 months and decreased to 30-44% at 12 months. For SERMs, the proportion of persistent users at 6 months was 40-73% and decreased to 25-59% at 12 months. For parenteral treatment groups, the proportions of persistence with denosumab were 50-85% (6 month), 30-63% (12 month) and with teriparatide 40-75% (6 month) decreasing to 21-54% (12 month). Switching occurred most frequently in the alendronate group (2.8-5.8%) and in the teriparatide group (7.1-14%). Switching typically occurred in the first 6 months and decreased over time. Patients in the alendronate group most often switched to other oral or intravenous bisphosphonates and denosumab. CONCLUSION: Our results show suboptimal persistence to medications that varied across different databases and treatment switching was relatively rare.

Trends of Dispensed Opioids in Catalonia, Spain, 2007-19: A Population-Based Cohort Study of Over 5 Million Individuals.

Objective: To characterize the trend of opioid use (number of users, dispensations and oral morphine milligram equivalents) in Catalonia (Spain). Design, setting, and participants: This population-based cohort study included all individuals aged 18 years or older, registered in the Information System for Research in Primary Care (SIDIAP), which covers >75% of the population in Catalonia, Spain, from 1 January 2007, to 31 December 2019. Main exposure and outcomes: The exposures were all commercialized opioids and their combinations (ATC-codes): codeine, tramadol, oxycodone, tapentadol, fentanyl, morphine, and other opioids (dihydrocodeine, hydromorphone, dextropropoxyphene, buprenorphine, pethidine, pentazocine). The main outcomes were the annual figures per 1,000 individuals of 1) opioid users, 2) dispensations, and 3) oral morphine milligram equivalents (MME). Results were stratified separately by opioid types, age (5-year age groups), sex (male or female), living area (rural or urban), and socioeconomic status (from least, U1, to most deprived, U5). The overall trends were quantified using the percentage change (PC) between 2007 and 2019. Results: Among 4,656,197 and 4,798,114 residents from 2007 to 2019, the number of opioid users, dispensations and morphine milligram equivalents per 1,000 individuals increased 12% (percentage change: 95% confidence interval (CI) 11.9-12.3%), 105% (95% confidence interval 83%-126%) and 339% (95% CI 289%-390%) respectively. Tramadol represented the majority of opioid use in 2019 (61, 59, and 54% of opioid users, dispensations, and total MME, respectively). Individuals aged 80 years or over reported the sharpest increase regarding opioid users (PC: 162%), dispensations (PC: 424%), and MME (PC: 830%). Strong opioids were increasingly prescribed for non-cancer pains over the years. Conclusion: Despite the modest increase of opioid users, opioid dispensations and MME increased substantially, particularly in the older population. In addition, strong opioids were incrementally indicated for non-cancer pains over the years. These findings suggest a transition of opioid prescriptions from intermittent to chronic and weak to strong and call for more rigorous opioid stewardship.

Association between covid-19 vaccination, SARS-CoV-2 infection, and risk of immune mediated neurological events: population based cohort and self-controlled case series analysis.

OBJECTIVE: To study the association between covid-19 vaccines, SARS-CoV-2 infection, and risk of immune mediated neurological events. DESIGN: Population based historical rate comparison study and self-controlled case series analysis. SETTING: Primary care records from the United Kingdom, and primary care records from Spain linked to hospital data. PARTICIPANTS: 8 330 497 people who received at least one dose of covid-19 vaccines ChAdOx1 nCoV-19, BNT162b2, mRNA-1273, or Ad.26.COV2.S between the rollout of the vaccination campaigns and end of data availability (UK: 9 May 2021; Spain: 30 June 2021). The study sample also comprised a cohort of 735 870 unvaccinated individuals with a first positive reverse transcription polymerase chain reaction test result for SARS-CoV-2 from 1 September 2020, and 14 330 080 participants from the general population. MAIN OUTCOME MEASURES: Outcomes were incidence of Bell's palsy, encephalomyelitis, Guillain-Barré syndrome, and transverse myelitis. Incidence rates were estimated in the 21 days after the first vaccine dose, 90 days after a positive test result for SARS-CoV-2, and between 2017 and 2019 for background rates in the general population cohort. Indirectly standardised incidence ratios were estimated. Adjusted incidence rate ratios were estimated from the self-controlled case series. RESULTS: The study included 4 376 535 people who received ChAdOx1 nCoV-19, 3 588 318 who received BNT162b2, 244 913 who received mRNA-1273, and 120 731 who received Ad26.CoV.2; 735 870 people with SARS-CoV-2 infection; and 14 330 080 people from the general population. Overall, post-vaccine rates were consistent with expected (background) rates for Bell's palsy, encephalomyelitis, and Guillain-Barré syndrome. Self-controlled case series was conducted only for Bell's palsy, given limited statistical power, but with no safety signal seen for those vaccinated. Rates were, however, higher than expected after SARS-CoV-2 infection. For example, in the data from the UK, the standardised incidence ratio for Bell's palsy was 1.33 (1.02 to 1.74), for encephalomyelitis was 6.89 (3.82 to 12.44), and for Guillain-Barré syndrome was 3.53 (1.83 to 6.77). Transverse myelitis was rare (<5 events in all vaccinated cohorts) and could not be analysed. CONCLUSIONS: No safety signal was observed between covid-19 vaccines and the immune mediated neurological events of Bell's palsy, encephalomyelitis, Guillain-Barré syndrome, and transverse myelitis. An increased risk of Bell's palsy, encephalomyelitis, and Guillain-Barré syndrome was, however, observed for people with SARS-CoV-2 infection.

Flecainide and risk of skin neoplasms: Results of a large nested case-control study in Spain and Denmark.

Background: A previous study in Denmark suggested an increased melanoma risk associated with the use of flecainide. Objective: To study the association between flecainide use and the risk of melanoma and non-melanoma skin cancer in Spain and Denmark. Methods: We conducted a multi-database case-control study in (database/study period) Spain (SIDIAP/2005-2017 and BIFAP/2007-2017) and Denmark (Danish registries/2001-2018). We included incident cases of melanoma or non-melanoma skin cancer (NMSC) aged ≥18 with ≥2 years of previous data (≥10 years for Denmark) before the skin cancer and matched them to controls (10:1 by age and sex). We excluded persons with immunosuppression or previous cancer. We defined ever-use as any prescription fill and high-use as a cumulative dose of at least 200 g (reference: never-use). We categorized a cumulative dose for a dose-response assessment. We used conditional logistic regression to compute ORs (95% CI) adjusted for photosensitizing, anti-neoplastic, disease-specific drugs and comorbidities. Results: The total numbers of melanoma/NMSC cases included were 7,809/64,230 in SIDIAP, 4,661/31,063 in BIFAP, and 27,978/152,821 in Denmark. In Denmark, high-use of flecainide was associated with increased adjusted ORs of skin cancer compared with never-use [melanoma: OR 1.97 (1.38-2.81); NMSC: OR 1.34 (1.15-1.56)]. In Spain, an association between high-use of flecainide and NMSC was also observed [BIFAP: OR 1.42 (1.04-1.93); SIDIAP: OR 1.19 (0.95-1.48)]. There was a non-significant dose-response pattern for melanoma in Denmark and no apparent dose-response pattern for NMSC in any of the three databases. We found similar results for ever-use of flecainide. Conclusion: Flecainide use was associated with an increased risk of melanoma (Denmark only) and NMSC (Denmark and Spain) but without substantial evidence of dose-response patterns. Further studies are needed to assess for possible unmeasured confounders.

Smoking and Alcohol Intake but Not Muscle Strength in Young Men Increase Fracture Risk at Middle Age: A Cohort Study Linked to the Swedish National Patient Registry.

We aimed to determine the relationship between handgrip strength, smoking, and alcohol consumption in young men and fracture risk at middle age. Thus, we carried out a cohort study including young men undergoing conscription examination in Sweden from September 1969 to May 1970 at a typical age of 18 years. Data on muscle strength, height, weight, and lifestyle factors were linked to the National Patient Register 1987-2010. Handgrip strength was considered the main exposure and smoking and alcohol consumption as secondary exposures. Outcomes were all fractures (except face, skull, digits), major osteoporotic fractures (thoracic/lumbar spine, proximal humerus, distal forearm or hip), and major traumatic fractures (shaft of humerus, forearm, femur, or lower leg) based on ICD-9 and -10 codes. We used Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) according to handgrip strength as a continuous variable (per 1 SD), after adjustment for weight, height, parental education, smoking, and alcohol consumption. A total of 40,112 men were included, contributing 892,572 person-years. Overall, 3974 men fractured in middle age with the incidence rate (95% CI) of 44.5 (43.2-45.9) per 1000 person-years. The corresponding rates were12.2 and 5.6 per 1000 person-years for major osteoporotic and traumatic fractures, respectively. Handgrip strength-adjusted HR (95% CI) was 1.01 (0.98-1.05), 0.94 (0.88-1.00), and 0.98 (0.88-1.08) per SD for all, major osteoporotic, and major traumatic fractures, respectively. Adjusted HR (95% CI) for smokers (>21 cigarettes/d) was 1.44 (1.21, 1.71) for all fractures, while the association between alcohol consumption and hazards of fracture was J-shaped. Therefore, young adult handgrip strength was not associated with fracture risk in middle-age men, although smoking and high alcohol consumption did confer an increased risk. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

In-hospital care, complications, and 4-month mortality following a hip or proximal femur fracture: the Spanish registry of osteoporotic femur fractures prospective cohort study.

We have characterised 997 hip fracture patients from a representative 45 Spanish hospitals, and followed them up prospectively for up to 4 months. Despite suboptimal surgical delays (average 59.1 hours), in-hospital mortality was lower than in Northern European cohorts. The secondary fracture prevention gap is unacceptably high at 85%. PURPOSE: To characterise inpatient care, complications, and 4-month mortality following a hip or proximal femur fracture in Spain. METHODS: Design: prospective cohort study. Consecutive sample of patients ≥ 50 years old admitted in a representative 45 hospitals for a hip or proximal femur fragility fracture, from June 2014 to June 2016 and followed up for 4 months post-fracture. Patient characteristics, site of fracture, in-patient care (including secondary fracture prevention) and complications, and 4-month mortality are described. RESULTS: A total of 997 subjects (765 women) of mean (standard deviation) age 83.6 (8.4) years were included. Previous history of fracture/s (36.9%) and falls (43%) were common, and 10-year FRAX-estimated major and hip fracture risks were 15.2% (9.0%) and 8.5% (7.6%) respectively. Inter-trochanteric (44.6%) and displaced intra-capsular (28.0%) were the most common fracture sites, and fixation with short intramedullary nail (38.6%) with spinal anaesthesia (75.5%) the most common procedures. Surgery and rehabilitation were initiated within a mean 59.1 (56.7) and 61.9 (55.1) hours respectively, and average length of stay was 11.5 (9.3) days. Antithrombotic and antibiotic prophylaxis were given to 99.8% and 98.2% respectively, whilst only 12.4% received secondary fracture prevention at discharge. Common complications included delirium (36.1 %) and kidney failure (14.1%), with in-hospital and 4-month mortality of 2.1% and 11% respectively. CONCLUSIONS: Despite suboptimal surgical delay, post-hip fracture mortality is low in Spanish hospitals. The secondary fracture prevention gap is unacceptably high at > 85%, in spite of virtually universal anti-thrombotic and antibiotic prophylaxis.

Risks and Benefits of Bisphosphonate Therapies.

Bisphosphonates are the mainstay of osteoporosis treatment but also play a fundamental role in treating other bone diseases such as Osteogenesis Imperfecta, Pagets' disease, and in the prevention of adverse skeletal effects in certain cancers such as prostate cancer or multiple myeloma. In the last decades, the refinement of bisphosphonates and an increase in the number of new bisphosphonates commercialized has altered the clinical management of these diseases. Despite differences between randomized controlled trials and observational studies, overall all bisphosphonates licensed have proven to reduce the risk of fracture through the inhibition of bone resorption. Other beneficial effects include pain reduction in bone metastasis and potentially a decrease in mortality. However, the chronic nature of most of these disorders implies long-term treatments, which can be associated with long-term adverse effects. Some of the adverse effects identified include an increased risk of atypical femur fractures, osteonecrosis of the jaw, gastrointestinal side effects, or atrial fibrillation. The harm/benefit thinking and the constant update regarding these medications are vital in the day-to-day decision-making in clinical practices. The aims of this review are to compile the basic characteristics of these drugs and outline the most important benefits and side effects and provide a clinical context as well as a research agenda to fill the gaps in our knowledge.

Socioeconomic status and its association with the risk of developing hip fractures: a region-wide ecological study.

PURPOSE: To determine the association between socioeconomic deprivation (SES) and hip fracture risk. METHODS: Retrospective cohort study using a population-based database (primary care records) of over 5 million people. Eligibility: all living subjects registered during the period 2009-2012 and resident in an urban area. MEASURES: a validated SES composite index (proportion of unemployed, temporary workers, manual workers, low educational attainment and low educational attainment among youngsters) estimated for each area based on census data. OUTCOME: incident hip fracture rates as coded in medical records using ICD-10 codes. STATISTICS: zero-inflated Poisson models fitted to study the association between SES quintiles and hip fracture risk, adjusted for age, sex, obesity, smoking and alcohol consumption. RESULTS: Compared to the most deprived, wealthy areas had a higher hip fracture incidence (age- and sex-adjusted incidence 38.57 (37.14-40.00) compared to 34.33 (32.90-35.76) per 10,000 person-years). Similarly, most deprived areas had a crude and age- and sex-adjusted lower risk of hip fracture, RR of 0.71 (0.65-0.78) and RR of 0.90 (0.85-0.95), respectively, compared to wealthiest areas. The association was attenuated and no longer significant after adjustment for obesity: RR 0.96 (0.90-1.01). Further adjustment for smoking and high alcohol consumption did not make a difference. CONCLUSION: Wealthiest areas have an almost 30% increased risk of hip fracture compared to the most deprived. Differences in age-sex composition and a higher prevalence of obesity in deprived areas could explain this higher risk.

Use of proton pump inhibitors and risk of fragility hip fracture in a Mediterranean region.

OBJECTIVE: To determine whether there is an increased risk of hip fracture associated with the use of proton pump inhibitors in a Mediterranean area after adjusting for other potential risk factors. METHODS: Retrospective multicenter case-control study carried out in 6 primary health care centers in Catalonia, Spain. Cases were patients aged 50years and over with a fragility hip fracture registered between January 2007 and December 2010, matched with 2 controls by sex and age. DATA COLLECTED: use of proton pump inhibitors (type, dosage) in the 5years previous to the hip fracture, socio-demographic data, body mass index, alcohol and tobacco consumption as well as health conditions and drugs associated with an increase risk of fragility hip fracture. RESULTS: 358 cases were matched with 698 controls. The mean age was 82years old in both groups. Women represented 77.1% in the case group and 76.9% in the control group. Crude association between proton pump inhibitors and hip fracture was 1.44 (95% CI, 1.09-1.89) and adjusted OR was 1.24 (95% CI, 0.93-1.65). No association was found with the continuous or discontinuous use of proton pump inhibitors, OR 1.17 (95% CI, 0.77-1.79), and OR of 1.16 (95% CI, 0.85-1.60) respectively. No association was found when restricting the analysis by sex, OR of 1.19 (95% CI, 0.27-5.14) or by age, younger or older than 80years, OR of 0.72 (95% CI, 0.24-2.15). CONCLUSION: The use of proton pump inhibitors was not associated with an increased risk of hip fracture after adjusting for other risk factors in a Mediterranean area. This result suggests the existence of protective environmental factors linked to this southern area of Europe that eventually could compensate for the potential harm produced by proton pump inhibitors.