Physical Activity, Fitness, and Long-Term Risk of Amyotrophic Lateral Sclerosis: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVES: Observational studies have demonstrated an increased amyotrophic lateral sclerosis (ALS) risk among professional athletes in various sports. For moderately increased levels of physical activity and fitness, the results are diverging. Through a cohort study, we aimed to assess the relationship between indicators of physical activity and fitness (self-reported physical activity and resting heart rate) and long-term ALS risk. METHODS: From a large Norwegian cardiovascular health survey (1985-1999), we collected information on self-reported physical activity in leisure time, resting heart rate, and other cardiovascular risk factors. Patients with ALS were identified through health registries covering the whole population. We fitted Cox proportional hazard models to assess the risk of ALS according to levels of self-reported physical activity in 3 categories (1: sedentary; 2: minimum 4 hours per week of walking or cycling; 3: minimum 4 hours per week of recreational sports or hard training), and resting heart rate modeled both on the continuous scale and as quartiles of distribution. RESULTS: Out of 373,696 study participants (mean 40.9 [SD 1.1] years at inclusion), 504 (41.2% women) developed ALS during a mean follow-up time of 27.2 (SD 5.0) years. Compared with participants with the lowest level of physical activity, the hazard ratio was 0.71 (95% CI 0.53-0.95) for those with the highest level. There were no clear associations between resting heart rate and ALS in the total sample. In men, the hazard ratio of ALS was 0.71 (95% CI 0.53-0.95) for those reporting moderate levels of physical activity and 0.59 (95% CI 0.42-0.84) for those reporting high levels, compared with those reporting low levels. Men with resting heart rate in the lowest quartile had 32% reduced risk of ALS (hazard ratio 0.68, 95% CI 0.49-0.94) compared with those in the second highest quartile. In women, no association was detected between neither self-reported levels of physical activity nor resting heart rate and ALS risk. DISCUSSION: Indicators of high levels of physical activity and fitness are associated with a reduced risk of ALS more than 30 years later in men, but not in women.

Educational gradient in hip fracture incidence in Norway. The Norwegian Epidemiologic Osteoporosis Studies (NOREPOS).

Examining fracture dynamics by socioeconomic status may inform healthcare and prevention. We found a higher risk of hip fracture in men and women with lower educational level in Norway. However, by age 90 + years, the cumulative incidence was higher in those with higher education, due to their higher life expectancy. PURPOSE: Socioeconomic gradients are seen for several health outcomes in high-income countries. We aimed to examine possible educational gradients in risk of hip fracture in Norway and to describe the cumulative incidence of hip fracture by educational level. METHODS: In a population-wide cohort of Norwegians aged ≥ 50 years, information on attained education from Statistics Norway was linked to hospital-treated hip fractures and deaths during 2002-2019. We estimated relative fracture risk by educational level (primary, secondary or tertiary) in Cox proportional hazards regression. We also examined the cumulative incidence over attained age by gender and educational level in competing risk regression. RESULTS: The population included N = 1,389,858 individuals with 135,938 incident hip fractures. Compared with men who had attained tertiary education, hazard ratios (95% confidence intervals) for hip fracture were 1.44 (1.40, 1.49) in men with primary education only and 1.26 (1.22, 1.29) in men with secondary education. In women, the corresponding estimates were 1.28 (1.25, 1.31) and 1.16 (1.13, 1.19). In the age range 50 to 90 years, the highest cumulative incidence of hip fracture was seen in those with primary education. The gradient gradually diminished with advancing age and was reversed in the oldest (> 90 years) in both genders. CONCLUSIONS: There was a clear educational gradient in hip fracture incidence in both men and women in Norway, with a higher risk in people with lower education. Despite this, the cumulative incidence of hip fracture in old age was highest among people with higher education, due to their higher life expectancy.

A controlled weight loss intervention study among women of Somali background in Norway.

Background: Women of Somali background in Norway have a high prevalence of overweight and obesity, compared with women in the general Norwegian population. For lifestyle interventions to be applicable for immigrants to Norway, it is important to culturally tailor interventions in collaboration with relevant communities. The primary outcome was a difference in weight change between the intervention and control groups. Methods: In this interventional study, Somali women living in one borough of Oslo Municipality in Norway with body mass index (BMI) ≥27.0 kg.m-2 received a co-created, culturally tailored 12-month weight loss intervention consisting of 24 interactive sessions during the first three months, and monthly sessions for the next nine months, compared to a control group. Both groups were measured at baseline and 12 months. Results: A total of 169 participants were recruited, and 101 participants completed the follow-up. After multiple imputation, the mean difference in weight change adjusted for baseline weight, age, education, employment, marital status, number of children in the household and length of Norwegian residency was -1.6 kg (95 % CI -3.57, 0.43, p = 0.12) in the intervention compared to the control group. Conclusion: This culturally tailored intervention study demonstrated a modest non-significant effect on weight change after 12 months, possibly due to the short intervention duration and COVID-19. Further studies of a longer duration and considering the provision of childcare are needed to understand whether this approach can be transferred to other immigrant groups and genders.Trial registration: The study was registered at clinicaltrials.gov NCT04578067, 2020-09-29.

Iodine status and determinants in adults in Norway - results from a population-based health examination survey (The HUNT Study).

Background: In Norway, there is a lack of knowledge about the iodine status in the general and older adult population, and there is no established national monitoring programme for iodine. Several studies have indicated that iodine deficiency is prevalent in subgroups of the population. Salt iodisation is currently being considered as a measure to increase the population iodine status. In this cross-sectional study, the aim was to evaluate iodine status and determinants in the adult and older adult population in Mid-Norway, before salt iodisation is likely to be initiated. Methods: The study sample was a subsample of participants in the fourth wave of the population-based Trøndelag Health Study (HUNT4, 2017-2019) with available spot-urine samples. This subsample included participants with 25-64 years (n = 500) and 70-79 years (n = 250). The urine samples were analysed for iodine and creatinine. Information on the habitual intake of milk/yoghurt, fish, supplement use, use of thyroid medication and relevant background factors was collected through a general questionnaire. Multivariable quantile regression was used to model differences in the median urinary iodine concentration (UIC) by determinants. Estimates were weighted to match the age and sex distribution of the Norwegian population aged 25-79 years in 2019. Results: Median UIC was 97 µg/L (95% confidence interval [CI]: 92, 103) indicating borderline iodine deficiency at a group level. The median UIC increased with age, and iodine status was insufficient in participants below age 55 years (median 92 µg/L [95% CI: 85, 99]). Important determinants of UIC were habitual milk/yoghurt intake, daily supplement use and current use of thyroid medication, but not intake of lean or fatty fish. Risk of mild-to-moderate iodine deficiency was seen in those with a low intake of milk/yoghurt, no supplement use and who did not use thyroid medication. No group was identified as being at risk of iodine excess. Conclusion: Iodine status was adequate in older adults but mildly deficient in adults under 55 years. Milk intake, supplement use and use of thyroid medication are important determinants of iodine intake in Norway.

No change in 24-h sodium intake estimated from spot urine in Norwegian adults from 2006 to 2019: the population-based Trøndelag Health Study (HUNT).

OBJECTIVE: Monitoring time trends in salt consumption is important for evaluating the impact of salt reduction initiatives on public health outcomes. There has so far not been available data to indicate if salt consumption in Norway has changed during the previous decade. We aimed to assess whether average 24-h salt intake estimated from spot urine samples in the adult population of mid-Norway changed from 2006-2008 to 2017-2019 and to describe variations by sex, age and educational level. DESIGN: Repeated cross-sectional studies. SETTING: The population-based Trøndelag Health Study (HUNT). PARTICIPANTS: In each of two consecutive waves (HUNT3: 2006-2008 and HUNT4: 2017-2019), spot urine samples were collected from 500 men and women aged 25-64 years, in addition to 250 men and women aged 70-79 years in HUNT4. Based on spot urine concentrations of Na, K and creatinine and age, sex and BMI, we estimated 24-h Na intake using the International Cooperative Study on Salt and Blood Pressure (INTERSALT) equation for the Northern European region. RESULTS: Mean (95 % CI) estimated 24-h salt intakes in men were 11·1 (95 % CI 10·8, 11·3) g in HUNT3 and 10·9 (95 % CI 10·6, 11·1) g in HUNT4, P = 0·25. Corresponding values in women were 7·7 (95 % CI 7·5, 7·9) g and 7·7 (95 % CI 7·5, 7·9) g, P = 0·88. Mean estimated salt intake in HUNT4 decreased with increasing age in women, but not in men, and it did not differ significantly across educational level in either sex. CONCLUSIONS: Estimated 24-h salt intake in adult men and women in mid-Norway did not change from 2006-2008 to 2017-2019.

Dietary inflammatory pattern and risk of hip fracture in the Nurses' Health Study.

Our immune system activity is impacted by what we eat and can influence fracture risk under certain conditions. In this article, we show that postmenopausal women with a pro-inflammatory dietary pattern have an increased risk of hip fracture. PURPOSE: The immune system influences bone homeostasis and can increase the risk of fracture under certain pro-inflammatory conditions. Immune system activity is impacted by dietary patterns. Using the empirical dietary inflammatory pattern (EDIP), we investigated whether postmenopausal women with a pro-inflammatory dietary pattern had an increased risk of hip fracture. METHODS: The study population consisted of postmenopausal women participating in the Nurses' Health Study from 1980 to 2014, who reported information on lifestyle and health, including hip fractures, on biennial questionnaires, while semiquantitative food frequency questionnaires (FFQs) were completed every fourth year. Hazard ratios (HR) for hip fracture were computed using Cox proportional hazards models, adjusting for potential confounders. RESULTS: EDIP was calculated using intake information from the FFQ for 87,955 postmenopausal participants, of whom 2348 sustained a non-traumatic hip fracture during follow-up. After adjustment for confounders, there was a 7% increase in the risk of hip fracture per 1 SD increase in EDIP (HR 1.07, 95% CI 1.02-1.12), and the uppermost quintile had a 22% greater risk compared to the lowest (HR 1.22, 95% CI 1.06-1.40). For the separate components of the EDIP, we found that higher intakes of low-energy beverages (diet sodas) were independently associated with an increased risk of hip fracture, while higher intakes of green leafy vegetables were associated with a reduced risk. CONCLUSION: A pro-inflammatory dietary pattern was associated with an increased risk of hip fracture among postmenopausal women.

Plant-Based Diets and Risk of Hip Fracture in Postmenopausal Women.

Importance: Previous research has found that vegetarian diets are associated with lower bone mineral density and higher risk of fractures, but these studies did not differentiate the quality of the plant-based foods. Objective: To examine the association between the quality of plant-based diets (not necessarily vegan but also omnivorous) and hip fracture risk among postmenopausal women in the Nurses' Health Study. Design, Setting, and Participants: This cohort study analyzed data from 70 285 postmenopausal women who participated in the US Nurses' Health Study from 1984 through 2014. Data were analyzed from January 1 to July 31, 2023. Main outcomes and Measures: Hip fractures were self-reported on biennial questionnaires. Diet was assessed every 4 years using a validated semiquantitative food frequency questionnaire. Plant-based diet quality was assessed using 2 previously established indices: the healthful Plant-Based Diet Index (hPDI), for which healthy plant foods (whole grains, fruits, vegetables, nuts, legumes, vegetable oils, and tea or coffee) received positive scores, whereas less healthy plant foods (fruit juices, sweetened beverages, refined grains, potatoes, and sweets or desserts) and animal foods received reversed scores; and the unhealthful Plant-Based Diet Index (uPDI), for which positive scores were given to less healthy plant foods and reversed scores to healthy plant and animal foods. Quintile scores of 18 food groups were summed, with a theoretical range for both indices of 18 to 90 (highest adherence). Cox proportional hazards regression with time-varying covariates was used to compute hazard ratios (HRs) and 95% CIs for hip fracture. Results: In total, 70 285 participants (mean [SD] age, 54.92 [4.48] years; 100% White women) were included, and 2038 cases of hip fracture were ascertained during the study and for up to 30 years of follow-up. Neither the hPDI (HR for highest vs lowest quintile, 0.97 [95% CI, 0.83-1.14]) nor the uPDI (HR for highest vs lowest quintile, 1.02 [95% CI, 0.87-1.20]) for long-term diet adherence was associated with hip fracture risk. However, when examining recent intake for the highest vs lowest quintiles, the hPDI was associated with 21% lower risk of hip fracture (HR, 0.79 [95% CI, 0.68-0.92]; P = .02 for trend), and the uPDI was associated with 28% higher risk (1.28 [95% CI, 1.09-1.51]; P = .008 for trend). Conclusions and Relevance: Findings of this cohort study indicated that long-term adherence to healthful or unhealthful plant-based diets as assessed by hPDI and uPDI scores was not associated with hip fracture risk. Future research should clarify whether the associations observed with recent dietary intake are due to short-term effects of these dietary patterns, reverse causality, or both.

BCG vaccination and multiple sclerosis risk: A Norwegian cohort study.

INTRODUCTION: Bacillus Calmette-Guérin (BCG) vaccination induces long-lasting effects on the adaptive and innate immune systems and prevents development of experimental autoimmune encephalomyelitis and possibly also inflammatory disease activity in multiple sclerosis (MS). OBJECTIVE: The objective is to examine if BCG given in early adulthood decreases MS risk. METHODS: From 791,369 (52% females) Norwegians participating in a national tuberculosis screening program from 1963 to 1975, we collected information on BCG vaccination and tuberculosis disease status. Later, MS disease was ascertained through both the Norwegian MS Registry and Biobank and the Norwegian Death Registry. We used logistic regression models to assess the relationship between BCG vaccination and MS risk. RESULTS: In those BCG vaccinated, mean age at vaccination was 15.6 (standard deviation (SD) = 5.5) years. A total of 2862 (65% females) MS cases were retrieved. Overall, we found no association between MS risk and BCG vaccination. Compared to non-BCG-vaccinated individuals with no signs of tuberculosis infection, odds ratio (OR) for MS was 1.00 (95% confidence interval (CI) = 0.80-1.25) in the BCG-vaccinated group. In those not BCG vaccinated because of latent tuberculosis infection, the corresponding OR was 0.86 (95% CI = 0.66-1.13). CONCLUSION: We found no evidence of BCG vaccination or latent tuberculosis infection in young adulthood being linked to MS risk.

Pharmacological treatment of obesity in adults in Norway 2004-2022.

AIMS: To describe trends in the use of anti-obesity drugs in Norway during the period 2004-2022. MATERIALS AND METHODS: We assessed the annual utilization of any available drug indicated for obesity recorded in the nationwide Norwegian Prescribed Drug Register for adults (age 18-79 years) from 1 January 2004 to 31 December 2022. Prevalence was stratified by sex and age group (18-29 years and 10-year age groups thereafter). Additional analyses were performed in individuals initiating treatment with an anti-obesity drug and on the cost of the anti-obesity drugs since 2017. RESULTS: The prevalence of anti-obesity drug use decreased from 2009, when sibutramine and rimonabant were withdrawn from the market, and increased again after the approval of bupropion-naltrexone in 2017 and liraglutide in 2018. The use of the peripheral-acting anti-obesity drug orlistat decreased from 2004. In 2022, 1.04% of the adult Norwegian population (72.8% women) filled at least one prescription of bupropion-naltrexone, 0.91% used liraglutide (Saxenda; 74.2% women), and semaglutide without reimbursement was used by 0.68% (76.7% women). The prevalence increased with age, peaking in the age group 50 to 59 years, and decreased in older age groups. From 2017 to 2022, 2.8% of the adult residents initiated treatment with an anti-obesity drug. The total sale of those drugs increased from 1.1 million euros in 2017 to 91.8 million euros in 2022. CONCLUSIONS: The use of anti-obesity drugs in Norway has increased substantially in recent years, especially among women aged 40 to 59 years. Changes in availability and reimbursement have influenced the use of these drugs in recent years.

Premorbid lipid levels and long-term risk of ALS-a population-based cohort study.

OBJECTIVE: To assess the temporal relationship between premorbid lipid levels and long-term amyotrophic lateral sclerosis (ALS) risk. METHODS: From Norwegian cardiovascular health surveys (1974-2003), we collected information on total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucose, and other cardiovascular risk factors. ALS incidence and mortality were identified through validated Norwegian health registries. The relation between premorbid lipid levels and ALS risk was assessed by Cox regression models. RESULTS: Out of 640,066 study participants (51.5% females), 974 individuals (43.5% females) developed ALS. Mean follow-up time was 23.7 (SD 7.1) years among ALS cases. One mmol/l increase in LDL-C was associated with 6% increase in risk for ALS (hazard ratio 1.06 [95% CI: 1.01-1.09]). Higher levels of TC and TG were also associated with increased ALS risk, but only within the last 6-7 years prior to ALS diagnosis or death. No association between HDL-C and ALS risk was found. Adjusting for body mass index, birth cohort, smoking, and physical activity did not alter the results. CONCLUSIONS: Higher levels of LDL-C are associated with increased ALS risk over 40 years later, compatible with a causal relationship. The temporal relationship between TG, TC, and ALS risk suggests that increased levels of these lipid biomarkers represent consequences of ALS.

National health registries - a 'goldmine' for studying non-communicable disease occurrence in Norway - the NCDNOR project.

To estimate occurrence of non-communicable diseases (NCDs) over the life-course in the Norwegian population, national health registries are a vital source of information since they fully represent the entire non-institutionalised population. However, as they are mainly established for administrative purposes, more knowledge about how NCDs are recorded in the registries is needed. To establish this, we begin by counting the number of individuals registered annually with one or more NCDs in any of the registries. The study population includes all inhabitants who lived in Norway from 2004 to 2020 (N~6.4m). The NCD outcomes are diabetes, cardiovascular diseases, chronic obstructive lung diseases, cancer and mental disorders/substance use disorders. Further, we included hip fractures in our NCD concept. The data sources used to identify individuals with NCDs, including detailed information on diagnoses in primary and secondary health care and dispensings of prescription drugs, are the Cancer Registry of Norway, The Norwegian Patient Registry, The Norwegian Control and Payment of Health Reimbursement database, and The Norwegian Prescription Database. The number of individuals registered annually with an NCD diagnosis and/or a dispensed NCD drug increased over the study period. Changes over time may reflect changes in disease incidence and prevalence, but also changes in disease-specific guidelines, reimbursement schemes and access to and use of health services. Data from more than one health registry to identify individuals with NCDs are needed since the registries reflect different levels of health care services and therefore may reflect disease severity.

Vitamin D - a scoping review for Nordic nutrition recommendations 2023.

Vitamin D is an essential nutrient. Its role in calcium and phosphorous metabolism, and in the development and maintenance of a healthy skeleton is well documented. In addition, there is some evidence for vitamin D decreasing total mortality and cancer mortality modestly, but not cancer incidence. Vitamin D is unique, as both diet and sun induced production in skin are sources to this vitamin. Individual vitamin D status is thus a sum of both sun exposure and dietary intakes. The discovery of vitamin D receptors and the activation of biological active vitamin D in numerous tissues and organs in the body has given support to hypothesis on vitamin D having extra-skeletal functions. The scientific literature on vitamin D and several health outcomes is high in numbers and has been increasing exponentially the last two decades. However, despite this large body of scientific publications and improvement in study quality, vitamin D supplementation has not shown to give additional health benefits when status is in sufficient range (i.e. circulating 25 hydroxyvitamin D >50 nmol/L). Well-designed studies on insufficient or deficient individuals are lacking. The totality of evidence does not support that increased intake of vitamin D beyond current recommendation will have additional beneficial health effects.

Tuberculin responses after BCG vaccination predict amyotrophic lateral sclerosis risk.

Background: T cell infiltration around dying motor neurons is a hallmark of amyotrophic lateral sclerosis (ALS). It is not known if this immune response represents a cause or a consequence of the disease. We aimed to establish whether individual variation in regulation of a T cell driven immune response is associated with long-term ALS risk. Methods: Tuberculin skin test (TST) following BCG vaccination represents a standardized measure of a secondary T cell driven immune response. During a Norwegian tuberculosis screening program (1963-1975) Norwegian citizens born from 1910 to 1955 underwent TST. In those previously BCG vaccinated (median 7 years prior to TST), we related tuberculin skin tests to later ALS disease identified through validated Norwegian health registers. We fitted Cox proportional hazard models to investigate the association between tuberculin reactivity and ALS risk. Results: Among 324,629 participants (52 % women) with median age 22 (IQR 10) years at tuberculosis screening, 496 (50 % women) later developed ALS. Hazard ratio for ALS was 0.74 (95% CI 0.57-0.95) for those who remained TST negative compared to those who mounted a positive TST. The association was strongest when time between BCG immunization and TST was short. The associations observed persisted for more than four decades after TST measurement. Conclusions: Negative TST responses after BCG vaccination is associated with decreased long-term risk for ALS development, supporting a primary role for adaptive immunity in ALS development.

National monitoring of iodine, sodium, and vitamin D status in toddlers and women of childbearing age - results and lessons learned from a pilot study in Norway.

Background: Norway is lacking a population-based national monitoring program for iodine, sodium, and vitamin D status. Objective: The aim of this study was to pilot-test a study design for collecting biological samples from a country-representative sample of 2-year-old children and their mothers and to report results for iodine, salt, and vitamin D at baseline, before initiation of salt iodization in Norway. Design: In a cross-sectional study, we recruited 2-year-old children and their mothers during the routine 2-year check-up through 38 randomly selected health clinics in 2021. Spot urine samples were analyzed for iodine, creatinine, and sodium, and dried blood spots from the mothers were analyzed for thyroglobulin (Tg) and 25-hydroxyvitamin D (25(OH)D). Results: We aimed at including 400 mother-child pairs but recruited only 55 pairs. Major challenges were closed health clinics due to the COVID-19 pandemic, lack of motivation of the health personnel to prioritize recruiting, missing information about non-participation, and high workload for participants. The median urinary iodine concentration (UIC) was 123 (95% CI: 76, 228) µg/L in the toddlers and 83 (95% CI: 72, 99) µg/L in the mothers. The median urinary sodium concentration (UNaC) was 62 (95% CI: 37, 91) mmol/L in the toddlers and 93 (95% CI: 77, 107) mmol/L in the mothers. Of the mothers, 18% had levels of 25(OH)D <50 nmol/L (suboptimal status). Discussion and conclusion: Lessons learned from the pilot study will be used to design a national monitoring program for toddlers and women of childbearing age in Norway. The results indicate that 2-year-old children and women of childbearing age in Norway may have inadequate iodine intakes at the group level, while for vitamin D, most of the mothers had adequate status.

Postvaccination immune responses and risk of primary total hip arthroplasty-A population-based cohort study.

OBJECTIVE: To investigate the relationship between individual postvaccination immune responses and subsequent risk of total hip arthroplasty (THA) due to idiopathic osteoarthritis (OA) or rheumatoid arthritis (RA). METHOD: Results of tuberculin skin tests (TSTs) following the Bacille Calmette-Guerin (BCG) vaccination were used as a marker of individual immune responses. TST results from the mandatory mass tuberculosis screening program 1948-1975 (n = 236 770) were linked with information on subsequent THA during 1987-2020 from the Norwegian Arthroplasty Register. The multivariable Cox proportional hazard regression was performed. RESULTS: A total of 10 698 individuals received a THA during follow-up. In men, there was no association between TST and risk of THA due to OA (Hazard ratio [HR] 1.01, 95% confidence interval [CI] 0.92-1.12 for positive versus negative TST and HR 1.06, 95% CI 0.95-1.18 for strong positive vs negative TST), while the risk estimates increased with increasingly restrictive sensitivity analyses. In women, there was no association with THA due to OA for positive versus negative TST (HR 0.98, 95% CI 0.92-1.05), while a strong positive TST was associated with reduced risk of THA (HR 0.90, 95% CI 0.84-0.97). No significant associations were observed in the sensitivity analysis for women or for THA due to RA. CONCLUSION: Our results suggest that an increased postvaccination immune response is associated with a nonsignificant trend of increased risk of THA among men and a decreased risk among women, although risk estimates were small.

Explaining declining hip fracture rates in Norway: a population-based modelling study.

Background: Although age-standardised hip fracture incidence has declined in many countries during recent decades, the number of fractures is forecast to increase as the population ages. Understanding the drivers behind this decline is essential to inform policy for targeted preventive measures. We aimed to quantify how much of this decline could be explained by temporal trends in major risk factors and osteoporosis treatment. Methods: We developed a new modelling approach, Hip-IMPACT, based on the validated IMPACT coronary heart disease models. The model applied sex- and age stratified hip fracture numbers and prevalence of pharmacologic treatments and risk/preventive factors in 1999 and 2019, and best available evidence for independent relative risks of hip fracture associated with each treatment and risk/preventive factor. Findings: Hip-IMPACT explained 91% (2500/2756) of the declining hip fracture rates during 1999-2019. Two-thirds of the total decline was attributed to changes in risk/preventive factors and one-fifth to osteoporosis medication. Increased prevalence of total hip replacements explained 474/2756 (17%), increased body mass index 698/2756 (25%), and increased physical activity 434/2756 (16%). Reduced smoking explained 293/2756 (11%), and reduced benzodiazepine use explained (366/2756) 13%. Increased uptake of alendronate, zoledronic acid, and denosumab explained 307/2756 (11%), 104/2756 (4%) and 161/2756 (6%), respectively. The explained decline was partially offset by increased prevalence of type 2 diabetes and users of glucocorticoids, z-drugs, and opioids. Interpretation: Two-thirds of the decline in hip fractures from 1999 to 2019 was attributed to reductions in major risk factors and approximately one-fifth to osteoporosis medication. Funding: The Research Council of Norway.

Time-varying exposure to anti-osteoporosis drugs and risk of first-time hip fracture: a population wide study within the Norwegian Epidemiologic Osteoporosis Studies (NOREPOS).

We investigated the association between bisphosphonate and denosumab use and risk of hip fracture in Norway. These drugs protect against fractures in clinical trials, but their population-level effect is unknown. Our results showed lowered risk of hip fracture for treated women. Treatment of high-risk individuals could prevent future hip fractures. PURPOSE: To investigate whether bisphosphonates and denosumab reduced the risk of first-time hip fracture in Norwegian women when adjusting for a medication-based comorbidity index. METHODS: Norwegian women aged 50-89 in 2005-2016 were included. The Norwegian prescription database (NorPD) supplied data on exposures to bisphosphonates, denosumab, and other drugs for the calculation of the Rx-Risk Comorbidity Index. Information on all hip fractures treated in hospitals in Norway was available. Flexible parametric survival analysis was used with age as time scale and with time-varying exposure to bisphosphonates and denosumab. Individuals were followed until hip fracture or censoring (death, emigration, age 90 years), or 31 December 2016, whichever occurred first. Rx-Risk score was included as a time-varying covariate. Other covariates were marital status, education, and time-varying use of bisphosphonates or denosumab with other indications than osteoporosis. RESULTS: Of 1,044,661 women 77,755 (7.2%) were ever-exposed to bisphosphonate and 4483 (0.4%) to denosumab. The fully adjusted hazard ratios (HR) were 0.95 (95% confidence interval (CI): 0.91-0.99) for bisphosphonate use and 0.60 (95% CI: 0.47-0.76) for denosumab use. Bisphosphonate treatment gave a significantly reduced risk of hip fracture compared with the population after 3 years and denosumab after 6 months. Fracture risk was lowest in denosumab users who had previously used bisphosphonate: HR 0.42 (95% CI: 0.29-0.61) compared with the unexposed population. CONCLUSIONS: In population-wide real-world data, women exposed to bisphosphonates and denosumab had a lower hip fracture risk than the unexposed population after adjusting for comorbidity. Treatment duration and treatment history impacted fracture risk.

Cause-specific excess mortality after hip fracture: the Norwegian Epidemiologic Osteoporosis Studies (NOREPOS).

BACKGROUND: Information on cause of death may help appraise the degree to which the high excess mortality after hip fracture reflects pre-existing comorbidities or the injury itself. We aimed to describe causes of death and cause-specific excess mortality through the first year after hip fracture. METHODS: For studying the distribution of causes of death by time after hip fracture, we calculated age-adjusted cause-specific mortality at 1, 3, 6 and 12 months in patients hospitalized with hip fracture in Norway 1999-2016. Underlying causes of death were obtained from the Norwegian Cause of Death Registry and grouped by the European Shortlist for Causes of Death. For estimating excess mortality, we performed flexible parametric survival analyses comparing mortality hazard in patients with hip fracture (2002-2017) with that of age- and sex matched controls drawn from the Population and Housing Census 2001. RESULTS: Of 146,132 Norwegians with a first hip fracture, a total of 35,498 (24.3%) died within one year. By 30 days post-fracture, external causes (mainly the fall causing the fracture) were the underlying cause for 53.8% of deaths, followed by circulatory diseases (19.8%), neoplasms (9.4%), respiratory diseases (5.7%), mental and behavioural disorders (2.0%) and diseases of the nervous system (1.3%). By one-year post-fracture, external causes and circulatory diseases together accounted for approximately half of deaths (26.1% and 27.0%, respectively). In the period 2002-2017, cause-specific one-year relative mortality hazard in hip fracture patients vs. population controls ranged from 1.5 for circulatory diseases to 2.5 for diseases of the nervous system in women, and correspondingly, from 2.4 to 5.3 in men. CONCLUSIONS: Hip fractures entail high excess mortality from all major causes of death. However, the traumatic injury of a hip fracture is the most frequently reported underlying cause of death among older patients who survive less than one year after their fracture.