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.

Trabecular Bone Score Improves Early After Successful Kidney Transplantation Irrespective of Antiresorptive Therapy and Changes in Bone Mineral Density.

Background: Trabecular bone score (TBS) is a new tool to assess trabecular bone microarchitecture based on standard dual-energy x-ray absorptiometry (DXA) of lumbar spine images. TBS may be important to assess bone quality and fracture susceptibility in kidney transplant recipients (KTRs). This study aimed to investigate the effect of different bone therapies on TBS in KTRs. Methods: We reanalyzed DXA scans to assess TBS in 121 de novo KTRs at baseline, 10 wk, and 1 y. This cohort, between 2007 and 2009, participated in a randomized, placebo-controlled trial evaluating the effect of ibandronate versus placebo in addition to vitamin D and calcium. Results: Although bone mineral density (BMD) Z scores showed a subtle decrease in the first weeks, TBS Z scores increased from baseline to 10 wk for both treatment groups, followed by a slight decline at 12 mo. When comparing treatment groups and adjusting for baseline TBS, there were no differences found in TBS at 12 mo (P = 0.419). Correlation between TBS and BMD at baseline was weak (Spearman's ρ = 0.234, P = 0.010), and change in TBS was not correlated with changes in lumbar spine BMD in either of the groups (ρ = 0.003, P = 0.973). Conclusions: Treatment with ibandronate or vitamin D and calcium did not affect bone quality as measured by TBS in de novo KTRs, but TBS increased early, irrespective of intervention. Changes in TBS and BMD during the study period were not correlated, indicating that these measurements reflect different aspects of bone integrity. TBS may complement BMD assessment in identifying KTRs with a high fracture risk.

Secular reduction of excess mortality in hip fracture patients >85 years.

BACKGROUND: More than 20% of the hip fracture patients die within the first year after the incident. Few data are available on the trends in mortality following a hip fracture. The present aim was to study changes in excess mortality after hip fracture from 1978/79 up to 1996/97. METHODS: Data on 5180 hip fracture patients aged ≥ 50 years, identified in three earlier, well validated, incidence studies from Oslo were used. The studies took place in the two years periods 1978-79 and 1989-89 and in a one year period from 1st of May 1996 to 30th of April 1997. The study was designed as a historic cohort study. Exposure was sustaining a hip fracture in the registration periods. Outcome was death of all causes. Age- and sex-specific one year-mortality rates were provided by Statistics Norway. Standardized mortality ratios (SMR) were calculated for the three cohorts for each sex and age-group, for the 0-6 months, 6-12 months, 0-1 year, 1-5 years and 5-10 years intervals after fracture. To assess the duration of the excess mortality in hip fracture patients, time-framed Kaplan-Meier curves for consecutive 5-years intervals were conducted for the hip fracture patients and the corresponding background population. Only patients still alive at the start of the time interval were included. One sample log rank tests were used to test for statistical significance. RESULTS: The one-year SMR ranged from 3.64 (2.82 - 4.61) to 4.53 (3.67 - 5.54) in men and from 2.78 (2.39 - 3.19) to 3.60 (3.19 - 4.05) in women. In the 0-6 months interval a reduction in SMR from 1978/79 to 1996/97 was observed in women aged ≥85 years. The duration of excess mortality ranged from two years in men ≥85 years to more than ten years in men and women aged 65-84 years. CONCLUSION: Excess mortality among hip fracture patients remains high. Over the decades, a reduced excess mortality was mainly seen in the oldest patients, suggesting that specific efforts intending to improve prevention and treatment of osteoporosis and osteoporotic fractures in the youngest elderly are required.

High prevalence of low bone mineral density but normal trabecular bone score in Norwegian elite Para athletes.

Background: Low bone mineral density (BMD) increases the risk of bone stress injuries (BSI) and is one of several clinical concerns in Para athlete sports medicine. However, whether bone microarchitecture is altered in Para athletes is not known. Objective: We aimed to investigate BMD, bone microarchitecture and incidence of bone stress injuries in Norwegian elite Para athletes. Design: In this cross-sectional study in Para athletes, Dual energy x-ray absorptiometry (iDXA, Lunar, GE Health Care) derived areal BMD, trabecular bone score (TBS), a surrogate marker for bone microarchitecture, and body composition (body weight (BW), lean body mass (LBM), fat mass (FM), fat percentage) were investigated and compared between ambulant and non-ambulant athletes. Also, the association between BMD, TBS and body composition variables was investigated. Incidence of BSI was assessed with a questionnaire and confirmed by a sports physician in a clinical interview. BMD Z-score <-1 was defined as low and ≤-2 as osteoporotic. TBS ≥ 1.31 was normal, 1.23-1.31 intermediate and <1.23 low. Results: Among 38 athletes (26 ± 6 yrs, 14 females), BMD Z-score was low in 19 athletes, and osteoporotic in 11 athletes' lumbar spine (LS) or femoral neck (FN). BMD was lower in non-ambulant vs. ambulant athletes both in LS (1.13 ± 0.19 vs. 1.25 ± 0.14 g/cm2, p = 0.030) and FN (0.90 ± 0.15 vs. 1.07 ± 0.16 g/cm2, p = 0.003). TBS was normal for all athletes. BMD Z-score in LS was positively associated with TBS (r = 0.408, p = 0.013), body weight (r = 0.326, p = 0.046) and lean body mass (r = 0.414, p = 0.010), but not with fat mass or fat percentage. None of the athletes reported any BSI. Conclusions: Half of the Norwegian elite Para athletes had low BMD, and 29% had BMD Z-score <-2 suggesting osteoporosis. Non-ambulant athletes were more prone to low BMD than ambulant athletes. However, despite high prevalence of low BMD, TBS was normal in all athletes, and BSI was absent in this young population.

Autoimmune Thyroid Disorders in Autoimmune Addison Disease.

CONTEXT: Autoimmune thyroid disease is the most common endocrine comorbidity in autoimmune Addison disease (AAD), but detailed investigations of prevalence and clinical course are lacking. OBJECTIVE: This work aimed to provide comprehensive epidemiological and clinical data on autoimmune thyroid disorders in AAD. METHODS: A nationwide registry-based study including 442 patients with AAD and autoimmune thyroid disease were identified through the Norwegian National Registry of Autoimmune Diseases. RESULTS: Of 912 registered AAD patients, 442 (48%) were diagnosed with autoimmune thyroid disease. A total of 380 (42%) had autoimmune hypothyroidism. Of the 203 with available thyroid function tests at time of diagnosis, 20% had overt hypothyroidism, 73% had subclinical hypothyroidism, and 7% had thyroid levels in the normal range. Negative thyroid peroxidase antibodies was found in 32%. Ninety-eight percent were treated with levothyroxine, 5% with combination therapy with liothyronine or thyroid extracts, and 1% were observed without treatment. Seventy-eight patients (9%) were diagnosed with Graves disease (GD), of whom 16 (21%) were diagnosed with autoimmune hypothyroidism either before onset or after remission of GD. At the end of follow-up, 33% had normal thyroid hormone levels without antithyroid-drugs or levothyroxine treatment. The remaining had either active disease (5%), had undergone ablative treatment (41%), or had developed autoimmune hypothyroidism (21%). CONCLUSION: The true prevalence of hypothyroidism in AAD is lower than reported in the current literature. Careful consideration of the indication to start thyroxin therapy is warranted. Long-term remission rates in GD patients with AAD are comparable to recent reports on long-term follow-up of patients without AAD.

Individual Variation in Adaptive Immune Responses and Risk of Hip Fracture-A NOREPOS Population-Based Cohort Study.

Immune-mediated bone loss significantly impacts fracture risk in patients with autoimmune disease, but to what extent individual variations in immune responses affect fracture risk on a population level is unknown. To examine how immune responses relate to risk of hip fracture, we looked at the individual variation in a post-vaccination skin test response that involves some of the immune pathways that also drive bone loss. From 1963 to 1975, the vast majority of the Norwegian adult population was examined as part of the compulsory nationwide Norwegian mass tuberculosis screening. These examinations included standardized tuberculin skin tests (TSTs). Our study population included young individuals (born 1940 to 1960 and aged 14 to 30 years at examination) who had all received Bacille Calmette-Guerin (BCG) vaccination after a negative TST at least 1 year prior and had no signs of tuberculosis upon clinical examination. The study population ultimately included 244,607 individuals, whose data were linked with a national database of all hospitalized hip fractures in Norway from 1994 to 2013. There were 3517 incident hip fractures during follow-up. Using a predefined Cox model, we found that men with a positive or a strong positive TST result had a 20% (hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.01-1.44) and 24% (HR = 1.24, 95% CI 1.03-1.49) increased risk of hip fracture, respectively, compared with men with a negative TST. This association was strengthened in sensitivity analyses. Total hip bone mineral density (BMD) was available for a limited subsample and similarly revealed a non-significantly reduced BMD among men with a positive TST. Interestingly, no such clear association was observed in women. An increased immune response after vaccination is associated with an increased risk of hip fracture decades later among men, possibly because of increased immune-mediated bone loss. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).