BACKGROUND:Adrenal crisis is a life-threatening emergency. Despite preventive strategies, previous reports suggest increasing incidence and substantial mortality, but robust validated data are limited. OBJECTIVE:To assess temporal trends in adrenal crisis incidence and identify associated risk factors. METHODS:We studied 1040 patients with autoimmune or idiopathic primary adrenal insufficiency enrolled in the Norwegian Addison Registry. Medical records were reviewed for crisis-related hospitalizations between 2000 and 2023. Overt adrenal crisis was defined by acute clinical deterioration with hemodynamic or biochemical abnormalities, whereas incipient crisis was defined by typical symptoms without objective abnormalities. RESULTS:During a median follow-up of 15 years, 660 patients (63%) experienced crisis-related hospitalizations, and 265 (25%) had an overt adrenal crisis after diagnosis. The incidence of overt crises was 3.2 per 100 person-years and that of incipient crises was 6.9 per 100 person-years. Admission rates for incipient crises increased significantly over time (p < 0.001), whereas overt crisis rates remained stable. Among 1754 admissions, five deaths (0.3%) were attributed to adrenal crisis. Both younger and older age (p < 0.001) and type 1 diabetes (incidence rate ratio 2.09, 95% confidence interval 1.45-3.01; p < 0.001) were associated with increased overt crisis risk. Daily corticosteroid dose was not associated with crisis risk. Prehospital stress dosing was used in about 50% of admissions. CONCLUSIONS:Overt adrenal crisis was uncommon and crisis-related in-hospital mortality was exceptionally low. Crisis risk was independent of replacement dose but increased in patients with type 1 diabetes. Strengthening education and implementation of prehospital stress dosing may further reduce the burden of adrenal crises.

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.

Background Few previous studies have assessed overall morbidity at the individual level with respect to future risk of hip fracture. The aim of this register-based cohort study was to examine the association between morbidity measured by the medication-based Rx-Risk Comorbidity Index (Rx-Risk) and the risk of first hip fracture. Methods Individual-level data on medications dispensed from pharmacies (2005–2016) was retrieved from the Norwegian Prescription Database and used to calculate Rx-Risk for each calendar year. Information on first hip fractures (2006–2017) was obtained from a nationwide hip fracture database. Individuals ≥ 51 years who filled at least one prescription during the study period comprised the population at risk. Using Rx-Risk as a time-varying exposure variable, relative risk estimates were obtained by a negative binomial model. Results During 2006–2017, 94,104 individuals sustained a first hip fracture. A higher Rx-Risk was associated with increased risk of hip fracture within all categories of age and sex. Women with the highest Rx-Risk (> 25) had a relative risk of 6.1 (95% confidence interval (CI): 5.4, 6.8) compared to women with Rx-Risk ≤ 0, whereas the corresponding relative risk in women with Rx-Risk 1–5 was 1.4 (95% CI: 1.3, 1.4). Similar results were found in men. Women > 80 years with Rx-Risk 21–25 had the highest incidence rate (514 (95% CI: 462, 566) per 10, 000 person years). The relative increase in hip fracture risk with higher Rx-Risk was most pronounced in the youngest patients aged 51–65 years. Conclusions Rx-Risk is a strong predictor of hip fracture in the general outpatient population and may be useful to identify individuals at risk in a clinical setting and in future studies.

The aim of the present review is to discuss the roles of vitamin K (phylloquinone or menaquinones) and vitamin K-dependent proteins, and the combined action of the vitamins K and D, for the maintenance of bone health. The most relevant vitamin K-dependent proteins in this respect are osteocalcin and matrix Gla-protein (MGP). When carboxylated, these proteins appear to have the ability to chelate and import calcium from the blood to the bone, thereby reducing the risk of osteoporosis. Carboxylated osteocalcin appears to contribute directly to bone quality and strength. An adequate vitamin K status is required for the carboxylation of MGP and osteocalcin. In addition, vitamin K acts on bone metabolism by other mechanisms, such as menaquinone 4 acting as a ligand for the nuclear steroid and xenobiotic receptor (SXR). In this narrative review, we examine the evidence for increased bone mineralization through the dietary adequacy of vitamin K. Summarizing the evidence for a synergistic effect of vitamin K and vitamin D3, we find that an adequate supply of vitamin K, on top of an optimal vitamin D status, seems to add to the benefit of maintaining bone health. More research related to synergism and the possible mechanisms of vitamins D3 and K interaction in bone health is needed.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

We aimed to investigate the risk of hip fracture associated with zoledronic acid treatment compared to alendronate on a population level. The risk of hip fracture was lower in women using zoledronic acid and higher in women who had discontinued treatment. The findings support the effectiveness of intravenous bisphosphonate. To investigate whether zoledronic acid (ZOL) was associated with a lower risk of the first hip fracture than alendronate (ALN) in Norway using real-world data. Nationwide data on drugs dispensed in outpatient pharmacies were individually linked with all hospital-treated hip fractures. Individuals aged 50–89 years without previous hip fracture were included at their first filling of a prescription for ALN or ZOL during 2005–2016. Hazard ratios (HRs) with 95

Bone loss occurs both before and after kidney transplantation. Kidney transplant recipients have a high fracture risk, but how do we identify those most at risk? DXA scans measure bone mass, but we can also use DXA images of the hip to assess hip structural geometry and strength using a special software called Hip Structure Analysis. We studied the effect of a bone preserving and strengthening medication called bisphosphonate, in 127 patients during the first year after kidney transplantation. We found that hip geometry and strength parameters remain stable during the first year after transplantation irrespective of bisphosphonate use.

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. 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. 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. 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. 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.

Objective :Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood.Design: Cross-sectional study.Methods: We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 mu g tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH.Results :Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = -0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (-0.15 normalized protein expression [NPX], P = .0001, and -0.25 NPX, P = .0003, respectively).Conclusions :We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small.

BackgroundLow 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.ObjectiveWe aimed to investigate BMD, bone microarchitecture and incidence of bone stress injuries in Norwegian elite Para athletes.DesignIn 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.ResultsAmong 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.ConclusionsHalf 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.

Abstract Disclosure: Å.B. Sævik: None. G. Ueland: None. A. Åkerman: None. P. Methlie: None. M. Quinkler: None. A. Jørgensen: None. C. Höybye: None. A.W. Debowska: None. B. Nedrebø: None. A. Dahle: None. S. Carlsen: None. A.E. Tomkowicz: None. S.T. Sollid: None. I. Nermoen: None. K. Grønning: None. P.M. Dahlqvist: None. G. Grimnes: None. J. Skov: None. T. Finnes: None. S.F. Valland: None. S.E. Holte: None. J. Wahlberg: None. O. Kämpe: None. S. Bensing: None. E.S. Husebye: None. M. Øksnes: None. Background: Population-based studies have shown a wider use of cardiovascular medications in AAD and an increased risk of ischemic heart disease, most pronounced in women. These data suggest that a subgroup of patients may be especially vulnerable, emphasizing the need for clinical tools to evaluate cardiovascular risk at an individual level in AAD. Methods: We first mapped 177 cardiovascular and inflammatory biomarkers in patients with AAD compared with healthy controls overall and stratified for sex (false discovery rate, FDR 5%). Second, we explored biomarker associations to the frequency of adrenal crises and quality of life (P<0.050), and any impact of very high ACTH exposure on biomarker profiles by change in biomarker profiles in patients without residual adrenocortical function (RAF) following injection of ACTH (FDR 5%). Results: Nineteen (11%) biomarkers significantly differed between patients with AAD and controls after correction for multiple testing, of which all but one (ST1A1) were higher in AAD. The greatest difference in biomarker value was noted for FGF21 (difference 0.80 NPX, P = 0.004). When stratified for sex, seven of the 19 biomarkers were significantly higher in female patients compared to controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9 + PGF), but no significant differences were found between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crisis (r = 0.415, P = 0.006) and AddiQoL-30 scores (r = -0.347, P = 0.028). PD-L2 and leptin significantly declined 60 minutes after injection of ACTH in AAD without RAF (-0.15 NPX, P = 0.0001 and -0.25 NPX, P = 0.0003, respectively). Conclusion: We demonstrate marked differences in cardiovascular and inflammatory biomarker profiles in patients with AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with the frequency of adrenal crises and reduced quality of life. Very high ACTH levels reduce PD-L2 and leptin in a glucocorticoid-independent manner, although the overall effect on biomarker profiles seems small. Presentation: Saturday, June 17, 2023

Purpose: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison’s disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin. Methods: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS). Results: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min (p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points (p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges. Conclusion: Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD.

Abstract 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.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

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.