Multiple radiologist review of adrenal CT still frequently misses lateralized surgical primary aldosteronism.

Patients with primary aldosteronism (PA) have increased morbidity and mortality compared to those with essential hypertension. Accurate detection of lateralized PA is important so that affected patients can receive potentially curative adrenalectomy. However, around 40% of patients with lateralized PA have "normal" adrenal glands on computed tomography (CT). Additional independent review of imaging has been shown to improve diagnostic accuracy in many areas of imaging. Therefore, the authors sought to establish if multi-reader re-assessment of previously reported normal CT scans would result in increased detection of surgically remediable disease. The authors found that re-assessment of CT imaging by one, two, or three additional radiologists (or a combination thereof) slightly increased the detection of lateralized disease, but these differences were not statistically significant (p > .05). Readers had low inter-observer agreement (kappa = 0.17). If detection of a discrete nodule on CT was made a prerequisite for adrenal vein sampling (AVS), a second read by another reviewer would still result in an excess of missed cases (84.2%, 36.8%, and 65.8%, respectively, for each of the three independent reviewers). Therefore, a "normal" CT does not preclude the possibility of lateralized PA. Adrenal vein sampling should still be strongly considered wherever available and whenever surgery is considered for treatment of PA, irrespective of CT findings.

Time to Benefit of Surgery vs Targeted Medical Therapy for Patients With Primary Aldosteronism: A Meta-analysis.

CONTEXT: Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, but the comparative outcomes of targeted treatment remain unclear. OBJECTIVE: To compare the clinical outcomes in patients treated for primary aldosteronism over time. METHODS: Medline and EMBASE were searched. Original studies reporting the incidence of mortality, major adverse cardiovascular outcomes (MACE), progression to chronic kidney disease, or diabetes following adrenalectomy vs medical therapy were selected. Two reviewers independently abstracted data and assessed study quality. Standard meta-analyses were conducted using random-effects models to estimate relative differences. Time to benefit meta-analyses were conducted by fitting Weibull survival curves to estimate absolute risk differences and pooled using random-effects models. RESULTS: 15 541 patients (16 studies) with PA were included. Surgery was consistently associated with an overall lower risk of death (hazard ratio [HR] 0.34, 95% CI 0.22-0.54) and MACE (HR 0.55, 95% CI 0.36-0.84) compared with medical therapy. Surgery was associated with a significantly lower risk of hospitalization for heart failure (HR 0.48 95% CI 0.34-0.70) and progression to chronic kidney disease (HR 0.62 95% CI 0.39-0.98), and nonsignificant reductions in myocardial infarction and stroke. In absolute terms, 200 patients would need to be treated with surgery instead of medical therapy to prevent 1 death after 12.3 (95% CI 3.1-48.7) months. CONCLUSION: Surgery is associated with lower all-cause mortality and MACE than medical therapy for PA. For most patients, the long-term surgical benefits outweigh the short-term perioperative risks.

Biomarkers to Guide Medical Therapy in Primary Aldosteronism.

Primary aldosteronism (PA) is an endocrinopathy characterized by dysregulated aldosterone production that occurs despite suppression of renin and angiotensin II, and that is non-suppressible by volume and sodium loading. The effectiveness of surgical adrenalectomy for patients with lateralizing PA is characterized by the attenuation of excess aldosterone production leading to blood pressure reduction, correction of hypokalemia, and increases in renin-biomarkers that collectively indicate a reversal of PA pathophysiology and restoration of normal physiology. Even though the vast majority of patients with PA will ultimately be treated medically rather than surgically, there is a lack of guidance on how to optimize medical therapy and on key metrics of success. Herein, we review the evidence justifying approaches to medical management of PA and biomarkers that reflect endocrine principles of restoring normal physiology. We review the current arsenal of medical therapies, including dietary sodium restriction, steroidal and nonsteroidal mineralocorticoid receptor antagonists, epithelial sodium channel inhibitors, and aldosterone synthase inhibitors. It is crucial that clinicians recognize that multimodal medical treatment for PA can be highly effective at reducing the risk for adverse cardiovascular and kidney outcomes when titrated with intention. The key biomarkers reflective of optimized medical therapy are unsurprisingly similar to the physiologic expectations following surgical adrenalectomy: control of blood pressure with the fewest number of antihypertensive agents, normalization of serum potassium without supplementation, and a rise in renin. Pragmatic approaches to achieve these objectives while mitigating adverse effects are reviewed.

Subclinical Primary Aldosteronism and Cardiovascular Health: A Population-Based Cohort Study.

BACKGROUND: Primary aldosteronism, characterized by overt renin-independent aldosterone production, is a common but underrecognized form of hypertension and cardiovascular disease. Growing evidence suggests that milder and subclinical forms of primary aldosteronism are highly prevalent, yet their contribution to cardiovascular disease is not well characterized. METHODS: This prospective study included 1284 participants between the ages of 40 and 69 years from the randomly sampled population-based CARTaGENE cohort (Québec, Canada). Regression models were used to analyze associations of aldosterone, renin, and the aldosterone-to-renin ratio with the following measures of cardiovascular health: arterial stiffness, assessed by central blood pressure (BP) and pulse wave velocity; adverse cardiac remodeling, captured by cardiac magnetic resonance imaging, including indexed maximum left atrial volume, left ventricular mass index, left ventricular remodeling index, and left ventricular hypertrophy; and incident hypertension. RESULTS: The mean (SD) age of participants was 54 (8) years and 51% were men. The mean (SD) systolic and diastolic BP were 123 (15) and 72 (10) mm Hg, respectively. At baseline, 736 participants (57%) had normal BP and 548 (43%) had hypertension. Higher aldosterone-to-renin ratio, indicative of renin-independent aldosteronism (ie, subclinical primary aldosteronism), was associated with increased arterial stiffness, including increased central BP and pulse wave velocity, along with adverse cardiac remodeling, including increased indexed maximum left atrial volume, left ventricular mass index, and left ventricular remodeling index (all P<0.05). Higher aldosterone-to-renin ratio was also associated with higher odds of left ventricular hypertrophy (odds ratio, 1.32 [95% CI, 1.002-1.73]) and higher odds of developing incident hypertension (odds ratio, 1.29 [95% CI, 1.03-1.62]). All the associations were consistent when assessing participants with normal BP in isolation and were independent of brachial BP. CONCLUSIONS: Independent of brachial BP, a biochemical phenotype of subclinical primary aldosteronism is negatively associated with cardiovascular health, including greater arterial stiffness, adverse cardiac remodeling, and incident hypertension.

A Population-Based Registry Study of Extended Bisphosphonate Use: Minimal Shift After Landmark Publications About Shorter Treatment Duration.

Optimal duration of bisphosphonate therapy was unknown until the FLEX study was published in 2006 showing a 5-year course to be adequate for most women. In 2008, a link between long-term bisphosphonate and atypical femoral fractures was reported and confirmed in later studies. We hypothesized these landmark observations should have led to a decrease in use of bisphosphonates for >5 or 10 years, from 2010 onward. The Manitoba Bone Mineral Density (BMD) Registry with linkage to provincial pharmacy data was used to determine the percentage of long- and very long-term bisphosphonate users from therapy start. The cohort comprised women aged >50 years with BMD between 1995 and 2018 with oral bisphosphonate first prescribed for >90 days with adherence >75% in the first year. For each calendar year of continued therapy, the percentage of patients and medication possession rate was tabulated. The percentage of users beyond 5 years was compared among patients who started therapy in 1998-2004 (those taking 5 years of therapy still finish before 2010) versus 2005-2012 (all new therapy starts overlap 2010 in those taking ≥5 years of treatment). The cohort included 2991 women with mean follow-up 8.8 (1.3) years, 64.9% of whom took continuous oral bisphosphonate for >5 years and 41.9% for >10 years. In the earlier versus later era, there were 74.4% versus 70.2% who completed 5 years. With respect to longer treatment, there were 68.0% and 60.5% of patients treated for 6 or more years (p < 0.0001) and 46.6% versus 33.5% treated for >10 years (p = 0.08). Medication possession rate was >79% in every year of therapy. Landmark studies leading to more limited bisphosphonate courses may have slightly reduced longer-term treatment, but up to one-third of adherent patients in the modern era still receive continuous bisphosphonate therapy for >10 years. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Bone turnover markers for assessment of anti-resorptive effect in clinical practice: A good idea meets the problem of measurement uncertainty.

OBJECTIVES: Bone turnover markers (BTM) are measures for understanding the effect of anti-resorptives upon osteoclast activity. Post-hoc trial data suggests reduction in BTM of 40% may represent a target for defining appropriate response to therapy. We modeled clinical application of this target threshold in an individual patient setting where assay measurement uncertainty and biological variation are included. DESIGN: Using serum C-telo-peptide (ß-CTX), we constructed hypothetical scenarios of ß-CTX measurement pre and post bisphosphonate therapy. Using typical ß-CTX assay characteristics (analytical coefficient of variation, CV 5.0%) and published intra-individual ß-CTX data for post-menopausal women (CV 18.0%), we calculated the post-therapy ß-CTX that must be seen on single repeat measure for 95% confidence that the observed result was ≥40% below baseline. Sensitivity analyses considered greater and lesser variations in the combined sources of variation. RESULTS: The one-tailed 95% reference change value for any detectable therapeutic decrease in ß-CTX was 22%. However, to have 95% confidence of having achieved a reduction ≥40%, an observed ß-CTX decrease of ≥56% is required. Larger decreases are needed for scenarios of greater analytical or intra-individual variation. CONCLUSIONS: Although population data suggest a ß-CTX decrease of 40% is commensurate with adequate therapeutic response to anti-resorptives, application to an individual patient where measurement and natural variation are present is problematic. ß-CTX decreases much >40% are required to be confident of having achieved the optimal treatment response. It is uncertain whether this is a legitimate change to be expected in all individual patients and therefore clinical application of this threshold is uncertain.

Screening for Primary Aldosteronism Among Hypertensive Adults with Obstructive Sleep Apnea: A Retrospective Population-Based Study.

BACKGROUND: Hypertension plus obstructive sleep apnea (OSA) is recommended in some guidelines as an indication to screen for primary aldosteronism (PA), yet prior data has brought the validity of this recommendation into question. Given this context, it remains unknown whether this screening recommendation is being implemented into clinical practice. METHODS: We conducted a population-based retrospective cohort study of all adult Ontario (Canada) residents with hypertension plus OSA from 2009 to 2020 with follow-up through 2021 utilizing provincial health administrative data. We measured the proportion of individuals who underwent PA screening via the aldosterone-to-renin ratio by year. We further examined screening rates among patients with hypertension plus OSA by the presence of concurrent hypokalemia and resistant hypertension. Clinical predictors associated with screening were assessed via Cox regression modeling. RESULTS: The study cohort included 53,130 adults with both hypertension and OSA, of which only 634 (1.2%) underwent PA screening. Among patients with hypertension, OSA, and hypokalemia, the proportion of eligible patients screened increased to 2.8%. Among patients ≥65 years with hypertension, OSA, and prescription of ≥4 antihypertensive medications, the proportion of eligible patients screened was 1.8%. Older age was associated with a decreased likelihood of screening while hypokalemia and subspecialty care with internal medicine, cardiology, endocrinology, or nephrology were associated with an increased likelihood of screening. No associations with screening were identified with sex, rural residence, cardiovascular disease, diabetes, or respirology subspecialty care. CONCLUSIONS: The population-level uptake of the guideline recommendation to screen all patients with hypertension plus OSA for PA is exceedingly low.

General Comorbidity Indicators Contribute to Fracture Risk Independent of FRAX: Registry-Based Cohort Study.

CONTEXT: FRAX® estimates 10-year fracture probability from osteoporosis-specific risk factors. Medical comorbidity indicators are associated with fracture risk but whether these are independent from those in FRAX is uncertain. OBJECTIVE: We hypothesized Johns Hopkins Aggregated Diagnosis Groups (ADG®) score or recent hospitalization number may be independently associated with increased risk for fractures. METHODS: This retrospective cohort study included women and men age ≥ 40 in the Manitoba BMD Registry (1996-2016) with at least 3 years prior health care data and used linked administrative databases to construct ADG scores along with number of hospitalizations for each individual. Incident Major Osteoporotic Fracture and Hip Fracture was ascertained during average follow-up of 9 years; Cox regression analysis determined the association between increasing ADG score or number of hospitalizations and fractures. RESULTS: Separately, hospitalizations and ADG score independently increased the hazard ratio for fracture at all levels of comorbidity (hazard range 1.2-1.8, all P < 0.05), irrespective of adjustment for FRAX, BMD, and competing mortality. Taken together, there was still a higher than predicted rate of fracture at all levels of increased comorbidity, independent of FRAX and BMD but attenuated by competing mortality. Using an intervention threshold of major fracture risk >20%, application of the comorbidity hazard ratio multiplier to the patient population FRAX scores would increase the number of treatment candidates from 8.6% to 14.4%. CONCLUSION: Both complex and simple measures of medical comorbidity may be used to modify FRAX-based risk estimates to capture the increased fracture risk associated with multiple comorbid conditions in older patients.

Fracture risk in Asian-Canadian women is significantly over-estimated by the Canadian Association of Radiologists-Osteoporosis Canada risk prediction tool: retrospective cohort study.

Fracture risk calculators may not be accurate for all ethnicity groups. The Manitoba bone density registry was used to test the Canadian CAROC tool for predicting fracture risk in Asian-Canadian women. The tool significantly over-estimated fracture risk, suggesting that it may not be ideal for Asian-Canadian patients. PURPOSE: Health risk prediction tools based on largely White populations may lead to treatment inequity when applied to non-White populations where outcome rates differ. We examined the calibration of the Canadian Association of Radiologists-Osteoporosis Canada (CAROC) fracture risk prediction tool in self-identified Asian-Canadian women. METHODS: Retrospective cohort study of women over age 50 using the Manitoba BMD Registry. At first BMD, the intake questionnaire collected self-identification of ethnicity and fracture risk factors. 10-year fracture risk was estimated using CAROC and categorized into low, medium, or high fracture risk. Linked administrative databases identified incident osteoporotic fractures. Observed fracture rates were compared between White and Asian-Canadians and compared to the original CAROC risk stratification. RESULTS: There were 63,632 and 1703 women who self-identified as White-Canadian or Asian-Canadian, respectively, covering approximately 600,000 patient-years follow-up. There were 6588 incident fractures; a similar percentage of patients were assigned to each risk stratum at baseline by CAROC. A progressive rise in 10-year observed fracture rates occurred for each CAROC stratum in the White-Canadian population but much lower fracture rates than predicted in Asian-Canadian patients (p < 0.001). Fracture incidence rate ratios were 1.9-2.6 fold higher in White- vs Asian-Canadian patients for all strata (p < 0.001). In the CAROC moderate and high-risk categories, observed fracture rates in Asian-Canadian patients were typically lower than predicted, indicating poor model calibration. CONCLUSION: In Asian-Canadian women, observed osteoporosis fracture rates are lower than predicted when using the CAROC tool. Over-estimation of fracture risk may influence shared decision-making discussions.

Performance of Confirmatory Tests for Diagnosing Primary Aldosteronism: a Systematic Review and Meta-Analysis.

BACKGROUND: Confirmatory tests are recommended for diagnosing primary aldosteronism, but the supporting evidence is unclear. METHODS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials. Studies evaluating any guideline-recommended confirmatory test (ie, saline infusion test, salt loading test, fludrocortisone suppression test, and captopril challenge test), compared with a reference standard were included. The Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess the risk of bias. Meta-analyses were conducted using hierarchical summary receiver operating characteristic models. RESULTS: Fifty-five studies were included, comprising 26 studies (3654 participants) for the recumbent saline infusion test, 4 studies (633 participants) for the seated saline infusion test, 2 studies (99 participants) for the salt loading test, 7 studies (386 participants) for the fludrocortisone suppression test, and 25 studies (2585 participants) for the captopril challenge test. Risk of bias was high, affecting more than half of studies, and across all domains. Studies with case-control sampling overestimated accuracy by 7-fold (relative diagnostic odds ratio, 7.26 [95% CI, 2.46-21.43]) and partial verification or use of inconsistent reference standards overestimated accuracy by 5-fold (5.12 [95% CI, 1.48-17.77]). There were large variations in how confirmatory tests were conducted, interpreted, and verified. Under most scenarios, confirmatory testing resulted in an excess of missed cases. The certainty of evidence underlying each test (Grading of Recommendations, Assessment, Development, and Evaluations) was very low. CONCLUSIONS: Recommendations for confirmatory testing in patients with abnormal screening tests and high probability features of primary aldosteronism are based on very low-quality evidence and their routine use should be reconsidered.

A retrospective review of the community medicine needs from osteoporosis services in Canada.

BACKGROUND: Comprehensive, real-world osteoporosis care has many facets not explicitly addressed in practice guidelines. We sought to determine the areas of knowledge and practice needs in osteoporosis medicine for the purpose of developing an osteoporosis curriculum for specialist trainees and knowledge translation tools for primary care. METHODS: This was a retrospective review of referral questions received from primary care and specialists to an academic, multi-disciplinary tertiary osteoporosis and metabolic bone clinic. There were 400 referrals in each of 5 years (2015-2019) selected randomly for review. The primary referral question was elucidated and assigned to one of 16 pre-determined referral topics reflecting questions in the care of osteoporosis and metabolic bone patients. The top 7 referral topics by frequency were determined while recording the referral source. RESULTS: The majority of referrals (71%) came from urban primary care. The most common specialists to request care included rheumatology, oncology, gastroenterology and orthopedic surgery (fracture liaison services). Primary care referrals predominantly requested assistance with routine osteoporosis assessments, bisphosphonate holidays, bisphosphonate adverse effects/alternatives, fractures occurring despite therapy and adverse changes on bone densitometry despite treatment. Specialists most often referred patients with complex secondary bone diseases or cancer. The main study limitation was that knowledge needs of referring physicians were inferred from the referral question rather than tested directly. CONCLUSION: By assessing actual community demand for services, this study identified several such topics that may be useful targets to develop high quality knowledge translation tools and curriculum design in programs training specialists in osteoporosis care.

Apparent "Rapid Loss" After Short-Interval Bone Density Testing in Menopausal Women Is Usually a Measurement Artifact.

CONTEXT: Medication may be considered when bone mineral density (BMD) loss is reported as "excessive." OBJECTIVE: We hypothesized that the rate of BMD change between 2 serial tests demonstrates higher random variability at shorter vs longer intervals, misclassifying some women as "rapid losers." METHODS: This retrospective observational cohort study in Manitoba, Canada included women aged > 55 years without osteoporosis medications or glucocorticoids. Using paired baseline (1998-2016) and repeat (2001-2018) BMD measurements, we estimated the distribution of annualized change (first to second BMD) at spine, hip, and femoral neck stratified by testing interval (2-2.9, 3-3.9,...9-9.9, ≥ 10.0 years). "Rapid annual bone loss" was defined as exceeding the 95th percentile for decreases from all measurement pairs. Odds ratios (OR) for rapid loss were estimated using regression models adjusted for age and clinical covariates. RESULTS: From 7126 paired BMD measurements, mean annualized change was constant yet standard deviations in BMD change were > 2-fold greater with intervals of 2 to 2.9 years vs ≥ 10 years(P < 0.001). "Rapid annual loss" was seen in ~10% of short-interval tests vs < 1% of long-interval tests. ORs for "rapid loss" progressively declined with increasing testing interval (spine 15.3 [4.8-48.9], total hip 9.3 [4.4-19.5], femoral neck 18.7 [6.8-51.3] for a 2- to 2.9-year testing interval; referent ≥ 10 years). CONCLUSION: There is a wider apparent range in annualized BMD loss with short-interval testing which greatly attenuates over longer intervals. BMD reports of "rapid loss" across shorter testing intervals likely reflect an artifact of BMD measurement error and should not be used as an indication for antifracture medication initiation.

Updated reference intervals for urine normetanephrine have no effect on test sensitivity but fewer false positives.

OBJECTIVE: We previously highlighted the problem of frequent false positives in 24 h urine normetanephrine(UNM) measurements owing to reference intervals that are inappropriately low for the population being screened for pheochromocytoma. Using a large population database, we devised new age-stratified reference intervals for the 24 h UNM test that were higher compared to previous. However, it was uncertain as to whether this would compromise test sensitivity for true pheochromocytoma cases. DESIGN AND METHODS: Retrospective analysis of all pheochromocytoma cases from a recently constructed provincial registry. All confirmed cases had their diagnostic UNM results retrospectively re-analysed according to the newly proposed UNM reference intervals to determine the percentage and phenotype of cases that might have been theoretically missed with the new reference range. RESULTS: After excluding pediatric and non-secretory head and neck paragangliomas, there were 60 confirmed pheochromocytoma cases. Using prior reference intervals, 51/60 (85%) had an abnormally high UNM. Of the 9 with normal UNM, 4 had a high urine metanephrine(UMN), 5 had normal levels of both UNM and UMN such that 55/60 had abnormal test results, representing the historical combined test sensitivity of 92%. Using the proposed reference interval, 43/60 (72%) had high UNM results. Of the 17 with normal UNM, 12 had high UMN, 5 had normal levels of both UNM and UMN. Therefore, 55/60 patients had had elevations in either UNM or UMN, corresponding to an identical combined test sensitivity of 92%. CONCLUSIONS: Reference intervals for UNM derived from actual clinical population screening data are higher than in traditional healthy volunteers. Use of these more appropriate reference intervals can significantly reduce the false positive rate without compromising test sensitivity for true pheochromocytoma.

Differential risk of fracture attributable to type 2 diabetes mellitus according to skeletal site.

BACKGROUND: Impaired bone quality, especially related to accumulation of advanced glycation end-products (AGEs) and higher incidence of falls contribute substantially to a higher risk of fracture associated with type 2 diabetes mellitus (T2DM). These factors may predispose to fractures more at skeletal sites where impaired bone toughness and falls play a larger pathogenic role (such as hip fractures) compared to skeletal sites where they are less important (such as vertebral fractures). OBJECTIVE: To determine if the associations of T2DM with prevalent and incident vertebral fractures are as strong as they are for hip and other non-vertebral fractures. METHODS: Amongst 80,238 individuals in the Manitoba Bone Density Program database (mean [SD] age 64.4 [11.1] years, 89.8% female, 8676 with diagnosed T2DM) with a baseline BMD test (1996-2016), we estimated hazard ratios (HRs) for incident clinical fracture at different skeletal sites in those with compared to those without T2DM using Cox proportional hazards models over a mean (SD) 9.0 (5.0) year follow-up period. We also estimated odds ratios for prevalent vertebral fracture on VFA images amongst 9594 individuals (mean [SD] 76 [6.8] years, 1185 with T2DM diagnosis at time of DXA-VFA) and for prior clinical fractures at different skeletal sites using logistic regression models. RESULTS: After multivariable adjustment, T2DM was associated with incident hip (HR 1.63, 95% CI 1.44 to 1.85) and proximal humerus fractures (HR 1.59, 95% CI 1.39 to 1.83), but was not associated with incident forearm fracture (HR 1.00, 95% CI 0.86 to 1.17) and only weakly with incident clinical vertebral fracture (HR 1.16, 95% CI 1.01 to 1.33). Similarly, T2DM was associated with prior hip (OR 1.78, 95% CI 1.21 to 2.61) and prior proximal humerus fracture (OR 1.31, 95% CI 1.02 to 1.68) but not with prior forearm (OR 0.89, 95% CI 0.74 to 1.06) or prevalent vertebral fracture on VFA images (OR 0.91, 95% CI 0.77 to 1.08). CONCLUSION: T2DM is a stronger risk factor for hip and proximal humerus fractures than for vertebral and wrist fractures. Further research is warranted to determine if the known differences in falls and/or bone quality between T2DM and age-related osteoporosis account for these differential associations.

Divergent Patterns of Antifracture Medication Use Following Fracture on Therapy: A Population-Based Cohort Study.

CONTEXT: Fracture on therapy should motivate better antifracture medication adherence. OBJECTIVE: This study aimed to describe osteoporosis medication adherence in women before and following a fracture. METHODS: This retrospective cohort analysis of antifracture medication possession ratios (MPR) among women in the Manitoba BMD Registry (1996-2013) included menopausal women who started antifracture drug therapy after a dual-energy x-ray absorptiometry (DXA)-BMD assessment with follow-up for 5 years during which a nontraumatic fracture occurred at least 1 year after starting treatment. Linked prescription records determined medication adherence (estimated by MPR) in 1-year intervals. The variable of interest was MPR in the year before and after the year in which the fracture occurred, with subgroup analyses according to duration of treatment pre-fracture. We chose an MPR of ≥ 0.50 to indicate minimum adherence needed for drug efficacy. RESULTS: There were 585 women with fracture on therapy, 193 (33%) had hip or vertebral fracture. Bisphosphonates accounted for 82.2% of therapies. Median MPR the year prior to fracture was 0.89 (IQR, 0.49-1.0) and 0.69 (IQR, 0.07-0.96) the year following the year of fracture (P < 0.0001). The percentage of women with MPR ≥ 0.5 pre-fracture was 73.8%, dropping to 57.3% post-fracture (P < 0.0001); when restricted to hip/vertebral fracture, results were similar (58.2% to 33.3%; P < 0.002). Among those with pre-fracture MPR < 0.5, only 21.7% achieved a post-fracture MPR ≥ 0.5. CONCLUSIONS: Although fracture on therapy may motivate sustained/improved adherence, MPR remains low or even declines after fracture in many. This could reflect natural decline in MPR with time but is paradoxical to expectations. Fracture on therapy represents an important opportunity for clinicians to reemphasize treatment adherence.

Apparent failed and discordant adrenal vein sampling: A potential confounding role of cortisol cosecretion?

OBJECTIVE: Adrenal vein sampling (AVS) and computed tomography (CT) often show confusingly discordant lateralisation results in primary aldosteronism (PA). We tested a biochemical algorithm using AVS data to detect cortisol cosecretion as a potential explanation for discordant cases. DESIGN: Retrospective analysis from a large PA + AVS database. PATIENTS: All patients with PA and AVS, 2005-2020. MEASUREMENTS: An algorithm using biochemical data from paired AVS + CT images was devised from physiological first principles and informed by data from unilateral, AVS-CT concordant patients. The algorithm involved calculations based upon the expectation that low cortisol levels exist in adrenal vein effluent opposite an aldosterone-and-cortisol-producing adrenal mass and may reverse lateralisation due to inflated aldosterone/cortisol ratios. MAIN OUTCOMES: The algorithm was applied to cases with discordant CT-AVS lateralisation to determine whether this might be a common or explanatory finding. Clinical and biochemical characteristics of identified cases were collected via chart review and compared to CT-AVS concordant cases to detect evidence of biological plausibility for cortisol cosecretion. RESULTS: From a total of 588 AVS cases, 141 AVS + CT pairs were clear unilateral PA cases, used to develop the three-step algorithm for AVS interpretation. Applied to 88 AVS + CT discordant pairs, the algorithm suggested possible cortisol cosecretion in 40%. Case review showed that the proposed cortisol cosecretors, as identified by the algorithm, had low/suppressed adrenocorticotropic hormone levels, larger average nodule size and lower plasma aldosterone. CONCLUSIONS: Pending external validation and outcome verification by surgery and tissue immunohistochemistry, cortisol cosecretion from aldosteronomas may be a common explanation for discordant CT-AVS results in PA.

External Validation of Clinical Prediction Models in Unilateral Primary Aldosteronism.

BACKGROUND: Targeted treatment of primary aldosteronism (PA) is informed by adrenal vein sampling (AVS), which remains limited to specialized centers. Clinical prediction models have been developed to help select patients who would most likely benefit from AVS. Our aim was to assess the performance of these models for PA subtyping. METHODS: This external validation study evaluated consecutive patients referred for PA who underwent AVS at a tertiary care referral center in Alberta, Canada during 2006-2018. In alignment with the original study designs and intended uses of the clinical prediction models, the primary outcome was the presence of lateralization on AVS. Model discrimination was evaluated using the C-statistic. Model calibration was assessed by comparing the observed vs. predicted probability of lateralization in the external validation cohort. RESULTS: The validation cohort included 342 PA patients who underwent AVS (mean age, 52.1 years [SD, 11.5]; 201 [58.8%] male; 186 [54.4%] with lateralization). Six published models were assessed. All models demonstrated low-to-moderate discrimination in the validation set (C-statistics; range, 0.60-0.72), representing a marked decrease compared with the derivation sets (range, 0.80-0.87). Comparison of observed and predicted probabilities of unilateral PA revealed significant miscalibration. Calibration-in-the-large for every model was >0 (range, 0.35-1.67), signifying systematic underprediction of lateralizing disease. Calibration slopes were consistently <1 (range, 0.35-0.87), indicating poor performance at the extremes of risk. CONCLUSIONS: Overall, clinical prediction models did not accurately predict AVS lateralization in this large cohort. These models cannot be reliably used to inform the decision to pursue AVS for most patients.