2 Minute Medicine Rewind November 4, 2019

Odanacatib for the Treatment of Postmenopausal Osteoporosis: Results of the LOFT Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial and LOFT Extension Study

1. The cathepsin K inhibitor odanacatib reduced the risk of fracture but was associated with significantly increased risk of cardiovascular events, specifically stroke, in postmenopausal women with osteoporosis compared to placebo.

Evidence Rating Level: 1 (Excellent)

Odanacatib, a cathepsin K inhibitor, reduces bone resorption without compromising bone formation, with further findings suggesting that it increases bone mineral density in postmenopausal women with low bone mass. Data from the Long-term Odanacatib Fracture Trial (LOFT) and LOFT Extension conducted at 388 outpatient clinics across 40 countries was utilized to assess the safety and efficacy of odanacatib to reduce bone fracture risk in postmenopausal women with osteoporosis. Women included in this double-blind, placebo-controlled study were postmenopausal for at least five years, had a reduced femoral neck or total hip bone mineral density (T-score -2.5 to -4.0) if no radiographic vertebral fracture, or T-score bone mineral density of -1.5 to -4.0 if concomitant with previous vertebral fracture. These participants were randomly assigned to oral odanacatib (50mg once weekly) or matching placebo, assessed using radiographs at baseline and then at six-month and 12-month follow-ups each year of the study. Cumulative incidence was significantly lower (p<0.001) in the odanacatib group compared to placebo for radiographic vertebral fractures (difference 4.1%; HR 0.46, 95% CI 0.40 to 0.53), hip fractures (difference 0.8%; HR 0.53, 95% CI 0.39 to 0.71), and non-vertrebral fractures (difference 1.6%; HR 0.77, 95% CI 0.68 to 0.87). Similar findings were noted when including the LOFT Extension study. Differences in composite cardiovascular endpoints from the LOFT odanacatib and placebo groups were not significant. While incidence of new-onset atrial fibrillation or flutter and myocardial infarction were not statistically significant between groups, odanacatib was associated with a significantly increased risk of stroke (difference 0.4%; HR 1.32, 95% CI 1.02 to 1.70, p=0.034). When including the LOFT Extension study, the odanacatib group was associated with increased risk of at least one cardiovascular endpoint compared to the placebo group (difference 0.7%; HR 1.17, 95% CI 1.02 to 1.36, p=0.29), as well as stroke (difference 0.6%; HR 1.37, 95% CI 1.10 to 1.71, p=0.0051). Therefore, this study suggests that vertebral fracture risk was reduced by odanacatib but this medication was also associated with elevated risk of cardiovascular events, specifically stroke. Due to these findings, it is important to consider the risks of odanacatib for the treatment of osteoporosis in postmenopausal women.

Selective Vulnerability of the Nucleus Basalis of Meynert Among Neuropathologic Subtypes of Alzheimer Disease

1. Widespread cholinergic deficits found in early-onset Alzheimer’s disease (AD) may be a result of neurofibrillary tangle accumulation in the nucleus basalis of Meynert, specifically in those with hippocampal sparing AD.

Evidence Rating Level: 2 (Good)

The nucleus basalis of Meynert (nbM) is a well-known target for cholinergic therapy, suggesting that Alzheimer’s disease (AD) subtype heterogeneity may illuminate differences in neuronal loss and neurofibrillary tangle (NFT) accumulation in the nbM. Three distinct patterns of corticolimbic neurofibrillary tangle (NFT) accumulation have been discovered in the following subtypes of AD, from least to most hippocampal involvement: 1) hippocampal sparing (HpSp) AD; 2) typical AD; and, 3) limbic predominant AD. This study was a cross-sectional, retrospective abstraction of clinical records and quantitative assessments of NFTs and neuron counts in the anterior nbM through the Florida Autopsied Multi-Ethnic (FLAME) cohort. Data was collected from 1991 to 2015, including 1,361 AD subtypes and 103 non-dementia controls. Median age at death was 72 (95% CI 66 to 80) years for HpSp AD, 81 (95% CI 76-86) years for typical AD, and 86 (95% CI 82-90) years for limbic predominant AD. It was found that the nbM of HpSP AD had the highest median count per 0.125mm2 of thioflavin S-positive NFTs (14 [9-20]), which was lower in typical AD (10 [5-16]) and lowest in limbic predominant AD (8 [5-11]), which were clinically significant differences (p<0.001). Median neuronal density per mm2 was lowest in HpSp AD (22 [17-28]), higher in typical AD (25 [19-30]), and highest in limbic predominant AD (26 [19-32]). Overlap of neuronal density and NFT accumulation were further assessed with multi-variable regression modeling, finding that NFT accumulation was inversely related with age of onset in HpSp AD (B -1.5, 95% CI -2.9 to -0.15, p=0.03) and typical AD (B -3.2, 95% CI -3.9 to -2.4, p<0.001). In HpSp AD, the number of NFTs was expected to be higher by 1.5 for every 10 years earlier the onset (95% CI -2.9 to -0.15, p=0.03). Higher NFT accumulation in nbM of typical AD was also associated with apolipoprotein E (APOE) ε4 allele (B 1.3; 95% CI 0.15 to 2.5, p=0.03), female sex (B 2.5, 95% CI 1.4 to 3.5, p<0.001), and lower Mini-Mental Status Examination scores (B -1.8, 95% CI -3.2 to -0.31, p=0.02). These variables were not associated with nbM-specific NFT accumulation in limbic predominant AD, though the neuron count in this group was expected to be lower by 4.6 for every 10 years earlier the onset (95% CI 2.3 to 7.0, p<0.001). This study suggests that NFT accumulation in the nbM may be an important factor in the cholinergic deficits found in early-onset AD, specifically those with HpSp AD. These findings highlight a noteworthy basis for considering specific variables during assessment of AD outcomes, such as age of onset, APOE genotype, and sex.

Association of Widespread Adoption of the 39-Week Rule With Overall Mortality Due to Stillbirth and Infant Death

1. Following the Joint Commission’s adoption of the 39-week rule to reduce early, elective deliveries, there has been a marginal significant increase in the stillbirth rate while overall mortality rates have remained relatively stable.

Evidence Rating Level: 2 (Good)

Studies on the association of mortality with the adoption of the Joint Commission’s 39-week rule have yielded inconsistent results thus far. While elective deliveries prior to the 39-week period may be associated with neonatal morbidity, prolonging pregnancy is also known to increase risk of stillbirth. This historical cohort study reviewed birth and infant death certificates in the United States to compare the preadoption period (2008-2009; n=7,322,234) with the postadoption period (2011-2012; n=6,972,626) of this rule. Births included in analyses were singleton and nonanomalous between 37 0/7 weeks’ and 42 6/7 weeks’ gestation. Investigators found a decrease in proportion of deliveries at 37 and 38 weeks and an increase in the proportion of deliveries at 39 and 40 weeks (p<0.001). The overall mortality rates during the preadoption and postadoption periods remained relatively stable (p=0.06) while the infant death rate decreased in the postadoption period (difference .01%, p<0.001). However, the stillbirth rate demonstrated a significant increase in the postadoption group compared to the preadoption group (difference 0.01%, p<0.001). Further analyses suggested that up to 34.2% of the reduction in mortality may be associated with the adoption of this rule. This study demonstrated that overall mortality rates remained steady during the two years following adoption of the 39-week rule even though there was an increase in stillbirth. While limited in terms of outcomes of interest in the groups studied, these findings suggest a need for further research on other variables that contribute to stillbirths while being offset by reduced infant deaths at term.

Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood

1. Acetaminophen burden, as measured by cord plasma samples, was associated with increased, dose-dependent risk of childhood Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder.

Evidence Rating Level: 2 (Good)

Fetal acetaminophen exposure has been found to increase risk of neurodevelopmental disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD). However, because many of these prior studies have depended on maternal self-reports, this prospective cohort study of 996 mother-infant dyads is the first to analyze archived cord plasma samples of three acetaminophen metabolites: unchanged acetaminophen, acetaminophen glucuronide, and 3-[N-acetyl-L-cystein-S-yl]-acetaminophen. This subset of the Boston Birth Cohort participating between 1998 and 2018 included children with physician-diagnosed ADHD (25.8%), ASD (6.6%), ADHD+ASD (4.2%), other neurodevelopmental disorders (30.5%), as well as neurotypical children (32.8%). Each plasma sample included detectable, unchanged levels of acetaminophen. The second tertile (OR 2.26, 95% CI 1.40 to 3.69) and third tertile (OR 2.86, 95% CI 1.77 to 4.67) of cord acetaminophen burden were associated with increased odds of ADHD. Similar results were found for those diagnosed with ASD, with increased odds in the second tertile (OR 2.14, 95% CI 0.93 to 5.13) and third tertile (OR 3.62, 95% CI 1.62 to 8.60). Analyses across confounders such as substance use, preterm birth, child age and sex, and maternal indication yielded consistent associations between acetaminophen burden and both ADHD (ORs 2.3 to 3.5) and ASD (ORs 1.6 to 4.1). As a study that relied on cord plasma biomarkers rather than self-reports of acetaminophen use, its findings suggest that in utero exposure to acetaminophen may be associated in a dose-dependent manner with increased odds of developing ADHD or ASD.

Effect of Continued Folic Acid Supplementation Beyond the First Trimester of Pregnancy on Cognitive Performance in the Child: A Follow-Up Study From a Randomized Controlled Trial (FASSTT Offspring Trial)

1. Folic acid supplementation prevents neural tube deficits during pregnancy, but if continued beyond the recommended first trimester, may positively impact neurodevelopment and cognitive performance in children at seven years of age.

Evidence Rating Level: 2 (Good)

Periconceptional folic acid (FA) supplementation is a protective factor against neural tube defects (NTD), with the recommended time period for this supplementation being limited to the first trimester. This randomized controlled trial of Folic Acid Supplementation during the Second and Third Trimesters (FASSTT) conducted from 2006 to 2007 investigated the potential benefits of FA supplementation during the second and third trimesters of pregnancy on child neurocognitive performance at seven years of age. Mothers were randomly assigned to 400μg/d FA or placebo, starting at 14 weeks’ gestation until pregnancy, with all mothers receiving FA during the first trimester. Children of the participating mothers were evaluated at either age three years (n=39) or seven years (n=70) with the Bayley’s Scale of Infant and Toddler Development (BSITD-III) or Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), respectively, due to test age requirements and normative data. At seven years, the FA group’s cognitive performance was stronger than the placebo group in word reasoning (mean scaled score [SS] difference 1.4, p=0.027). At three years of age, the FA group outperformed the placebo group in general cognition (mean SS difference 0.8, p=0.040). Compared to a nationally representative sample of British children aged seven years, WPPSI-III scores in the FA group were higher in verbal intelligence quotient (IQ; p<0.001), performance IQ (p=0.035), general language (p=0.002), and full scale IQ (p=0.001). The study placebo group, compared to this national sample, demonstrated significant but smaller differences in WPPSI-III scores for verbal IQ (p-0.034) and full scale IQ (p=0.017). The findings of this study suggest that, beyond prevention of NTD, continued FA supplementation throughout the second and third trimesters may yield positive neurocognitive outcomes in children compared to those who only receive FA during the first trimester.

 Image: PD

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