Publications by authors named "Steven R Cummings"

368 Publications

What cut-point in gait speed best discriminates community dwelling older adults with mobility complaints from those without? A pooled analysis from the Sarcopenia Definitions and Outcomes Consortium.

J Gerontol A Biol Sci Med Sci 2021 Jun 24. Epub 2021 Jun 24.

University of Florida, Gainesville, FL.

Background: Cut-points to define slow walking speed have largely been derived from expert opinion.

Methods: Study participants (13,589 men and 5,043 women aged ≥65years) had walking speed (m/s) measured over 4-6 meters (mean ± SD: 1.20 ± 0.27 m/s in men and 0.94 ± 0.24 m/s in women.) Mobility limitation was defined as self-reported any difficulty with walking ~1/4 mile (prevalence: 12.6% men, 26.4% women). Sex-stratified classification and regression tree (CART) models with 10-fold cross-validation identified walking speed cut-points that optimally discriminated those who reported mobility limitation from those who did not.

Results: Among 5,043 women, CART analysis identified two cut-points, classifying 4,144 (82.2%) with walking speed ≥0.75 m/s, which we labeled as "fast"; 478 (9.5%) as "intermediate" (walking speed ≥0.62 m/s but <0.75 m/s); and 421 (8.3%) as "slow" (walking speed <0.62 m/s). Among 13,589 men, CART analysis identified three cut-points, classifying 10,001 (73.6%) with walking speed ≥1.00 m/s ("very fast"); 2,901 (21.3%) as "fast" (walking speed ≥0.74 m/s but <1.00 m/s); 497 (3.7%) as "intermediate" (walking speed ≥0.57 m/s but <0.74 m/s); and 190 (1.4%) as "slow" (walking speed <0.57 m/s). Prevalence of self-reported mobility limitation was lowest in the "fast" or "very fast" (11% for men and 19% for women) and highest in the "slow" (60.5% in men and 71.0% in women). Rounding the two slower cut-points to 0.60 m/s and 0.75 m/s reclassified very few participants.

Conclusions: Cut-points in walking speed of ~0.60 m/s and 0.75 m/s discriminate those with self-reported mobility limitation from those without.
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http://dx.doi.org/10.1093/gerona/glab183DOI Listing
June 2021

Assessment of a Risk-Based Approach for Triaging Mammography Examinations During Periods of Reduced Capacity.

JAMA Netw Open 2021 03 1;4(3):e211974. Epub 2021 Mar 1.

Department of Radiology, University of Washington School of Medicine, Seattle.

Importance: Breast cancer screening, surveillance, and diagnostic imaging services were profoundly limited during the initial phase of the coronavirus disease 2019 (COVID-19) pandemic.

Objective: To develop a risk-based strategy for triaging mammograms during periods of decreased capacity.

Design, Setting, And Participants: This population-based cohort study used data collected prospectively from mammography examinations performed in 2014 to 2019 at 92 radiology facilities in the Breast Cancer Surveillance Consortium. Participants included individuals undergoing mammography. Data were analyzed from August 10 to November 3, 2020.

Exposures: Clinical indication for screening, breast symptoms, personal history of breast cancer, age, time since last mammogram/screening interval, family history of breast cancer, breast density, and history of high-risk breast lesion.

Main Outcomes And Measures: Combinations of clinical indication, clinical history, and breast cancer risk factors that subdivided mammograms into risk groups according to their cancer detection rate were identified using classification and regression trees.

Results: The cohort included 898 415 individuals contributing 1 878 924 mammograms (mean [SD] age at mammogram, 58.6 [11.2] years) interpreted by 448 radiologists, with 1 722 820 mammograms in individuals without a personal history of breast cancer and 156 104 mammograms in individuals with a history of breast cancer. Most individuals were aged 50 to 69 years at imaging (1 113 174 mammograms [59.2%]), and 204 305 (11.2%) were Black, 206 087 (11.3%) were Asian or Pacific Islander, 126 677 (7.0%) were Hispanic or Latina, and 40 021 (2.2%) were another race/ethnicity or mixed race/ethnicity. Cancer detection rates varied widely based on clinical indication, breast symptoms, personal history of breast cancer, and age. The 12% of mammograms with very high (89.6 [95% CI, 82.3-97.5] to 122.3 [95% CI, 108.1-138.0] cancers detected per 1000 mammograms) or high (36.1 [95% CI, 33.1-39.3] to 47.5 [95% CI, 42.4-53.3] cancers detected per 1000 mammograms) cancer detection rates accounted for 55% of all detected cancers and included mammograms to evaluate an abnormal mammogram or breast lump in individuals of all ages regardless of breast cancer history, to evaluate breast symptoms other than lump in individuals with a breast cancer history or without a history but aged 60 years or older, and for short-interval follow-up in individuals aged 60 years or older without a breast cancer history. The 44.2% of mammograms with very low cancer detection rates accounted for 13.1% of detected cancers and included annual screening mammograms in individuals aged 50 to 69 years (3.8 [95% CI, 3.5-4.1] cancers detected per 1000 mammograms) and all screening mammograms in individuals younger than 50 years regardless of screening interval (2.8 [95% CI, 2.6-3.1] cancers detected per 1000 mammograms).

Conclusions And Relevance: In this population-based cohort study, clinical indication and individual risk factors were associated with cancer detection and may be useful for prioritizing mammography in times and settings of decreased capacity.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.1974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994953PMC
March 2021

The TOPAZ study: a home-based trial of zoledronic acid to prevent fractures in neurodegenerative parkinsonism.

NPJ Parkinsons Dis 2021 Mar 1;7(1):16. Epub 2021 Mar 1.

Department of Medicine, Duke University School of Medicine, VA Medical Center, Durham, NC, USA.

The Trial of Parkinson's And Zoledronic acid (TOPAZ, https://clinicaltrials.gov/ct2/show/NCT03924414 ) is a unique collaboration between experts in movement disorders and osteoporosis to test the efficacy of zoledronic acid, an FDA-approved parenteral treatment for osteoporosis, for fracture prevention in people with neurodegenerative parkinsonism. Aiming to enroll 3,500 participants age 65 years or older, TOPAZ is one of the largest randomized, placebo-controlled clinical trials ever attempted in parkinsonism. The feasibility of TOPAZ is enhanced by its design as a U.S.- wide home-based trial without geographical limits. Participants receive information from multiple sources, including specialty practices, support groups and websites. Conducting TOPAZ in participants' homes takes advantage of online consent technology, the capacity to confirm diagnosis using telemedicine and the availability of research nursing to provide screening and parenteral therapy in homes. Home-based clinical research may provide an efficient, convenient, less expensive method that opens participation in clinical trials to almost anyone with parkinsonism.
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http://dx.doi.org/10.1038/s41531-021-00162-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921548PMC
March 2021

Clinical Trials Without Clinical Sites.

JAMA Intern Med 2021 May;181(5):680-684

San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, California.

Clinical trials conducted at clinical sites are limited to enrolling people who live nearby and are able to attend visits at clinics. Some types of clinical trials can be performed without clinical sites, which enables people to participate regardless of proximity to a clinical site or limitations that make visits difficult. Trials at clinical sites involve face-to-face relationships with in-person collection of informed consent, examinations, data, and specimens. In contrast, without clinical sites, informed consent and data are obtained online, limited examinations can be performed by telemedicine or visiting research nurses, biospecimens can be collected by visiting nurses or local laboratories, and treatments can be sent to homes or administered by nurses in participants' homes. Trials without clinical sites require internet access and must adapt to the lack of face-to-face interactions with study staff, with communication conducted by email, telephone, or video. Many trials cannot be performed entirely without clinical sites because they require examinations, tests, or treatments that must be given at a clinical site. However, some of the methods required for trials without sites, such as online data collection, follow-up visits by telemedicine or research nurses, and delivery of treatments to home, could reduce the need for visits to clinical sites and reduce the burden of participating in a clinical trial. When feasible, conducting clinical trials without clinical sites has the potential to expand participation and the generalizability of their results.
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http://dx.doi.org/10.1001/jamainternmed.2020.9223DOI Listing
May 2021

Response to "Red Cell Distribution Width Is a Risk Factor for Hip Fracture in Elderly Men Without Anemia".

J Bone Miner Res 2021 Jun 28;36(6):1203. Epub 2021 Jan 28.

San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA.

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http://dx.doi.org/10.1002/jbmr.4242DOI Listing
June 2021

Association of mammographic density measures and breast cancer "intrinsic" molecular subtypes.

Breast Cancer Res Treat 2021 May 4;187(1):215-224. Epub 2021 Jan 4.

Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN, 55905, USA.

Purpose: We evaluated the association of percent mammographic density (PMD), absolute dense area (DA), and non-dense area (NDA) with risk of "intrinsic" molecular breast cancer (BC) subtypes.

Methods: We pooled 3492 invasive BC and 10,148 controls across six studies with density measures from prediagnostic, digitized film-screen mammograms. We classified BC tumors into subtypes [63% Luminal A, 21% Luminal B, 5% HER2 expressing, and 11% as triple negative (TN)] using information on estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and tumor grade. We used polytomous logistic regression to calculate odds ratio (OR) and 95% confidence intervals (CI) for density measures (per SD) across the subtypes compared to controls, adjusting for age, body mass index and study, and examined differences by age group.

Results: All density measures were similarly associated with BC risk across subtypes. Significant interaction of PMD by age (P = 0.001) was observed for Luminal A tumors, with stronger effect sizes seen for younger women < 45 years (OR = 1.69 per SD PMD) relative to women of older ages (OR = 1.53, ages 65-74, OR = 1.44 ages 75 +). Similar but opposite trends were seen for NDA by age for risk of Luminal A: risk for women: < 45 years (OR = 0.71 per SD NDA) was lower than older women (OR = 0.83 and OR = 0.84 for ages 65-74 and 75 + , respectively) (P < 0.001). Although not significant, similar patterns of associations were seen by age for TN cancers.

Conclusions: Mammographic density measures were associated with risk of all "intrinsic" molecular subtypes. However, findings of significant interactions between age and density measures may have implications for subtype-specific risk models.
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http://dx.doi.org/10.1007/s10549-020-06049-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216504PMC
May 2021

Proteomic assessment of serum biomarkers of longevity in older men.

Aging Cell 2020 11 20;19(11):e13253. Epub 2020 Oct 20.

Oregon Health & Science University, Portland, OR, USA.

The biological bases of longevity are not well understood, and there are limited biomarkers for the prediction of long life. We used a high-throughput, discovery-based proteomics approach to identify serum peptides and proteins that were associated with the attainment of longevity in a longitudinal study of community-dwelling men age ≥65 years. Baseline serum in 1196 men were analyzed using liquid chromatography-ion mobility-mass spectrometry, and lifespan was determined during ~12 years of follow-up. Men who achieved longevity (≥90% expected survival) were compared to those who died earlier. Rigorous statistical methods that controlled for false positivity were utilized to identify 25 proteins that were associated with longevity. All these proteins were in lower abundance in long-lived men and included a variety involved in inflammation or complement activation. Lower levels of longevity-associated proteins were also associated with better health status, but as time to death shortened, levels of these proteins increased. Pathway analyses implicated a number of compounds as important upstream regulators of the proteins and implicated shared networks that underlie the observed associations with longevity. Overall, these results suggest that complex pathways, prominently including inflammation, are linked to the likelihood of attaining longevity. This work may serve to identify novel biomarkers for longevity and to understand the biology underlying lifespan.
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http://dx.doi.org/10.1111/acel.13253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681066PMC
November 2020

signatureSearch: environment for gene expression signature searching and functional interpretation.

Nucleic Acids Res 2020 12;48(21):e124

Institute for Integrative Genome Biology, 1207F Genomics Building, University of California, Riverside, CA 92521, USA.

signatureSearch is an R/Bioconductor package that integrates a suite of existing and novel algorithms into an analysis environment for gene expression signature (GES) searching combined with functional enrichment analysis (FEA) and visualization methods to facilitate the interpretation of the search results. In a typical GES search (GESS), a query GES is searched against a database of GESs obtained from large numbers of measurements, such as different genetic backgrounds, disease states and drug perturbations. Database matches sharing correlated signatures with the query indicate related cellular responses frequently governed by connected mechanisms, such as drugs mimicking the expression responses of a disease. To identify which processes are predominantly modulated in the GESS results, we developed specialized FEA methods combined with drug-target network visualization tools. The provided analysis tools are useful for studying the effects of genetic, chemical and environmental perturbations on biological systems, as well as searching single cell GES databases to identify novel network connections or cell types. The signatureSearch software is unique in that it provides access to an integrated environment for GESS/FEA routines that includes several novel search and enrichment methods, efficient data structures, and access to pre-built GES databases, and allowing users to work with custom databases.
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http://dx.doi.org/10.1093/nar/gkaa878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708038PMC
December 2020

Deep Learning With Electronic Health Records for Short-Term Fracture Risk Identification: Crystal Bone Algorithm Development and Validation.

J Med Internet Res 2020 10 16;22(10):e22550. Epub 2020 Oct 16.

Department of Medicine, University of California San Francisco, San Francisco, CA, United States.

Background: Fractures as a result of osteoporosis and low bone mass are common and give rise to significant clinical, personal, and economic burden. Even after a fracture occurs, high fracture risk remains widely underdiagnosed and undertreated. Common fracture risk assessment tools utilize a subset of clinical risk factors for prediction, and often require manual data entry. Furthermore, these tools predict risk over the long term and do not explicitly provide short-term risk estimates necessary to identify patients likely to experience a fracture in the next 1-2 years.

Objective: The goal of this study was to develop and evaluate an algorithm for the identification of patients at risk of fracture in a subsequent 1- to 2-year period. In order to address the aforementioned limitations of current prediction tools, this approach focused on a short-term timeframe, automated data entry, and the use of longitudinal data to inform the predictions.

Methods: Using retrospective electronic health record data from over 1,000,000 patients, we developed Crystal Bone, an algorithm that applies machine learning techniques from natural language processing to the temporal nature of patient histories to generate short-term fracture risk predictions. Similar to how language models predict the next word in a given sentence or the topic of a document, Crystal Bone predicts whether a patient's future trajectory might contain a fracture event, or whether the signature of the patient's journey is similar to that of a typical future fracture patient. A holdout set with 192,590 patients was used to validate accuracy. Experimental baseline models and human-level performance were used for comparison.

Results: The model accurately predicted 1- to 2-year fracture risk for patients aged over 50 years (area under the receiver operating characteristics curve [AUROC] 0.81). These algorithms outperformed the experimental baselines (AUROC 0.67) and showed meaningful improvements when compared to retrospective approximation of human-level performance by correctly identifying 9649 of 13,765 (70%) at-risk patients who did not receive any preventative bone-health-related medical interventions from their physicians.

Conclusions: These findings indicate that it is possible to use a patient's unique medical history as it changes over time to predict the risk of short-term fracture. Validating and applying such a tool within the health care system could enable automated and widespread prediction of this risk and may help with identification of patients at very high risk of fracture.
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http://dx.doi.org/10.2196/22550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600029PMC
October 2020

Association Between Variation in Red Cell Size and Multiple Aging-Related Outcomes.

J Gerontol A Biol Sci Med Sci 2021 Jun;76(7):1288-1294

San Francisco Coordinating Center, California.

Background: We tested whether greater variation in red blood cell size, measured by red cell distribution width (RDW), may predict aging-related degenerative conditions and therefore, serve as a marker of biological aging.

Methods: Three thousand six hundred and thirty-five community-dwelling older men were enrolled in the prospective Osteoporotic Fractures in Men Study. RDW was categorized into 4 groups (≤13.0%, 13.1%-14.0%, 14.1%-15.0%, and ≥15.1%). Functional limitations, frailty, strength, physical performance, and cognitive function were measured at baseline and 7.4 years later. Falls were recorded in the year after baseline; hospitalizations were obtained for 2 years after baseline. Mortality was assessed during a mean of 8.3 years of follow-up.

Results: Participants with greater variability in red cell size were weaker, walked more slowly, and had a worse cognitive function. They were more likely to have functional limitations (35.2% in the highest RDW category vs 16.0% in the lowest, p < .001) and frailty (30.3% vs 11.3%, p < .001). Those with greater variability in red cell size were more likely to develop new functional limitations and to become frail. The risk of having 2 or more falls was also greater (highest 19.2% vs lowest 10.3%, p < .001). The risk of hospitalization was higher in those with the highest variability (odds ratio [95% confidence interval], 1.8 [1.3-2.5]) compared with the lowest. Variability in red cell size was related to total and cause-specific mortality.

Conclusion: Greater variability in red cell size is associated with diverse aging-related outcomes, suggesting that it may have potential value as a marker for biological aging.
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http://dx.doi.org/10.1093/gerona/glaa217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202142PMC
June 2021

Cardiovascular Safety of Abaloparatide in Postmenopausal Women With Osteoporosis: Analysis From the ACTIVE Phase 3 Trial.

J Clin Endocrinol Metab 2020 11;105(11)

San Francisco Coordinating Center, Sutter Health, California; University of California, San Francisco, California.

Context: Abaloparatide is a US Food and Drug Administration-approved parathyroid hormone-related peptide analog for treatment of osteoporosis in postmenopausal women at high risk of fracture.

Objectives: We assessed the cardiovascular safety profile of abaloparatide.

Design: Review of heart rate (HR), blood pressure (BP), and cardiovascular-related adverse events (AEs), including major adverse cardiovascular events (MACEs) and heart failure (HF) from: (a) ACTIVE (NCT01343004), a phase 3 trial that randomized 2463 postmenopausal women with osteoporosis to abaloparatide, teriparatide, or placebo for 18 months; (b) ACTIVExtend (NCT01657162), where participants from the abaloparatide and placebo arms received alendronate for 2 years; and (c) a pharmacology study in 55 healthy adults.

Results: Abaloparatide and teriparatide transiently increased HR relative to placebo. Following first dose, mean (standard deviation [SD]) HR change from pretreatment to 1 hour posttreatment was 7.9 (8.5) beats per minute (bpm) for abaloparatide, 5.3 (7.5) for teriparatide, and 1.2 (7.1) for placebo. A similar pattern was observed over subsequent visits. In healthy volunteers, HR increase resolved within 4 hours. The corresponding change in mean supine systolic and diastolic BP 1 hour posttreatment was -2.7/-3.6 mmHg (abaloparatide), -2.0/-3.6 (teriparatide), and -1.5/-2.3 (placebo). The percentage of participants with serious cardiac AEs was similar among groups (0.9%-1.0%). In a post hoc analysis, time to first incidence of MACE + HF was longer with abaloparatide (P = 0.02 vs placebo) and teriparatide (P = 0.04 vs placebo).

Conclusions: Abaloparatide was associated with transient increases in HR and small decreases in BP in postmenopausal women with osteoporosis, with no increase in risk of serious cardiac AEs, MACE, or HF.
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http://dx.doi.org/10.1210/clinem/dgaa450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500469PMC
November 2020

Risks of Hip and Nonvertebral Fractures in Patients With CKD G3a-G5D: A Systematic Review and Meta-analysis.

Am J Kidney Dis 2020 10 9;76(4):521-532. Epub 2020 Jul 9.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.

Rationale & Objective: Disordered mineral metabolism complicates chronic kidney disease (CKD), but the effect of reduced kidney function on fracture risk has not been fully established. We conducted a systematic review and meta-analysis of the risks for hip and nonvertebral fractures in people with CKD. We also investigated the effects of age, sex, and CKD stage.

Study Design: Systematic review and meta-analysis.

Study Population: Adults with CKD glomerular filtration rate (GFR) categories 3a-5D (G3a-G5D) compared with adults without CKD G3a-G5D.

Selection Criteria For Studies: Observational studies.

Data Extraction: Data extraction was conducted by 1 reviewer and checked by a second reviewer.

Analytical Approach: MEDLINE, EMBASE, and Cochrane databases were searched in March 2018 and an update was conducted in November 2019. We used random-effects models to calculate pooled risk estimates and 95% CIs.

Results: 17 studies met the inclusion criteria. We included 13 studies in the hip fracture systematic review and 10 studies in the meta-analysis. Studies reported data from 250,440,035 participants; 5,798,566 with CKD G3a-G5D and 363,410 with hip fractures. 4 studies were included in the nonvertebral fracture analysis, reporting data from 1,396,976 participants; 464,978 with CKD G3a-G5D and 115,284 fractures. Studies reported data from participants aged 18 to older than 90 years. We found a significant increase in fracture risk both for hip (relative risk [RR], 2.36; 95% CI, 1.64-3.39) and nonvertebral fractures (RR, 1.47; 95% CI, 1.15-1.88). For hip fractures, younger patients (<65 years) had higher relative risk (RR, 7.66; 95% CI, 2.76-21.26) than older patients (>65 years; RR, 2.11; 95% CI, 1.41-3.16). Greater GFR loss was associated with higher relative risk for fractures.

Limitations: We could not assess the effects of bone mineral density, biochemical abnormalities, renal osteodystrophy, frailty, falls, or medications on risk for fractures.

Conclusions: Risks for hip and nonvertebral fractures are increased in CKD G3a-G5D. The relative risk of hip fracture is greater in the younger than the older population and increases progressively with loss of GFR. We suggest that fracture prevention should be a consideration in CKD at any age.
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http://dx.doi.org/10.1053/j.ajkd.2020.02.450DOI Listing
October 2020

The senescence-associated secretome as an indicator of age and medical risk.

JCI Insight 2020 06 18;5(12). Epub 2020 Jun 18.

Robert and Arlene Kogod Center on Aging.

Produced by senescent cells, the senescence-associated secretory phenotype (SASP) is a potential driver of age-related dysfunction. We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20-90 years (retrospective cross-sectional) was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60-90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis (prospective longitudinal) or ovarian cancer (prospective case-control) were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes. We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), TNF receptor superfamily member 6 (FAS), osteopontin (OPN), TNF receptor 1 (TNFR1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.
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http://dx.doi.org/10.1172/jci.insight.133668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406245PMC
June 2020

The risk of hip and non-vertebral fractures in type 1 and type 2 diabetes: A systematic review and meta-analysis update.

Bone 2020 08 29;137:115457. Epub 2020 May 29.

Academic Unit of Bone Metabolism, The Mellanby Centre for Bone Research, University of Sheffield, UK. Electronic address:

Background: Diabetes is associated with increased fracture risk but we do not know what affects this risk. We investigated the risk of hip and non-vertebral fractures in diabetes and whether this risk was affected by age, gender, body mass index, diabetes type and duration, insulin use and diabetic complications.

Methods: We selected a previously published review to be updated. MEDLINE, Embase and Cochrane databases were searched up to March 2020. We included observational studies with age and gender-adjusted risk of fractures in adults with diabetes compared to adults without diabetes. We extracted data from published reports that we summarised using random effects model.

Findings: From the 3140 records identified, 49 were included, 42 in the hip fracture analysis, reporting data from 17,571,738 participants with 319,652 fractures and 17 in the non-vertebral fracture review, reporting data from 2,978,487 participants with 181,228 fractures. We found an increase in the risk of fracture in diabetes both for hip (RR 4.93, 3.06-7.95, in type 1 diabetes and RR1.33, 1.19-1.49, in type 2 diabetes) and for non-vertebral fractures (RR 1.92, 0.92-3.99, in type 1 and RR 1.19, 1,11-1.28 in type 2). At the hip, the risk was higher in the younger population in both type 1 and type 2 diabetes. In those with type 2 diabetes, longer diabetes duration and insulin use was associated with an increased risk. We did not investigate the effect of bone density, falls, anti-diabetic drugs and hypoglycemia.

Conclusion: Diabetes is associated with an increase in both hip and non-vertebral fracture risk.
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http://dx.doi.org/10.1016/j.bone.2020.115457DOI Listing
August 2020

Muscle Mass Assessed by the D3-Creatine Dilution Method and Incident Self-reported Disability and Mortality in a Prospective Observational Study of Community-Dwelling Older Men.

J Gerontol A Biol Sci Med Sci 2021 01;76(1):123-130

Department of Nutrition Sciences, University of California, Berkeley.

Background: Whether low muscle mass is a risk factor for disability and mortality is unclear. Associations between approximations of muscle mass (including lean mass from dual-energy x-ray absorptiometry [DXA]), and these outcomes are inconsistent.

Methods: Muscle mass measured by deuterated creatine (D3Cr) dilution and appendicular lean mass (ALM, by DXA) were assessed at the Year 14 Visit (2014-2016) of the prospective Osteoporotic Fractures in Men study (N = 1,425, age 77-101 years). Disability in activities of daily living (ADLs), instrumental ADLs, and mobility tasks was self-reported at the Year 14 visit and 2.2 years later; deaths were centrally adjudicated over 3.3 years. Relative risks and 95% confidence intervals (CI) were estimated per standard deviation decrement with negative binomial, logistic regression, or proportional hazards models.

Results: In age- and clinical center-adjusted models, the relative risks per decrement in D3Cr muscle mass/wgt was 1.9 (95% CI: 1.2, 3.1) for incident self-reported ADL disability; 1.5 (95% CI: 1.3, 1.9) for instrumental ADL disability; and 1.8 (95% CI: 1.5, 2.2) for mobility disability. In age-, clinical center-, and weight-adjusted models, the relative risks per decrement in D3Cr muscle mass was 1.8 (95% CI: 1.5, 2.2) for all-cause mortality. In contrast, lower DXA ALM was not associated with any outcome. Associations of D3Cr muscle mass with these outcomes were slightly attenuated after adjustment for confounding factors and the potentially mediating effects of strength and physical performance.

Conclusions: Low muscle mass as measured by D3Cr dilution is a novel risk factor for clinically meaningful outcomes in older men.
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http://dx.doi.org/10.1093/gerona/glaa111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756711PMC
January 2021

History of alendronate.

Bone 2020 08 11;137:115411. Epub 2020 May 11.

Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK; Mellanby Centre for Bone Research, University of Sheffield, Sheffield, UK.

Alendronate was synthesized in 1970s in a search for inhibitors of calcification. Istituto Gentili investigators identified it as a potent inhibitor of bone resorption and obtained a patent covering its use in the treatment of osteoporosis and other disorders of excessive bone resorption in the 1980s. Merck licensed alendronate in 1988 and its pharmaceutical chemists reformulated it as a sodium salt with good solubility in a tablet that reduced its potential for esophageal irritation. Clinical trials proved that it reduced bone turnover, increased BMD and reduced the risk of vertebral fractures in postmenopausal osteoporotic women. Merck sponsored a large clinical trials that won FDA approval for treatment of osteoporosis in postmenopausal women and showed that it reduced the risk of spine and hip fractures. Its approval in the US in 1995 spurred sales of bone densitometers and BMD testing to screen for low bone mineral density and identify osteoporosis. Bone mass measurement was supported by medical society guidelines and reimbursement by Medicare and other insurers in the USA. A 70 mg weekly instead of 10 mg daily dose of alendronate produced the same effect on BMD and biochemical markers of bone remodelling with greater convenience and reduced potential for upper GI adverse events. Consequently, by 2006, about 30 million prescriptions for alendronate were written annually in the U.S. for about 15% of postmenopausal women in the U.S. Thereafter, publicity about rare but concerning atypical femoral fractures (AFF) and osteonecrosis of the jaw (ONJ) along with the expiry of Merck's patent (in 2008) and cessation of their promotion of alendronate, and a decline in use of densitometry led to a steady slide in its use even among patients for whom the benefits of alendronate far outweigh its potential risks. Nevertheless, in 25 years since its regulatory approval, alendronate has undoubtedly prevented millions of fractures world-wide.
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http://dx.doi.org/10.1016/j.bone.2020.115411DOI Listing
August 2020

The Importance of Muscle Versus Fat Mass in Sarcopenic Obesity: A Re-evaluation Using D3-Creatine Muscle Mass Versus DXA Lean Mass Measurements.

J Gerontol A Biol Sci Med Sci 2020 06;75(7):1362-1368

Research Institute, California Pacific Medical Center, San Francisco.

Background: The combination of sarcopenia and obesity has been associated with physical impairment in older people. However, previous research has relied on assessments of lean mass as a surrogate for muscle mass. We postulate that inaccurate measures of muscle mass may have obscured the role of obesity in sarcopenia and related outcomes. Our aim was to clarify the interactions of muscle and fat with physical performance and adverse outcomes using an accurate measure of muscle mass.

Methods: In a longitudinal study of >1,300 older men (mean age 84 years), we compared a direct measurement of muscle mass (D3 creatine dilution; D3Cr) with an approximation of muscle mass (appendicular lean mass [ALM] by dual-energy x-ray absorptiometry [DXA]) and their associations with measures of physical performance (gait speed, chair stand time) and adverse outcomes (incident injurious falls and mobility problems). We measured percent fat mass by DXA.

Results: Low D3Cr muscle mass was strongly associated with decreased performance and increased risk of adverse outcomes. Increased fat mass had little association after accounting for D3Cr muscle mass. In contrast, DXA ALM was minimally associated with performance or adverse outcomes, and fatness remained associated with both outcomes after accounting for DXA ALM.

Conclusions: When an accurate assessment of muscle mass (rather than lean mass) is used, reduced muscle mass is highly associated with important outcomes and the negative effects of adiposity are minimal, suggesting that obesity has little relevance for the understanding of important adverse health outcomes of sarcopenia in older men.
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http://dx.doi.org/10.1093/gerona/glaa064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302180PMC
June 2020

Walking Speed and Muscle Mass Estimated by the D-Creatine Dilution Method Are Important Components of Sarcopenia Associated With Incident Mobility Disability in Older Men: A Classification and Regression Tree Analysis.

J Am Med Dir Assoc 2020 12 4;21(12):1997-2002.e1. Epub 2020 May 4.

Research Institute, California Pacific Medical Center, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA. Electronic address:

Objectives: It is unknown whether muscle mass measured by the D-creatine dilution method is a superior predictor of incident mobility disability than traditional components of sarcopenia definitions (including grip strength, walking speed, appendicular lean mass). The objective of this study was to determine the relative importance of strength; physical performance; and lean, fat, and muscle mass in predicting incident mobility disability in older men.

Design: Longitudinal cohort study of participants in the Osteoporotic Fractures in Men (MrOS) study.

Setting And Participants: Muscle mass was assessed by D-creatine dilution in 1098 men (aged 83.7 ± 3.7 years). Participants also completed anthropomorphic measures, 6-m walking speed (m/s), grip strength (kg), chair stands (seconds), and dual x-ray absorptiometry appendicular lean mass (ALM), and total body fat percentage. Men self-reported incident mobility disability defined by the development of an inability to complete at least one of walking 2-3 blocks, climbing 10 steps, or carrying 10 lb over 2.2 ± 0.3 years.

Methods: Classification and regression tree analysis was conducted to determine relative variable importance and algorithm cutpoints for predicting incident mobility disability. Given the proximity of walking speed with the primary outcome (mobility disability), analyses were conducted with and without walking speed.

Results: Walking speed followed by DCr muscle mass/weight were the most important variables (variable importance: 53% and 12%, respectively) in the prediction of self-reported incident mobility disability. DCr muscle mass was the most important variable in predicting incident mobility disability when walking speed was excluded, followed by chair stands (variable importance: 35% and 33%, respectively). Body fat percentage, ALM, and grip strength were not selected as nodes in either analysis and had low or negligible variable importance.

Conclusions And Implications: This study has provided valuable insights into the importance of different variables in predicting incident mobility disability in older men. Muscle mass by DCr may be a key tool for predicting the risk of negative outcomes in older adults in the future, particularly in post-acute and long-term care settings.
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http://dx.doi.org/10.1016/j.jamda.2020.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8057698PMC
December 2020

Individual and joint trajectories of change in bone, lean mass and physical performance in older men.

BMC Geriatr 2020 05 5;20(1):161. Epub 2020 May 5.

Oregon Health and Science University, Portland, OR, USA.

Background: Declines in bone, muscle and physical performance are associated with adverse health outcomes in older adults. However, few studies have described concurrent age-related patterns of change in these factors. The purpose of this study was to characterize change in four properties of muscle, physical performance, and bone in a prospective cohort study of older men.

Methods: Using repeated longitudinal data from up to four visits across 6.9 years from up to 4681 men (mean age at baseline 72.7 yrs. ±5.3) participating in the Osteoporotic Fractures in Men (MrOS) Study, we used group-based trajectory models (PROC TRAJ in SAS) to identify age-related patterns of change in four properties of muscle, physical performance, and bone: total hip bone mineral (BMD) density (g/m) and appendicular lean mass/ht (kg/m), by DXA; grip strength (kg), by hand dynamometry; and walking speed (m/s), by usual walking pace over 6 m. We also described joint trajectories in all pair-wise combinations of these measures. Mean posterior probabilities of placement in each trajectory (or joint membership in latent groups) were used to assess internal reliability of the model. The number of trajectories for each individual factor was limited to three, to ensure that the pair-wise determination of joint trajectories would yield a tractable number of groups as well as model fit considerations.

Results: The patterns of change identified were generally similar for all measures, with three district groups declining over time at roughly similar rates; joint trajectories revealed similar patterns with no cross-over or convergence between groups. Mean posterior probabilities for all trajectories were similar and consistently above 0.8 indicating reasonable model fit to the data.

Conclusions: Our description of trajectories of change with age in bone mineral density, grip strength, walking speed and appendicular lean mass found that groups identified by these methods appeared to have little crossover or convergence of change with age, even when considering joint trajectories of change in these factors.
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http://dx.doi.org/10.1186/s12877-020-01560-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201689PMC
May 2020

Zoledronate.

Bone 2020 08 27;137:115390. Epub 2020 Apr 27.

Department of Clinical Medicine, University of Oslo, Oslo, Norway.

Zoledronate is the most potent and most long-acting bisphosphonate in clinical use, and is administered as an intravenous infusion. Its major uses are in osteoporosis, Paget's disease, and in myeloma and cancers to reduce adverse skeletal related events (SREs). In benign disease, it is a first- or second-line treatment for osteoporosis, achieving anti-fracture efficacy comparable to that of the RANKL blocker, denosumab, over 3 years, and it reduces fracture risk in osteopenic older women. It is the preferred treatment for Paget's disease, achieving higher rates of remissions which are much more prolonged than with any other agent. Some trials have suggested that it reduces mortality, cardiovascular disease and cancer, but these findings are not consistent across all studies. It is nephrotoxic, so should not be given to those with significant renal impairment, and, like other potent anti-resorptive agents, can cause hypocalcemia in patients with severe vitamin D deficiency, which should be corrected before administration. Its most common adverse effect is the acute phase response, seen in 30-40% of patients after their first dose, and much less commonly subsequently. Clinical trials in osteoporosis have not demonstrated increases in osteonecrosis of the jaw or in atypical femoral fractures. Observational databases are currently inadequate to determine whether these problems are increased in zoledronate users. Now available as a generic, zoledronate is a cost-effective agent for fracture prevention and for management of Paget's disease, but wider provision of infusion facilities is important to increase patient access. There is a need to further explore its potential for reducing cancer, cardiovascular disease and mortality, since these effects could be substantially more important than its skeletal actions.
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http://dx.doi.org/10.1016/j.bone.2020.115390DOI Listing
August 2020

Denosumab in postmenopausal women with osteoporosis and diabetes: Subgroup analysis of FREEDOM and FREEDOM extension.

Bone 2020 05 10;134:115268. Epub 2020 Feb 10.

School of Medicine, University of California San Francisco, San Francisco, CA, USA.

Purpose: Diabetes and osteoporosis occur frequently in older adults and are both associated with increased fracture risk. Denosumab treatment reduced new vertebral, nonvertebral, and hip fractures over 3 years, with continued low fracture incidence for up to 10 years in postmenopausal women with osteoporosis. However, its effects in diabetic subjects with osteoporosis have not yet been investigated.

Methods: Post hoc analysis of the 3-year, placebo-controlled FREEDOM study and 7-year Extension included postmenopausal women with osteoporosis and diabetes. Effects on BMD, vertebral, and nonvertebral fracture incidence were evaluated.

Results: Of 7808 subjects in FREEDOM, 508 with diabetes received denosumab (n = 266) or placebo (n = 242). Among those, BMD increased significantly with denosumab versus placebo in FREEDOM, and continued to increase during the Extension in long-term (continuing denosumab) and crossover (placebo to denosumab) denosumab subjects. In FREEDOM, denosumab-treated subjects with diabetes had significantly lower new vertebral fracture rates (1.6%) versus placebo (8.0%) (RR: 0.20 [95% CI 0.07-0.61]; p = .001). Nonvertebral fracture incidence was higher with denosumab (11.7%) versus placebo (5.9%) (HR: 1.94 [95% CI 1.00-3.77]; p = .046), although there were fewer hip fractures with denosumab (World Health Organization, 2017 [1]) than placebo (4; nonsignificant). During the first 3 years in FREEDOM Extension, new vertebral and nonvertebral fracture incidences were low in long-term and crossover denosumab diabetic groups (≤6%), consistent with the overall Extension population; yearly nonvertebral fracture incidence was comparable to the FREEDOM placebo group.

Conclusion: Denosumab significantly increased BMD and decreased vertebral fracture risk in subjects with osteoporosis and diabetes. No reduction in nonvertebral fractures was observed.
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http://dx.doi.org/10.1016/j.bone.2020.115268DOI Listing
May 2020

A Pooled Analysis of Fall Incidence From Placebo-Controlled Trials of Denosumab.

J Bone Miner Res 2020 06 2;35(6):1014-1021. Epub 2020 Apr 2.

San Francisco Coordinating Center, California Pacific Medical Center (CPMC), Research Institute and the University of California, San Francisco, CA, USA.

Recent studies suggest that the RANK/RANKL system impacts muscle function and/or mass. In the pivotal placebo-controlled fracture trial of the RANKL inhibitor denosumab in women with postmenopausal osteoporosis, treatment was associated with a lower incidence of non-fracture-related falls (p = 0.02). This ad hoc exploratory analysis pooled data from five placebo-controlled trials of denosumab to determine consistency across trials, if any, of the reduction of fall incidence. The analysis included trials in women with postmenopausal osteoporosis and low bone mass, men with osteoporosis, women receiving adjuvant aromatase inhibitors for breast cancer, and men receiving androgen deprivation therapy for prostate cancer. The analysis was stratified by trial, and only included data from the placebo-controlled period of each trial. A time-to-event analysis of first fall and exposure-adjusted subject incidence rates of falls were analyzed. Falls were reported and captured as adverse events. The analysis comprised 10,036 individuals; 5030 received denosumab 60 mg subcutaneously once every 6 months for 12 to 36 months and 5006 received placebo. Kaplan-Meier estimates showed an occurrence of falls in 6.5% of subjects in the placebo group compared with 5.2% of subjects in the denosumab group (hazard ratio = 0.79; 95% confidence interval 0.66-0.93; p = 0.0061). Heterogeneity in study designs did not permit overall assessment of association with fracture outcomes. In conclusion, denosumab may reduce the risk of falls in addition to its established fracture risk reduction by reducing bone resorption and increasing bone mass. These observations require further exploration and confirmation in studies with muscle function or falls as the primary outcome. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..
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http://dx.doi.org/10.1002/jbmr.3972DOI Listing
June 2020

Red Cell Distribution Width Is a Risk Factor for Hip Fracture in Elderly Men Without Anemia.

J Bone Miner Res 2020 05 19;35(5):869-874. Epub 2020 Mar 19.

San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA.

Red cell distribution width (RDW), routinely assessed as a component of a complete blood count (CBC), quantifies the variation in the size of red blood cells. It increases with age, and increased RDW predicts many aging-related diseases and mortality. However, whether it also predicts hip fracture is unknown. We prospectively evaluated the association between RDW and hip fracture using data from the Osteoporotic Fracture in Men (MrOS) study. RDW was measured in 3635 men (aged 71 to 99 years) along with bone mineral density (BMD) in MrOS. RDW ranged from 11.3% to 32.9% (median 14.0%; interquartile range 13.5% to 14.8%) and was categorized into four groups (≤13.0%, 13.1% to 14.0%, 14.1% to 15.0%, ≥15.1%). Study participants with a hemoglobin level <13.0 g/dL were classified as having anemia. During an average 8.1 years, 164 men suffered hip fractures. The risks of hip fractures increased with increase of RDW category. Furthermore, there was a significant interaction between anemia and RDW: An association between RDW and hip fractures was only observed in participants without anemia. In those without anemia, the relative hazard of hip fractures increased with increases in RDW category: Men in the highest RDW category had a 2.8 times higher risk of hip fractures than men in the lowest group (95% confidence interval 1.1 to 7.1). The risks of all-clinical fractures were also increased along with higher RDW values. Additionally, RDW was significantly associated with the risk of having a fall but not with femoral neck or total hip BMD. In conclusion, RDW and anemia defined by hemoglobin are widely available routine laboratory measurements that together could indicate increased risk of hip fracture, reflecting the neuromuscular effects of aging rather than lower hip BMD. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744556PMC
May 2020

Accelerating the Search for Interventions Aimed at Expanding the Health Span in Humans: The Role of Epidemiology.

J Gerontol A Biol Sci Med Sci 2020 01;75(1):77-86

Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.

Background: Extensive work in basic and clinical science suggests that biological mechanisms of aging are causally related to the development of disease and disability in late life. Modulation of the biological mechanisms of aging can extend both life span and health span in animal models, but translation to humans has been slow.

Methods: Summary of workshop proceedings from the 2018-2019 Epidemiology of Aging Workshop hosted by the Intramural Research Program at the National Institute on Aging.

Results: Epidemiologic studies play a vital role to progress in this field, particularly in evaluating new risk factors and measures of biologic aging that may influence health span, as well as developing relevant outcome measures that are robust and relevant for older individuals.

Conclusions: Appropriately designed epidemiological studies are needed to identify targets for intervention and to inform study design and sample size estimates for future clinical trials designed to promote health span.
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http://dx.doi.org/10.1093/gerona/glz230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175971PMC
January 2020

Can Classification and Regression Tree Analysis Help Identify Clinically Meaningful Risk Groups for Hip Fracture Prediction in Older American Men (The MrOS Cohort Study)?

JBMR Plus 2019 Oct 21;3(10):e10207. Epub 2019 Aug 21.

California Pacific Medical Center Research Institute San Francisco CA USA.

Although the WHO fracture risk algorithm (FRAX) is used to predict fracture, the utility of some simple machine-learning methods, such as classification and regression trees (CARTs) should be evaluated to determine their efficacy in fracture prediction. Follow-up time for the hip fracture analyses of 5977 community-dwelling American men aged ≥65 years old was truncated to 10 years. There were 172 (2.9%) men who had an incident nontraumatic hip fracture. The CARTs were developed using hip BMD and common clinical risk factors as follows: model 1 = using classification with continuous variables of age, total hip BMD, and femoral neck BMD, or together with common clinical risk factors; and model 2 = using classification with continuous variables of age, total hip BMD, femoral neck BMD, FRAX score, osteoporosis by -score at the hip, and common clinical risk factors. The predictive performance of risk models derived from CARTs was compared with the basic classification of FRAX at 3% (basic model). From model 1, discriminators selected by CART were total hip BMD, age, and femoral neck BMD; no other clinical risk factors were selected. From model 2, discriminators selected by CART were FRAX score, femoral neck BMD, and age. Compared with the basic model using only a high-risk group by FRAX ≥3%, no significantly improved predictive performance was demonstrated by model 1 or model 2 as identified by CART with the area under the receiver-operating characteristic curve for each model of 0.714 (95% CI, 0.676 to 0.751) or 0.726 (95% CI, 0.690 to 0.762) versus 0.703 (95% CI, 0.667 to 0.740), respectively. The improved overall net reclassification improvement index was 0.02 (95% CI, -0.04 to 0.08) and 0.05 (95% CI, -0.01 to 0.10), respectively. Although a FRAX category is a good clinical indicator for hip fracture risk, a simple classification by age and BMD may provide an alternative way to estimate a clinical risk level of 3.0%. © 2019 The Authors. is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820460PMC
October 2019

Automated volumetric breast density measures: differential change between breasts in women with and without breast cancer.

Breast Cancer Res 2019 10 28;21(1):118. Epub 2019 Oct 28.

Department of Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Background: Given that breast cancer and normal dense fibroglandular tissue have similar radiographic attenuation, we examine whether automated volumetric density measures identify a differential change between breasts in women with cancer and compare to healthy controls.

Methods: Eligible cases (n = 1160) had unilateral invasive breast cancer and bilateral full-field digital mammograms (FFDMs) at two time points: within 2 months and 1-5 years before diagnosis. Controls (n = 2360) were matched to cases on age and date of FFDMs. Dense volume (DV) and volumetric percent density (VPD) for each breast were assessed using Volpara™. Differences in DV and VPD between mammograms (median 3 years apart) were calculated per breast separately for cases and controls and their difference evaluated by using the Wilcoxon signed-rank test. To simulate clinical practice where cancer laterality is unknown, we examined whether the absolute difference between breasts can discriminate cases from controls using area under the ROC curve (AUC) analysis, adjusting for age, BMI, and time.

Results: Among cases, the VPD and DV between mammograms of the cancerous breast decreased to a lesser degree (- 0.26% and - 2.10 cm) than the normal breast (- 0.39% and - 2.74 cm) for a difference of 0.13% (p value < 0.001) and 0.63 cm (p = 0.002), respectively. Among controls, the differences between breasts were nearly identical for VPD (- 0.02 [p = 0.92]) and DV (0.05 [p = 0.77]). The AUC for discriminating cases from controls using absolute difference between breasts was 0.54 (95% CI 0.52, 0.56) for VPD and 0.56 (95% CI, 0.54, 0.58) for DV.

Conclusion: There is a small relative increase in volumetric density measures over time in the breast with cancer which is not found in the normal breast. However, the magnitude of this difference is small, and this measure alone does not appear to be a good discriminator between women with and without breast cancer.
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http://dx.doi.org/10.1186/s13058-019-1198-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819393PMC
October 2019

Association of change in muscle mass assessed by D -creatine dilution with changes in grip strength and walking speed.

J Cachexia Sarcopenia Muscle 2020 02 17;11(1):55-61. Epub 2019 Oct 17.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.

Background: Muscle mass declines with age. However, common assessments used to quantify muscle mass are indirect. The D -creatine (D Cr) dilution method is a direct assessment of muscle mass; however, longitudinal changes have not been examined in relation to changes in other measures of muscle mass, strength, and performance.

Methods: A convenience sample of 40 men from the Osteoporotic Fractures in Men Study (mean age = 83.3 years, standard deviation = 3.9) underwent repeat assessment of D Cr muscle mass, dual-energy X-ray absorptiometry (DXA) lean mass, grip strength, and walking speed at two time points approximately 1.6 years apart (2014-2016). One-sample t-tests and Pearson correlations were used to examine changes in DXA total body lean mass, DXA appendicular lean mass/height , DXA appendicular lean mass/weight, D Cr muscle mass, D Cr muscle mass/weight, grip strength, walking speed, and weight.

Results: D -creatine muscle mass, D Cr muscle mass/weight, grip strength, and walking speed all significantly declined (all P < 0.01). The change in DXA measures of lean mass was moderately correlated with changes in D Cr muscle mass. There was no significant correlation between the change in DXA measures of lean mass and change in walking speed (all P > 0.05). The change in D Cr muscle mass/weight was moderately correlated with change in walking speed (r = 0.33, P < .05). The change in grip strength was weakly correlated with the change in DXA measures of lean mass and D Cr muscle mass (r = 0.19-0.32).

Conclusions: The results of our study provide new insights regarding the decline in muscle strength and D Cr muscle mass. The D Cr method may be a feasible tool to measure declines in muscle mass over time.
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http://dx.doi.org/10.1002/jcsm.12494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015254PMC
February 2020

Association Between Drug Treatments for Patients With Osteoporosis and Overall Mortality Rates: A Meta-analysis.

JAMA Intern Med 2019 Nov;179(11):1491-1500

Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco.

Importance: Previous studies have reported that drug treatments, particularly treatment with bisphosphonates, is associated with reduced overall mortality rates in addition to decreased fracture risk. If so, drug treatments should be recommended for this reason alone, regardless of a patient's risk of fracture.

Objective: To assess whether randomized clinical trials demonstrate that treatment with bisphosphonates, particularly zoledronate, is associated with reduced mortality rates.

Data Sources: Science Direct, MEDLINE, Embase, and the Cochrane Library were searched for randomized placebo-controlled clinical trials of drug treatments for osteoporosis published after 2009 and published or in press before April 19, 2019. Conference abstracts from annual osteoporosis society meetings were also included in the search.

Study Selection: Included studies were clinical trials that (1) were randomized and placebo-controlled; (2) studied drug treatments with proven antifracture efficacy; (3) used agents at the approved dose for treatment of osteoporosis; and (4) had a duration of 1 year or more. Abstracts from the literature searches were reviewed for inclusion and exclusion criteria, and mortality rate data were abstracted from the article by 1 researcher and validated by a second. A total of 2045 records were screened; 38 (1.8%) were included in the meta-analyses.

Data Extraction And Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist was followed for abstracting data and assessing data quality and validity. Data were pooled using random-effects models, and between-study variability was assessed using the I2 index. The risk of bias for each study was assessed, and funnel plots and Egger and Begg statistics were used to evaluate publication bias.

Main Outcomes And Measures: Associations of all drug treatments, particularly bisphosphonate and zoledronate treatments, with overall mortality.

Results: Of 38 clinical trials that included 101 642 unique participants, 38 were included in the meta-analyses of all drug treatments (45 594 participants randomized to placebo; 56 048 to treatment); 21 clinical trials, of bisphosphonate treatments (20 244 participants randomized to placebo; 22 623 to treatment); and 6 clinical trials, of zoledronate treatments (6944 participants randomized to placebo; 6926 to treatment). No significant association was found between all drug treatments for osteoporosis and overall mortality rate (risk ratio [RR], 0.98; 95% CI, 0.91-1.05; I2 = 0%). Clinical trials of bisphosphonate treatment (RR, 0.95; 95% CI, 0.86-1.04) showed no significant association with overall mortality. Also, clinical trials of zoledronate treatment (RR, 0.88; 95% CI, 0.68-1.13) showed no association with overall mortality rate; however, evidence existed for heterogeneity of the results (I2 = 48.2%).

Conclusions And Relevance: Results of this meta-analysis suggest that bisphosphonate treatment may not be associated with reduced overall mortality rates in addition to decreased fracture risk and should only be recommended to reduce fracture risk. Additional trials are needed to clarify whether treatment with zoledronate reduces mortality rates.
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http://dx.doi.org/10.1001/jamainternmed.2019.2779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704731PMC
November 2019
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