Evidence-Based Criteria for Sarcopenia with Clinically Important Weakness

A recent conference sponsored by the Biomarkers Consortium of the Foundation of the National Institutes of Health (FNIH) brought together representatives from academia, health professions organizations, the private sector, the National Institutes of Health (NIH), and the Food and Drug Administration (FDA) to review and discuss new preliminary evidence for the diagnosis of sarcopenia with clinically important weakness. Sarcopenia has been defined as age-related loss of muscle mass and strength. Numerous epidemiologic studies have shown that various measures of sarcopenia are important predictors of disability and mortality, although the relationship between muscle mass and outcomes is not always consistent (1–5). In recent years, multiple pathways that influence muscle growth have been elucidated and have led to promising new therapeutic opportunities to prevent or treat sarcopenia (6). Development of these novel molecules for clinical use has been impeded by the lack of consensus about criteria for case findings, as well as appropriate outcome measures. Two working groups have previously proposed guidelines for the definition of sarcopenia based on expert opinion (7,8). However, no evidence- based consensus guidelines for the diagnosis of clinically important sarcopenia have been published.

Based on this perceived need, starting in 2008, the FNIH sponsored a consortium of investigators who pooled individual subject level data from existing data resources to develop evidence-based criteria for the definition of clinically significant weakness and low muscle mass. The consortium worked from a conceptual framework assuming that one of the main causes of mobility disability is weakness and one of the causes of weakness is low lean mass. Between 2009 and 2012, the consortium analyzed data on over 31,000 older adults representing multiple cohort studies and clinical trials.

At the conference, representatives from participating organizations initially spoke about their priorities and needs regarding the development of this relatively new area of aging. Subsequently, the Project investigators presented the data sets, explained their analytical strategies, and summarized their main findings. Primary indicators, which were selected based on prior literature, models of causation, and feasibility of use in clinical practice, included objective measures of physical performance, grip strength, and body composition by dual energy radiographic absorptiometry. Using a variety of analytical techniques, with a focus on classification and regression tree analyses, the investigators developed models using thresholds for reduced mobility performance as a gold standard to derive cut points for reduced strength and then used strength to derive cut points for reduced muscle mass. These models and cut points were then subjected to numerous sensitivity analyses.

Breakout groups, panels, and surveys were used to obtain feedback from all conference attendees on the concerns of the sponsoring organizations and on the data-based processes. Overall, there was strong support for using mobility and strength testing as the primary gold standard and relevant outcome for problems of muscle weakness and low muscle mass. Most conference participants felt that low muscle mass without weakness was not clinically relevant. Although the measurement of grip strength was acknowledged to be highly feasible in clinical settings, some participants recommended that grip strength serve only as a screen for clinically important weakness, followed by more detailed testing of lower extremity strength. Many participants felt that further data for evidence-based criteria are needed from more disabled and chronically ill populations than were available for study in the Project data sets. Based on this feedback, the investigators are pursuing further analyses, exploring potential new funding, and seeking investigative partners with relevant data sets. A summary of conference recommendations will be circulated to interested professional organizations for written commentary. The conference agenda and the slides of some of the speakers can be viewed at http://biomarkersconsortium.org/sarcopenia_pdfs.html.

APPENDIX

Members of the Sarcopenia Consortium of the Foundation of the National Institutes of Health (in alphabetical order):

1. Dawn Alley, PhD, site PI, Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD

2. Peggy M. Cawthon, PhD, site PI, California Pacific Medical Center, Research Institute, San Francisco, California

3. Tien Dam, MD, site PI, Assistant Professor of Clinical Project Medicine Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY

4. Chanda Dhutta, PhD, National Institute on Aging (NIA) Advisor to Sarcopenia Project

5. Luigi Ferrucci, MD, PhD, Advisory Board, Scientific Director director, National Institute on Aging, Bethesda, Maryland

6. Maren Fragala,PhD, site co-investigator, University of Connecticut Health Center and University of Central Florida,

7. Jack Guralnik, MD, PhD, Advisory Board Professor of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland

8. Judy Hannah, PhD, Adviser to sarcopenia project

9. Tammy Harris, MD, site PI, Section Chief, Interdisciplinary Studies of Aging, Laboratory of Population Science Intramural Research Program, National Institute on Aging, National Institutes of Health, Bethesda, Maryland

10. Anne Kenny, site PI, Professor, Center on Aging University of Connecticut Health Center, Farmington, Connecticut

11. Stephen Kritchevsky, PhD, Advisory Board Professor, Wake Forest University School of Medicine, Winston Salem, North Carolina

12. Douglas P. Kiel, MD, MPH, Advisory Board and site co-investigator Senior scientist, Hebrew Senior Life Institute for Aging Research, Professor of Medicine, Harvard Medical School, Boston, Massachusetts

13. Robert McLean DSc, site PI Assistant scientist II, Hebrew Senior Life Institute for Aging Research Assistant Professor of Medicine, Harvard Medical School; Boston, Massachusetts

14. Katherine Peters, MS, Statistician, California Pacific Medical Center, Research Institute, San Francisco, California

15. Dragos Roman, MD, FDA adviser to sarcopenia conference, FDA, Rockvilled, Maryland

16. Carmen Castaneda-Sceppa, MD, PhD, Bouve College of Health Sciences Northeastern University, Boston, Massachusetts

17. Michelle Shardell, PhD, biostatistician, University of Maryland School of Medicine, site PI

18. Stephanie Studenski, Project PI, University of Pittsburgh School of Medicine and VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania

19. Maria Vassileva, PhD, Scientific Program manager FNIH, Bethesda, Maryland

Data contributed to this project were derived from the following studies, which were generously supported by funding as described:

Study of Osteoporotic Fractures (SOF): the SOF is supported by National Institutes of Health funding. The NIA provides support under the following grant numbers: R01AG005407, R01AR35582, R01AR35583, R01AR35584, R01AG005394, R01AG027574, and R01AG027576.

The Osteoporotic Fractures in Men Study is supported by NIH funding. The following institutes provide support: the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the NIA, the National Center for Research Resources, and NIH Road Map for Medical Research under the following grant numbers: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01- AG027810, and UL1 RR024140.

Framingham Heart Study: Supported by funding from the NIH, including the—National Heart, Lung, and Blood Institute (Grant Number N01-HC-25195) and the National Institute of Arthritis Musculoskeletal and Skin Diseases and National Institute on Aging (Grant Number R01 AR/AG41398).

Kenney clinical trials: supported by the NIH and other sources as follows: MO1-RR06192, R01-AG18887, NNG04GK63G; 5P60AG13631; Patrick and Catherine Donaghue Medical Research Foundation; American Federation on Aging, Paul Beeson Faculty Scholar Program.

Boston Puerto Rican Health Study: P01AG023394 and P50HL105185.

Rancho Bernardo Study: supported by the NIH through the National Institute on Aging Grants AG07181 and AG028507 and the National Institute of Diabetes and Digestive and Kidney Diseases, Grant DK31801).

InCHIANTI: Italian Ministry of Health and USA. NIA supported the InCHIANTI Study as a targeted project (ICS 110.1 RS97.71; Contracts N01-AG-916413, N01-AG-821336, 263 MD 9164 13, and 263 MD 821336; and the NIA Intramural Research Program).

Aging and Body Composition (Health ABC): NIA Contracts N01-AG-6-2101; N01-AG-6-2103; N01-AG- 6-2106; this research was supported in part by the Intramural Research Program of the National Institute on Aging.

AGES-Reykjavik: National Institutes of Health (N01- AG-12100); National Institute on Aging Intramural Research Program; Hjartavernd (Icelandic Heart Association); Althingi (the Icelandic Parliament).