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J Frailty Aging. Author manuscript; available in PMC 2015 September 14. Published in final edited form as: J Frailty Aging. 2014 ; 3(4): 199–204. doi:10.14283/jfa.2014.24.
DESIGNING DRUG TRIALS FOR SARCOPENIA IN OLDER ADULTS WITH HIP FRACTURE – A TASK FORCE FROM THE INTERNATIONAL CONFERENCE ONFRAILTY AND SARCOPENIA RESEARCH (ICFSR)
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B. VELLAS1,2, R. FIELDING3, R. MILLER4, Y. ROLLAND1, S. BHASIN5, J. MAGAZINER6, and H. BISCHOFF-FERRARI7 ON BEHALF OF THE ICFSR TASK FORCE MEMBERS 1Centre
Hospitalier Universitaire de Toulouse, Toulouse, France 2Inserm UMR1027, Université de Toulouse, Toulouse, France 3Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA 4Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Raleigh-Durham, NC, USA 5Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 6Department of Epidemiology & Public Health Director, University of Maryland School of Medicine, Baltimore, MD, USA 7Department of Geriatrics and Aging Research, University of Zurich, Zurich, Switzerland
Abstract Author Manuscript Author Manuscript
In May 2012, a Sarcopenia Consensus Summit was convened by the Foundation of the National Institutes of Health (FNIH), National Institute of Aging (NIA), and the U.S. Food and Drug Administration (FDA); and co-sponsored by five pharmaceutical companies. At this summit, sarcopenia experts from around the world worked to develop agreement on a working definition of sarcopenia, building on the work of previous efforts to generate a consensus. With the ultimate goal of improving function and independence in individuals with sarcopenia, the Task Force focused its attention on people at greatly increased risk of muscle atrophy as a consequence of hip fracture. The rationale for looking at this population is that since hip fracture is a recognized condition, there is a clear regulatory path forward for developing interventions. Moreover, patients with hip fracture may provide an appropriate population to advance understanding of sarcopenia, for example helping to define diagnostic criteria, develop biomarkers, understand the mechanisms that underlie the age-related loss of muscle mass and strength, and identify endpoints for clinical trials that are reliable, objective, and clinically meaningful. Task Force members agreed that progress in treating sarcopenia will require strengthening of partnerships between academia, industry, and government agencies, and across continents to reach consensus on diagnostic criteria, optimization of clinical trials design, and identification of improved treatment and preventive strategies. In this report, the main results of the Task Force discussion are presented.
Corresponding author: Bruno Vellas, MD. Gérontopôle, CHU Toulouse; Service de Médecine Interne et Gérontologie Clinique. 170 Avenue de Casselardit, 31059 Toulouse, France. Phone: +33 (0)5 6177-6425; Fax: +33 (0)5 6177-6475. [email protected]. Conflicts of interests: The TF cost was financed by the ICFSR conference and registration fees
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Keywords Sarcopenia; hip fracture; clinical trials; skeletal muscle; aging
Introduction
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As people are living longer, sarcopenia - the age related loss of muscle mass and strength is becoming increasingly prevalent as a cause of disability and loss of independence. Developing treatments for sarcopenia, however, faces challenges on multiple fronts. Some people consider sarcopenia a part of normal aging rather than a condition requiring intervention. In addition, regulatory and commercial paths for sarcopenia treatments are untrodden, in part because of the lack of consensus on a definition of sarcopenia. Defining sarcopenia as a recognized condition or a manifestation of a recognized condition, and developing diagnostic criteria for the condition are necessary prerequisites for gaining regulatory approval of therapeutic products for this condition. In May 2012, a Sarcopenia Consensus Summit was convened by the Foundation of the National Institutes of Health (FNIH), National Institute of Aging (NIA), and the U.S. Food and Drug Administration (FDA); and co-sponsored by five pharmaceutical companies. At this summit, sarcopenia experts from around the world worked to develop agreement on a working definition of sarcopenia (1), building on the work of previous efforts to generate a consensus (2, 3). While progress was made towards developing a better understanding of sarcopenia, a consensus definition remains elusive.
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Hip fracture is universally accepted as a recognized condition, and it is understood that prefracture and post-fracture muscle loss compromise functional capacity. Moreover, hip fracture increases risk of institutionalization (15–35% may be institutionalized), risk of falls, and mortality (18–33% die within 1 year). Thus, a task force of experts in sarcopenia met on March 12, 2014 in Barcelona, Spain, at the International Conference on Frailty and Sarcopenia Research (ICFSR) to explore whether using hip fracture as the diagnosed condition in drug trials could represent a path forward toward achieving regulatory approval for sarcopenia treatments in older adults. The Task Force was convened by the Global Aging Research Network (GARN), a collaboration of the International Association of Gerontology and Geriatrics (IAGG).
Change in body composition and function after hip fracture Author Manuscript
The Baltimore Hip Studies (BHS) have been conducted for over 25 years with the goal of identifying, developing, and evaluating strategies to optimize recovery from hip fracture. Analysis of data from the BHS have shown significant decreases in total body mass, lean mass, and bone mineral density were observed 10 days to 2 months following hip fracture (4, 5). Sarcopenia, defined as appendicular lean mass normalized for height, was found in about 35% of women at baseline (3–10 days after hip fracture), increased to over 50% at 2 months, and increased further up to 12 months post-fracture (6). Patients also experience substantial functional consequences such that for patients functioning independently before fracture, a large percentage remain unable to climb 5 stairs, get in and out of the bath or on
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and off the toilet 12 months post-fracture (7). In another study testing the ability of subjects to walk 300 meters in 6 minutes, only 4% of hip-fracture patients were able to walk at this level at 2 months, and even by 12 months only 16% had achieved this level of mobility (8, 9). Hip fracture is a multi-faced problem requiring multi-domain interventions with different strategies addressing different impairments at different stages of the recovery process. However, researchers are only beginning to understand the optimal way of treating patients at different stages (including preventive approaches pre-fracture).
Diagnostic criteria for sarcopenia in older adults with hipfracture
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The loss of mobility imposed by hip fracture results in sarcopenia characterized by declining muscle mass, deficiencies in strength and power, functional limitations and eventually, disability. Different diagnostic criteria have been proposed for sarcopenia (2, 3, 10–12), but the field has yet to reach consensus on whether diagnosis should be based on muscle mass, strength, or functional limitations. In addition, the timing of the diagnosis relative to the injury is important. Following an acute injury, pain and delirium can complicate the diagnostic process. If surgery has been performed, post-surgical recommendations for recovery may range from bed rest to varying periods of partial weight-bearing exercise. These different management strategies, as well as co-morbidities and limited mobility, particularly among the very old, also influence the ability to diagnose sarcopenia.
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The prevalence of sarcopenia depends on how the condition is defined. For example, using Dual-Energy X-ray Absorptiometry (DXA) scanning to determine appendicular lean mass in 340 women 2–4 weeks following hip fracture, Di Monaco et al found that 58% were sarcopenic (13). In contrast, a study using bioelectrical impedance analysis (BIA) to calculate whole-body skeletal muscle mass in a hip fracture patients found that 71% were sarcopenic (14). Anthropometric measures (height, weight, sex) have also been used to predict muscle mass (15). Table 1 summarizes the advantages and disadvantages of different methods for diagnosing sarcopenia. Task force members advocated for testing the various definitions of sarcopenia against an important endpoint, such as falls. Since functional measures are the most clinically relevant, basing a trial on muscle mass could be problematic; however, if muscle mass and functional measures prove to be equivalent predictors of falls, muscle mass could be considered a more reliable and objective endpoint.
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Targeting hip fracture patients for sarcopenia clinical trials When to begin intervention depends on the goals of intervention. One argument in favor of intervening shortly after hip fracture occurs is that muscle loss may occur early after hip fracture. Comparing the fractured vs. non-fractured legs, at two months post-fracture the fractured leg shows less normal density muscle, more low-density muscle, and high intermuscular adipose tissue. In addition, the period of greatest risk for a subsequent fall and second fracture (16), as well as the greatest risk of mortality occurs close to the time of
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fracture (17). Thus, if the goal is to minimize muscle loss and reduce falls, intervention should begin early. However, a recent home-based exercise intervention program (8) found that when subjects started the intervention about two months post-fracture, there was no significant difference between the intervention and control arms in terms of functional measures even 12 months post-fracture. In another study where a home-based exercise intervention program was started approximately 9 months post-fracture, there was a modest improvement in function 6 months following randomization (18). Thus if the aim is to demonstrate functional improvement, there may be a benefit from waiting until the period of high risk has passed.
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Later studies may also be more likely to involve home-based interventions. Later studies would also be less likely to enroll subjects at high risk of adverse outcomes in the early stages. From the point of view of sponsors conducting a study, there is a fine balance between successful conduct of the study and generalizability. On the one hand, excluding subjects unlikely to benefit or at high risk of adverse events improves the likelihood of a successful trial. On the other hand there has recently been increased attention from regulatory agencies on the need to enroll representative populations (18). Thus, for example, in the Orwig study, only 19% of the 1276 patients identified were eligible for the study. Excluded were those with prefracture nursing home residency (24%), prefracture history of dementia (13%), cardiac disease (12%) or orthopedic hardware in the contralateral hip (10%). In Latham et al, only 15% of 1546 assessed subjects were enrolled. Many subjects refused to participate, died, or could not be reached by the study coordinators. Inclusion rates of only 15–19% raise doubts about the applicability of the results to real-life populations.
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Trial design issues The Task Force discussed various trial design issues that must be considered. These are summarized below: Inpatient or outpatient study This may vary depending on where the study will be conducted. In the United States, the typical length of hospital stay following hip fracture is about 5 days, followed by discharge to a rehabilitation facility; whereas in Europe patients typically are hospitalized longer. Suggested inclusion criteria (Table 2).
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moderate degree of ADL impairment and mobility limitation (e.g. difficulty or dependence in two or more basic, instrumental or mobility activities).
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presence of the condition (i.e., hip fracture) using objective and precise measures. Need to operationalize the indication so that it can be ascertained accurately and reliably using both self-reported and performance based measures.
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Residence in community or assisted living preferred since institutionalized patients tend to have more comorbidities.
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Should sarcopenia be an eligibility criteria? Arguments for and against were presented;.
Suggested exclusion criteria:
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Subjects who are unlikely to respond, will respond differently, or may be at risk of adverse events.
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Subjects who were unable to walk without human assistance before fracture as well as those with limiting neuromuscular conditions that my affect mobility or physical function.
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Severe cognitive deficits, severe depression, progressive neurologic disease or previous stroke.
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Comorbid conditions that could affect response to treatment or compromise the safety of the treatment, e.g. cancer, anemia, terminal illness, end-stage renal disease requiring dialysis, some cardiovascular conditions such as recent myocardial infarction, acute coronary syndrome or stroke; organ dysfunction (with established cutoffs for relevant measures).
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Marked obesity
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Currently using other drugs that may affect drug metabolism or response.
Drug specific exclusions:
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For trials of promyogenic drugs, there may be an increased risk of cardiovascular disease especially in older adults with multiple co-morbid conditions. Therefore, individuals with certain cardiovascular conditions or those at high risk of cardiovascular events may be excluded.
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For trials of androgens and selective androgen receptor modulators (SARM) exclude those with conditions that may be affected by androgens (e.g., those with prostate cancer or breast cancer, or with elevated prostate specific antigen [PSA] or International prostate symptom score [IPSS] or hematocrit >50%, or untreated severe obstructive sleep apnea %), as well as those with conditions that may affect the response to androgens (20).
Questionable exclusions: •
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Osteoporosis and vitamin D deficiency occur are highly prevalent in hip fracture patients. Since Vitamin D may affect physical function especially at very low levels, consider excluding those with severe deficiency and replacing Vitamin D in others with a dose that would raise 25(OH)D into normal range, then monitor levels.
Timing of intervention following hip fracture The suggestion was made to take a middle ground (4–12 weeks after fracture) since in first four weeks multiple medical and post-surgical issues may complicate recovery. Also, most patients are involved in rehab programs at this early stage.
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Randomization and stratification
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Randomization is necessary to ensure that groups are comparable at baseline and to reduce selection bias. However, hip fracture patients often have a high prevalence of comorbidities, necessitating other allocation strategies to minimize the risk of imbalance between the treatment arms. Further, in multi-domain trials that combine pharmaceutical treatment with physical activity, decisions must be made whether to allow physical activity to distribute randomly or to control physical activity so that different drug treatment arms have a similar “dose” of physical activity. Controlling physical activity offers the advantage of smaller sample sizes but introduces numerous challenges with regard to implementation of the intervention and ensuring adherence to the program. Trial duration
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Shorter durations result in reduced costs and lower attrition; however, longer duration trials may be needed to acquire information about safety and efficacy. Trials of 6–12 months may provide the best trade-off. For example, trials of testosterone and exercise have shown improvements in muscle mass, strength, and function over a 6 month duration (20–23). Efficacy outcomes - Primary outcome measures should assess an aspect of the condition that is clinically meaningful, can be measured safely, reproducibly, and precisely. These measures may be performance based or self-reported, each type with advantages and disadvantages (24). Therefore, inclusion of both types of measures would provide a more comprehensive assessment of efficacy. Performance based measures should be aligned with self-reported measures and the subjects’ functional limitations and symptoms. For example, walking speed is an excellent integrated measure of physical function and mobility disability. It can be measured precisely and reproducibly, is responsive to intervention, predictive of health outcomes, and Minimal Clinically Important Differences (MCIDs) are known (25, 26). Gait speed measures can utilize a short or long walk and can also be incorporated into composite measures such as the Short Physical Performance Battery (SPPB) and Physical Functional Performance Test (PFP), as well as selfreported measures such as the Physical Functioning scale (PF-10). Self-reported measures can include specific questions that allow for dichotomous analysis.
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Measures should have a plausible link to the mechanism of action. For example, promyogenic anabolic therapies are expected to result in increased muscle mass and strength, leading to improved physical function, increased independence, improved health perceptions, and improvements in other health-related outcomes. Therefore, trials of such drugs should include muscle mass and performance as outcomes, but will also need to show that the intervention results in meaningful improvement in patient’s life.
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Maintaining independence is of primary importance in the lives of hip fracture patients. More than half of patients with hip fracture lose their ability to function independently, primarily because of mobility limitations. This often results in nursing home placement and also increases health care costs (7).
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The Activity Measure for Post-Acute Care (AM-PAC) is a measure of disability in activities of daily living, mobility and social functioning. The MCID is known and is related to outcomes including mortality (18).
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Other outcomes: pain, mood and affect, well-being, falls, fall-related injuries, hospitalizations, death
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Biomarkers of muscle mass and strength are necessary and useful to power a trial, but insufficient to establish efficacy (7, 23, 27).
Imaging and biomarkers for sarcopenia trials in olderadults with hip fracture
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Biomarkers for sarcopenia are used not only diagnostically but also to track disease progression and response to therapy. As with their use in diagnosis, each method has advantages and disadvantages. For example, CT precisely measures direct physical properties of muscle but exposes patients to radiation. In an elderly individual, CT is likely to show loss of normal density muscle, increased low density muscle, increased myocellular lipid accumulation and intermuscular fat. MRI provides similar information and has the additional capacity for multiple slice acquisition, however it comes with a higher cost and higher subject burden. DXA assesses both bone and soft tissue density with high precision and reliability but is affected by hydration levels and does not allow for assessment of the fractured limb where the magnitude of muscle and strength loss may be greater than in the unfractured limb. Additional non-invasive measures, including ultrasound, bioelectrical impedance, assessment of serum metabolites (28) and genomic studies offer other approaches to assessing muscle mass, although so far, none of these assessments has the sensitivity to be used as a primary outcome in clinical trials. Nonetheless, incorporating biomarkers into trials offers the potential to provide important information, e.g. to show target engagement in phase 1b trials; as well as validation of the approaches for use in future trials.
Intervention: treatment and prevention
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The Task Force addressed whether trials should focus on prevention or treatment. For promyogenic drugs, a prevention trial would probably be unrealistic given the huge sample size required, the uncertainty about efficacy, and the lack of knowledge about long-term safety. Moreover, a prevention trial would require identification of individuals at risk, which is not at this point well defined. However, a treatment trial of a pro-myogencic drug in patients with hip fracture would provide a more favorable risk/benefit ratio. The primary endpoint could be, for example, improved function, with prevention of falls a secondary endpoint with functional significance. Similar endpoints have been incorporated into interventional studies discussed earlier, such as those conducted as part of the Baltimore Hip Studies. Prevention trials are also underway. For example, DO-HEALTH is a clinical trial taking place in 7 European cities to determine whether combining exercise with vitamin D and omega-3 fatty acids will prevent disease in older age. Over 2,000 seniors have been enrolled, including subjects classified as pre-frail and those with a history of falls. The five primary J Frailty Aging. Author manuscript; available in PMC 2015 September 14.
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endpoints include incidence of non-vertebral fractures and functional decline, as well as endpoints related to cardiovascular and brain health and immunity. All clinical endpoints are supported by biomarker studies.
Conclusions
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With the ultimate goal of improving function and independence in individuals with sarcopenia, the Task Force focused its attention on people at greatly increased risk of muscle atrophy as a consequence of hip fracture. The rationale for looking at this population is that since hip fracture is a recognized condition, there is a clear regulatory path forward for developing interventions. Moreover, patients with hip fracture may provide an appropriate population to advance understanding of sarcopenia, for example helping to define diagnostic criteria, develop biomarkers, understand the mechanisms that underlie the age-related loss of muscle mass and strength, and identify endpoints for clinical trials that reliable, objective, and clinically meaningful. Task Force members agreed that progress in treating sarcopenia will require strengthening of partnerships between academia, industry, and government agencies, and across continents to reach consensus on diagnostic criteria, optimization of clinical trials design, and identification of improved treatment and preventive strategies.
Acknowledgments
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Members of the ICFSR Task Force: Gabor Abellan van Kan (Toulouse, France), Lisa J. Bain (Elverson, USA), Cécile Bonhomme (Torcé, France), Denis Breuillé (Lausanne, Switzerland), Francesca Cerreta (London, United Kingdom), Alfonso Cruz-Jentoft (Madrid, Spain), Dominique Dardevet (Ceyrat, France), Justine Davies (London, United Kingdom), Susanna Del Signore (Chilly Mazarin, France), Stephen Donahue (Tarrytown, USA), Philippe Guillet (Chilly Mazarin, France), Michaela Hoehne (Lutry, Switzerland), Makoto Kashiwa (Saitama, Japan), Valerie Legrand (Nanterre, France), Fady Malik (San Francisco, USA), Erwin Meijer (Schiphol Airport, The Netherlands), Marco Pahor (Gainesville, USA), Robert Pordy (Tarrytown, USA), Leocadio Rodriguez-Manas (Madrid, Spain), Daniel Rooks (Cambridge, USA), Fariba Roughead (Minnetonka, USA), Klaudius Siegfried (Langen, Germany), Alan J Sinclair (Bedfordshire, United Kingdom), Elisabeth Stöcklin (Wurmisweg, Switzerland), Laszlo Tanko (Basel, Switzerland), Sjors Verlaan (Schiphol Airport, The Netherlands), Sander Wijers (Wageningen, The Netherlands).
References
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1. Brotto M. Lessons from the FNIH-NIA-FDA sarcopenia consensus summit. IBMS Bonekey. 2012; 9:210. [PubMed: 23741531] 2. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010; 39:412–423. [PubMed: 20392703] 3. Fielding RA, Vellas B, Evans WJ, et al. Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J Am Med Dir Assoc. 2011; 12:249–256. [PubMed: 21527165] 4. D’Adamo CR, Hawkes WG, Miller RR, et al. Short-term changes in body composition after surgical repair of hip fracture. Age Ageing. 2014; 43:275–280. [PubMed: 24370941] 5. Fox KM, Magaziner J, Hawkes W, Yu Yahiro J, Hebel JR, Zimmerman SI, Holden L, Michael R. Loss of Bone Density and Lean Body Mass After Hip Fracture. Osteoporosis Intl. 2000; 11(1):31– 35. 6. Chiles N, Alley D, Hawkes W, Orwig D. Sarcopenia and Functional Recovery After Hip Fracture. Gerontologist. 2011; 51:230.
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7. Magaziner J, Hawkes W, Hebel JR, et al. Recovery from hip fracture in eight areas of function. J Gerontol A Biol Sci Med Sci. 2000; 55:M498–507. [PubMed: 10995047] 8. Orwig DL, Hochberg M, Yu-Yahiro J, et al. Delivery and outcomes of a yearlong home exercise program after hip fracture: a randomized controlled trial. Arch Intern Med. 2011; 171:323–331. [PubMed: 21357809] 9. Magaziner J. Baltimore Hip Studies, Cohort 4. Unpublished Data. 10. Baumgartner RN, Koehler KM, Gallagher D, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol. 1998; 147:755–763. [PubMed: 9554417] 11. Delmonico MJ, Harris TB, Lee JS, et al. Alternative definitions of sarcopenia, lower extremity performance, and functional impairment with aging in older men and women. J Am Geriatr Soc. 2007; 55:769–774. [PubMed: 17493199] 12. Newman AB, Kupelian V, Visser M, et al. Sarcopenia: alternative definitions and associations with lower extremity function. J Am Geriatr Soc. 2003; 51:1602–1609. [PubMed: 14687390] 13. Di Monaco M, Vallero F, Di Monaco R, Tappero R. Prevalence of sarcopenia and its association with osteoporosis in 313 older women following a hip fracture. Arch Gerontol Geriatr. 2011; 52:71–74. [PubMed: 20207030] 14. Fiatarone Singh MA, Singh NA, Hansen RD, et al. Methodology and baseline characteristics for the Sarcopenia and Hip Fracture study: a 5-year prospective study. J Gerontol A Biol Sci Med Sci. 2009; 64:568–574. [PubMed: 19228788] 15. Mitchell SJ, Hilmer SN, Kirkpatrick CM, et al. Estimation of lean body weight in older women with hip fracture. J Nutr Health Aging. 2012; 16:188–192. [PubMed: 22323357] 16. Nymark T, Lauritsen JM, Ovesen O, et al. Short time-frame from first to second hip fracture in the Funen County Hip Fracture Study. Osteoporos Int. 2006; 17:1353–1357. [PubMed: 16823545] 17. Haentjens P, Magaziner J, Colon-Emeric CS, et al. Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med. 2010; 152:380–390. [PubMed: 20231569] 18. Latham NK, Harris BA, Bean JF, et al. Effect of a home-based exercise program on functional recovery following rehabilitation after hip fracture: a randomized clinical trial. JAMA. 2014; 311:700–708. [PubMed: 24549550] 19. Studies in support of special populations: Geriatrics E7; International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; 1993. 20. Bhasin S. The brave new world of function-promoting anabolic therapies: testosterone and frailty. J Clin Endocrinol Metab. 2010; 95:509–511. [PubMed: 20133471] 21. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010; 363:109–122. [PubMed: 20592293] 22. Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996; 335:1–7. [PubMed: 8637535] 23. Storer TW, Magliano L, Woodhouse L, et al. Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. J Clin Endocrinol Metab. 2003; 88:1478–1485. [PubMed: 12679426] 24. Latham NK, Mehta V, Nguyen AM, et al. Performance-based or self-report measures of physical function: which should be used in clinical trials of hip fracture patients? Arch Phys Med Rehabil. 2008; 89:2146–2155. [PubMed: 18996244] 25. Fried LP, Guralnik JM. Disability in older adults: evidence regarding significance, etiology, and risk. J Am Geriatr Soc. 1997; 45:92–100. [PubMed: 8994496] 26. Perera S, Mody SH, Woodman RC, Studenski SA. Meaningful change and responsiveness in common physical performance measures in older adults. J Am Geriatr Soc. 2006; 54:743–749. [PubMed: 16696738] 27. Binder EF, Brown M, Sinacore DR, et al. Effects of extended outpatient rehabilitation after hip fracture: a randomized controlled trial. JAMA. 2004; 292:837–846. [PubMed: 15315998] 28. Lustgarten MS, Price LL, Phillips EM, Fielding RA. Serum glycine is associated with regional body fat and insulin resistance in functionally-limited older adults. PLoS One. 2013; 8:e84034. [PubMed: 24391874]
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Table 1
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Methods for assessing sarcopenia in patients with hip fracture (modified from Rolland Y et al. Clin Geriatr Med 2011;27:423–47)
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Characteristic measured
Assessment tool
Advantages
Disadvantages
Muscle mass
DXA
Precise Validated Reliable Non-invasive Practical Inexpensive Specific to muscle Somewhat sensitive to change Fairly easy to do Constant across populations Low radiation dose
Does not predict adverse events Analytical differences across instruments Cannot assess fractured limb
BIA or anthropometic measures
Validated Non-invasive Inexpensive Easy to administer
Not specific to muscle Not sensitive to change
CT scan
Precise Measures direct physical property of muscle
Radiation exposure
MRI
Precise No radiation exposure Capacity for multiple slice acquisition
Technical complications Higher cost
Grip strength
Validated Reliable Non-invasive Practical Easy to do anywhere Inexpensive Predicts adverse events Constant across populations Somewhat specific to muscle
Not sensitive to change
Lower extremity strength
Practical Inexpensive Sensitive to change Predicts adverse events Constant across populations Somewhat reliable Somewhat validated Somewhat non-invasive
Limited by pain or fear Not easy to do anywhere
Muscle power
Inexpensive Predicts adverse events Somewhat validated Somewhat reliable
Limited by pain and fear Invasive Impractical Not easy to do anywhere
SPPB
Validated Reliable Non-invasive Practical Inexpensive Sensitive to change Predicts adverse events Constant across populations Fairly easy to do anywhere
Not specific to muscle
Muscle strength/power
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Questions
Prediction of adverse event Consistency across populations
Sensitivity to change Constancy across populations
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Table 2
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Exemple of inclusion criteria for sarcopenia trials in patientswith hip fracture •
Age limit: 65 years of age or order
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Residence in a community dwelling or assisted living facility
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Confirmed fall-related hip fracture within 3 months
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Confirmed surgical repair of hip fracture
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Difficulty or dependence in two or more basic, instrumental, or mobility activities and needing some assistance as indicated by the AM-PAC stage 2 or 3
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Screening evaluation between 4 and 12 weeks of fracture, but after completion of the acute in-hospital care and traditional rehabilitation
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Able to provide informed consent
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J Frailty Aging. Author manuscript; available in PMC 2015 September 14. Published in final edited form as: J Frailty Aging. 2014 ; 3(4): 199–204. doi:10.14283/jfa.2014.24.
DESIGNING DRUG TRIALS FOR SARCOPENIA IN OLDER ADULTS WITH HIP FRACTURE – A TASK FORCE FROM THE INTERNATIONAL CONFERENCE ONFRAILTY AND SARCOPENIA RESEARCH (ICFSR)
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B. VELLAS1,2, R. FIELDING3, R. MILLER4, Y. ROLLAND1, S. BHASIN5, J. MAGAZINER6, and H. BISCHOFF-FERRARI7 ON BEHALF OF THE ICFSR TASK FORCE MEMBERS 1Centre
Hospitalier Universitaire de Toulouse, Toulouse, France 2Inserm UMR1027, Université de Toulouse, Toulouse, France 3Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA 4Muscle Metabolism Discovery Performance Unit, GlaxoSmithKline, Raleigh-Durham, NC, USA 5Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA 6Department of Epidemiology & Public Health Director, University of Maryland School of Medicine, Baltimore, MD, USA 7Department of Geriatrics and Aging Research, University of Zurich, Zurich, Switzerland
Abstract Author Manuscript Author Manuscript
In May 2012, a Sarcopenia Consensus Summit was convened by the Foundation of the National Institutes of Health (FNIH), National Institute of Aging (NIA), and the U.S. Food and Drug Administration (FDA); and co-sponsored by five pharmaceutical companies. At this summit, sarcopenia experts from around the world worked to develop agreement on a working definition of sarcopenia, building on the work of previous efforts to generate a consensus. With the ultimate goal of improving function and independence in individuals with sarcopenia, the Task Force focused its attention on people at greatly increased risk of muscle atrophy as a consequence of hip fracture. The rationale for looking at this population is that since hip fracture is a recognized condition, there is a clear regulatory path forward for developing interventions. Moreover, patients with hip fracture may provide an appropriate population to advance understanding of sarcopenia, for example helping to define diagnostic criteria, develop biomarkers, understand the mechanisms that underlie the age-related loss of muscle mass and strength, and identify endpoints for clinical trials that are reliable, objective, and clinically meaningful. Task Force members agreed that progress in treating sarcopenia will require strengthening of partnerships between academia, industry, and government agencies, and across continents to reach consensus on diagnostic criteria, optimization of clinical trials design, and identification of improved treatment and preventive strategies. In this report, the main results of the Task Force discussion are presented.
Corresponding author: Bruno Vellas, MD. Gérontopôle, CHU Toulouse; Service de Médecine Interne et Gérontologie Clinique. 170 Avenue de Casselardit, 31059 Toulouse, France. Phone: +33 (0)5 6177-6425; Fax: +33 (0)5 6177-6475. [email protected]. Conflicts of interests: The TF cost was financed by the ICFSR conference and registration fees
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Keywords Sarcopenia; hip fracture; clinical trials; skeletal muscle; aging
Introduction
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As people are living longer, sarcopenia - the age related loss of muscle mass and strength is becoming increasingly prevalent as a cause of disability and loss of independence. Developing treatments for sarcopenia, however, faces challenges on multiple fronts. Some people consider sarcopenia a part of normal aging rather than a condition requiring intervention. In addition, regulatory and commercial paths for sarcopenia treatments are untrodden, in part because of the lack of consensus on a definition of sarcopenia. Defining sarcopenia as a recognized condition or a manifestation of a recognized condition, and developing diagnostic criteria for the condition are necessary prerequisites for gaining regulatory approval of therapeutic products for this condition. In May 2012, a Sarcopenia Consensus Summit was convened by the Foundation of the National Institutes of Health (FNIH), National Institute of Aging (NIA), and the U.S. Food and Drug Administration (FDA); and co-sponsored by five pharmaceutical companies. At this summit, sarcopenia experts from around the world worked to develop agreement on a working definition of sarcopenia (1), building on the work of previous efforts to generate a consensus (2, 3). While progress was made towards developing a better understanding of sarcopenia, a consensus definition remains elusive.
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Hip fracture is universally accepted as a recognized condition, and it is understood that prefracture and post-fracture muscle loss compromise functional capacity. Moreover, hip fracture increases risk of institutionalization (15–35% may be institutionalized), risk of falls, and mortality (18–33% die within 1 year). Thus, a task force of experts in sarcopenia met on March 12, 2014 in Barcelona, Spain, at the International Conference on Frailty and Sarcopenia Research (ICFSR) to explore whether using hip fracture as the diagnosed condition in drug trials could represent a path forward toward achieving regulatory approval for sarcopenia treatments in older adults. The Task Force was convened by the Global Aging Research Network (GARN), a collaboration of the International Association of Gerontology and Geriatrics (IAGG).
Change in body composition and function after hip fracture Author Manuscript
The Baltimore Hip Studies (BHS) have been conducted for over 25 years with the goal of identifying, developing, and evaluating strategies to optimize recovery from hip fracture. Analysis of data from the BHS have shown significant decreases in total body mass, lean mass, and bone mineral density were observed 10 days to 2 months following hip fracture (4, 5). Sarcopenia, defined as appendicular lean mass normalized for height, was found in about 35% of women at baseline (3–10 days after hip fracture), increased to over 50% at 2 months, and increased further up to 12 months post-fracture (6). Patients also experience substantial functional consequences such that for patients functioning independently before fracture, a large percentage remain unable to climb 5 stairs, get in and out of the bath or on
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and off the toilet 12 months post-fracture (7). In another study testing the ability of subjects to walk 300 meters in 6 minutes, only 4% of hip-fracture patients were able to walk at this level at 2 months, and even by 12 months only 16% had achieved this level of mobility (8, 9). Hip fracture is a multi-faced problem requiring multi-domain interventions with different strategies addressing different impairments at different stages of the recovery process. However, researchers are only beginning to understand the optimal way of treating patients at different stages (including preventive approaches pre-fracture).
Diagnostic criteria for sarcopenia in older adults with hipfracture
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The loss of mobility imposed by hip fracture results in sarcopenia characterized by declining muscle mass, deficiencies in strength and power, functional limitations and eventually, disability. Different diagnostic criteria have been proposed for sarcopenia (2, 3, 10–12), but the field has yet to reach consensus on whether diagnosis should be based on muscle mass, strength, or functional limitations. In addition, the timing of the diagnosis relative to the injury is important. Following an acute injury, pain and delirium can complicate the diagnostic process. If surgery has been performed, post-surgical recommendations for recovery may range from bed rest to varying periods of partial weight-bearing exercise. These different management strategies, as well as co-morbidities and limited mobility, particularly among the very old, also influence the ability to diagnose sarcopenia.
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The prevalence of sarcopenia depends on how the condition is defined. For example, using Dual-Energy X-ray Absorptiometry (DXA) scanning to determine appendicular lean mass in 340 women 2–4 weeks following hip fracture, Di Monaco et al found that 58% were sarcopenic (13). In contrast, a study using bioelectrical impedance analysis (BIA) to calculate whole-body skeletal muscle mass in a hip fracture patients found that 71% were sarcopenic (14). Anthropometric measures (height, weight, sex) have also been used to predict muscle mass (15). Table 1 summarizes the advantages and disadvantages of different methods for diagnosing sarcopenia. Task force members advocated for testing the various definitions of sarcopenia against an important endpoint, such as falls. Since functional measures are the most clinically relevant, basing a trial on muscle mass could be problematic; however, if muscle mass and functional measures prove to be equivalent predictors of falls, muscle mass could be considered a more reliable and objective endpoint.
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Targeting hip fracture patients for sarcopenia clinical trials When to begin intervention depends on the goals of intervention. One argument in favor of intervening shortly after hip fracture occurs is that muscle loss may occur early after hip fracture. Comparing the fractured vs. non-fractured legs, at two months post-fracture the fractured leg shows less normal density muscle, more low-density muscle, and high intermuscular adipose tissue. In addition, the period of greatest risk for a subsequent fall and second fracture (16), as well as the greatest risk of mortality occurs close to the time of
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fracture (17). Thus, if the goal is to minimize muscle loss and reduce falls, intervention should begin early. However, a recent home-based exercise intervention program (8) found that when subjects started the intervention about two months post-fracture, there was no significant difference between the intervention and control arms in terms of functional measures even 12 months post-fracture. In another study where a home-based exercise intervention program was started approximately 9 months post-fracture, there was a modest improvement in function 6 months following randomization (18). Thus if the aim is to demonstrate functional improvement, there may be a benefit from waiting until the period of high risk has passed.
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Later studies may also be more likely to involve home-based interventions. Later studies would also be less likely to enroll subjects at high risk of adverse outcomes in the early stages. From the point of view of sponsors conducting a study, there is a fine balance between successful conduct of the study and generalizability. On the one hand, excluding subjects unlikely to benefit or at high risk of adverse events improves the likelihood of a successful trial. On the other hand there has recently been increased attention from regulatory agencies on the need to enroll representative populations (18). Thus, for example, in the Orwig study, only 19% of the 1276 patients identified were eligible for the study. Excluded were those with prefracture nursing home residency (24%), prefracture history of dementia (13%), cardiac disease (12%) or orthopedic hardware in the contralateral hip (10%). In Latham et al, only 15% of 1546 assessed subjects were enrolled. Many subjects refused to participate, died, or could not be reached by the study coordinators. Inclusion rates of only 15–19% raise doubts about the applicability of the results to real-life populations.
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Trial design issues The Task Force discussed various trial design issues that must be considered. These are summarized below: Inpatient or outpatient study This may vary depending on where the study will be conducted. In the United States, the typical length of hospital stay following hip fracture is about 5 days, followed by discharge to a rehabilitation facility; whereas in Europe patients typically are hospitalized longer. Suggested inclusion criteria (Table 2).
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moderate degree of ADL impairment and mobility limitation (e.g. difficulty or dependence in two or more basic, instrumental or mobility activities).
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presence of the condition (i.e., hip fracture) using objective and precise measures. Need to operationalize the indication so that it can be ascertained accurately and reliably using both self-reported and performance based measures.
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Residence in community or assisted living preferred since institutionalized patients tend to have more comorbidities.
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Should sarcopenia be an eligibility criteria? Arguments for and against were presented;.
Suggested exclusion criteria:
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Subjects who are unlikely to respond, will respond differently, or may be at risk of adverse events.
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Subjects who were unable to walk without human assistance before fracture as well as those with limiting neuromuscular conditions that my affect mobility or physical function.
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Severe cognitive deficits, severe depression, progressive neurologic disease or previous stroke.
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Comorbid conditions that could affect response to treatment or compromise the safety of the treatment, e.g. cancer, anemia, terminal illness, end-stage renal disease requiring dialysis, some cardiovascular conditions such as recent myocardial infarction, acute coronary syndrome or stroke; organ dysfunction (with established cutoffs for relevant measures).
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Marked obesity
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Currently using other drugs that may affect drug metabolism or response.
Drug specific exclusions:
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For trials of promyogenic drugs, there may be an increased risk of cardiovascular disease especially in older adults with multiple co-morbid conditions. Therefore, individuals with certain cardiovascular conditions or those at high risk of cardiovascular events may be excluded.
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For trials of androgens and selective androgen receptor modulators (SARM) exclude those with conditions that may be affected by androgens (e.g., those with prostate cancer or breast cancer, or with elevated prostate specific antigen [PSA] or International prostate symptom score [IPSS] or hematocrit >50%, or untreated severe obstructive sleep apnea %), as well as those with conditions that may affect the response to androgens (20).
Questionable exclusions: •
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Osteoporosis and vitamin D deficiency occur are highly prevalent in hip fracture patients. Since Vitamin D may affect physical function especially at very low levels, consider excluding those with severe deficiency and replacing Vitamin D in others with a dose that would raise 25(OH)D into normal range, then monitor levels.
Timing of intervention following hip fracture The suggestion was made to take a middle ground (4–12 weeks after fracture) since in first four weeks multiple medical and post-surgical issues may complicate recovery. Also, most patients are involved in rehab programs at this early stage.
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Randomization and stratification
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Randomization is necessary to ensure that groups are comparable at baseline and to reduce selection bias. However, hip fracture patients often have a high prevalence of comorbidities, necessitating other allocation strategies to minimize the risk of imbalance between the treatment arms. Further, in multi-domain trials that combine pharmaceutical treatment with physical activity, decisions must be made whether to allow physical activity to distribute randomly or to control physical activity so that different drug treatment arms have a similar “dose” of physical activity. Controlling physical activity offers the advantage of smaller sample sizes but introduces numerous challenges with regard to implementation of the intervention and ensuring adherence to the program. Trial duration
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Shorter durations result in reduced costs and lower attrition; however, longer duration trials may be needed to acquire information about safety and efficacy. Trials of 6–12 months may provide the best trade-off. For example, trials of testosterone and exercise have shown improvements in muscle mass, strength, and function over a 6 month duration (20–23). Efficacy outcomes - Primary outcome measures should assess an aspect of the condition that is clinically meaningful, can be measured safely, reproducibly, and precisely. These measures may be performance based or self-reported, each type with advantages and disadvantages (24). Therefore, inclusion of both types of measures would provide a more comprehensive assessment of efficacy. Performance based measures should be aligned with self-reported measures and the subjects’ functional limitations and symptoms. For example, walking speed is an excellent integrated measure of physical function and mobility disability. It can be measured precisely and reproducibly, is responsive to intervention, predictive of health outcomes, and Minimal Clinically Important Differences (MCIDs) are known (25, 26). Gait speed measures can utilize a short or long walk and can also be incorporated into composite measures such as the Short Physical Performance Battery (SPPB) and Physical Functional Performance Test (PFP), as well as selfreported measures such as the Physical Functioning scale (PF-10). Self-reported measures can include specific questions that allow for dichotomous analysis.
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Measures should have a plausible link to the mechanism of action. For example, promyogenic anabolic therapies are expected to result in increased muscle mass and strength, leading to improved physical function, increased independence, improved health perceptions, and improvements in other health-related outcomes. Therefore, trials of such drugs should include muscle mass and performance as outcomes, but will also need to show that the intervention results in meaningful improvement in patient’s life.
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Maintaining independence is of primary importance in the lives of hip fracture patients. More than half of patients with hip fracture lose their ability to function independently, primarily because of mobility limitations. This often results in nursing home placement and also increases health care costs (7).
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The Activity Measure for Post-Acute Care (AM-PAC) is a measure of disability in activities of daily living, mobility and social functioning. The MCID is known and is related to outcomes including mortality (18).
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Other outcomes: pain, mood and affect, well-being, falls, fall-related injuries, hospitalizations, death
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Biomarkers of muscle mass and strength are necessary and useful to power a trial, but insufficient to establish efficacy (7, 23, 27).
Imaging and biomarkers for sarcopenia trials in olderadults with hip fracture
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Biomarkers for sarcopenia are used not only diagnostically but also to track disease progression and response to therapy. As with their use in diagnosis, each method has advantages and disadvantages. For example, CT precisely measures direct physical properties of muscle but exposes patients to radiation. In an elderly individual, CT is likely to show loss of normal density muscle, increased low density muscle, increased myocellular lipid accumulation and intermuscular fat. MRI provides similar information and has the additional capacity for multiple slice acquisition, however it comes with a higher cost and higher subject burden. DXA assesses both bone and soft tissue density with high precision and reliability but is affected by hydration levels and does not allow for assessment of the fractured limb where the magnitude of muscle and strength loss may be greater than in the unfractured limb. Additional non-invasive measures, including ultrasound, bioelectrical impedance, assessment of serum metabolites (28) and genomic studies offer other approaches to assessing muscle mass, although so far, none of these assessments has the sensitivity to be used as a primary outcome in clinical trials. Nonetheless, incorporating biomarkers into trials offers the potential to provide important information, e.g. to show target engagement in phase 1b trials; as well as validation of the approaches for use in future trials.
Intervention: treatment and prevention
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The Task Force addressed whether trials should focus on prevention or treatment. For promyogenic drugs, a prevention trial would probably be unrealistic given the huge sample size required, the uncertainty about efficacy, and the lack of knowledge about long-term safety. Moreover, a prevention trial would require identification of individuals at risk, which is not at this point well defined. However, a treatment trial of a pro-myogencic drug in patients with hip fracture would provide a more favorable risk/benefit ratio. The primary endpoint could be, for example, improved function, with prevention of falls a secondary endpoint with functional significance. Similar endpoints have been incorporated into interventional studies discussed earlier, such as those conducted as part of the Baltimore Hip Studies. Prevention trials are also underway. For example, DO-HEALTH is a clinical trial taking place in 7 European cities to determine whether combining exercise with vitamin D and omega-3 fatty acids will prevent disease in older age. Over 2,000 seniors have been enrolled, including subjects classified as pre-frail and those with a history of falls. The five primary J Frailty Aging. Author manuscript; available in PMC 2015 September 14.
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endpoints include incidence of non-vertebral fractures and functional decline, as well as endpoints related to cardiovascular and brain health and immunity. All clinical endpoints are supported by biomarker studies.
Conclusions
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With the ultimate goal of improving function and independence in individuals with sarcopenia, the Task Force focused its attention on people at greatly increased risk of muscle atrophy as a consequence of hip fracture. The rationale for looking at this population is that since hip fracture is a recognized condition, there is a clear regulatory path forward for developing interventions. Moreover, patients with hip fracture may provide an appropriate population to advance understanding of sarcopenia, for example helping to define diagnostic criteria, develop biomarkers, understand the mechanisms that underlie the age-related loss of muscle mass and strength, and identify endpoints for clinical trials that reliable, objective, and clinically meaningful. Task Force members agreed that progress in treating sarcopenia will require strengthening of partnerships between academia, industry, and government agencies, and across continents to reach consensus on diagnostic criteria, optimization of clinical trials design, and identification of improved treatment and preventive strategies.
Acknowledgments
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Members of the ICFSR Task Force: Gabor Abellan van Kan (Toulouse, France), Lisa J. Bain (Elverson, USA), Cécile Bonhomme (Torcé, France), Denis Breuillé (Lausanne, Switzerland), Francesca Cerreta (London, United Kingdom), Alfonso Cruz-Jentoft (Madrid, Spain), Dominique Dardevet (Ceyrat, France), Justine Davies (London, United Kingdom), Susanna Del Signore (Chilly Mazarin, France), Stephen Donahue (Tarrytown, USA), Philippe Guillet (Chilly Mazarin, France), Michaela Hoehne (Lutry, Switzerland), Makoto Kashiwa (Saitama, Japan), Valerie Legrand (Nanterre, France), Fady Malik (San Francisco, USA), Erwin Meijer (Schiphol Airport, The Netherlands), Marco Pahor (Gainesville, USA), Robert Pordy (Tarrytown, USA), Leocadio Rodriguez-Manas (Madrid, Spain), Daniel Rooks (Cambridge, USA), Fariba Roughead (Minnetonka, USA), Klaudius Siegfried (Langen, Germany), Alan J Sinclair (Bedfordshire, United Kingdom), Elisabeth Stöcklin (Wurmisweg, Switzerland), Laszlo Tanko (Basel, Switzerland), Sjors Verlaan (Schiphol Airport, The Netherlands), Sander Wijers (Wageningen, The Netherlands).
References
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Table 1
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Methods for assessing sarcopenia in patients with hip fracture (modified from Rolland Y et al. Clin Geriatr Med 2011;27:423–47)
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Characteristic measured
Assessment tool
Advantages
Disadvantages
Muscle mass
DXA
Precise Validated Reliable Non-invasive Practical Inexpensive Specific to muscle Somewhat sensitive to change Fairly easy to do Constant across populations Low radiation dose
Does not predict adverse events Analytical differences across instruments Cannot assess fractured limb
BIA or anthropometic measures
Validated Non-invasive Inexpensive Easy to administer
Not specific to muscle Not sensitive to change
CT scan
Precise Measures direct physical property of muscle
Radiation exposure
MRI
Precise No radiation exposure Capacity for multiple slice acquisition
Technical complications Higher cost
Grip strength
Validated Reliable Non-invasive Practical Easy to do anywhere Inexpensive Predicts adverse events Constant across populations Somewhat specific to muscle
Not sensitive to change
Lower extremity strength
Practical Inexpensive Sensitive to change Predicts adverse events Constant across populations Somewhat reliable Somewhat validated Somewhat non-invasive
Limited by pain or fear Not easy to do anywhere
Muscle power
Inexpensive Predicts adverse events Somewhat validated Somewhat reliable
Limited by pain and fear Invasive Impractical Not easy to do anywhere
SPPB
Validated Reliable Non-invasive Practical Inexpensive Sensitive to change Predicts adverse events Constant across populations Fairly easy to do anywhere
Not specific to muscle
Muscle strength/power
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Questions
Prediction of adverse event Consistency across populations
Sensitivity to change Constancy across populations
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Table 2
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Exemple of inclusion criteria for sarcopenia trials in patientswith hip fracture •
Age limit: 65 years of age or order
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Residence in a community dwelling or assisted living facility
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Confirmed fall-related hip fracture within 3 months
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Confirmed surgical repair of hip fracture
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Difficulty or dependence in two or more basic, instrumental, or mobility activities and needing some assistance as indicated by the AM-PAC stage 2 or 3
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Screening evaluation between 4 and 12 weeks of fracture, but after completion of the acute in-hospital care and traditional rehabilitation
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Able to provide informed consent
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