Bridging the gap between the laboratory and the clinic for patients with sarcopenia

Miles D Witham, Miles D Witham

Abstract

Sarcopenia-the age-related loss of skeletal muscle mass and strength-is a major public health issue. Sarcopenia is associated with an increased risk of falls, disability, dependency, institutionalization, hospital stay and early death. Finding interventions to stabilize, reverse or prevent sarcopenia is therefore a key goal for clinical ageing research. If patients are to eventually benefit from discovery science on ageing skeletal muscle, we need to build a translational pipeline that facilitates progress from laboratory science and epidemiology, through feasibility testing to early-phase, and eventually late-phase clinical trials. A number of barriers need to be overcome to make this pipeline work-in particular challenges around identifying people with sarcopenia in routine clinical practice, ensuring that we study patients with clearly defined sarcopenia rather than related conditions such as functional impairment, developing capacity to run trials for older people, and selecting trial outcomes of relevance to older people with multimorbidity. A further key point is that interventions should ideally have pleiotropic actions-i.e. beneficial actions across multiple organ systems, rather than treating sarcopenia alone. Such pleiotropic interventions may be the only way to avoid the perils of polypharmacy and drug interactions that bedevil care for many older people. Maximising the potential for scientific discoveries in the biology of ageing muscle to improve health requires that discovery scientists, translational clinical scientists and clinicians come together to exchange findings and shape each others ideas within a shared culture.

Keywords: Clinical research; Sarcopenia; Translational medicine; Trials.

Conflict of interest statement

Professor Witham has received grant funding for research into sarcopenia and physical function in older people from the UK National Institute for Health Research, the Chief Scientist Office, Scottish Government, and the Dunhill Medical Trust.

Figures

Fig. 1
Fig. 1
Difference in target populations for muscle studies in older people

References

    1. Barnett K, Mercer SW, Norbury M, Watt G, Wyke S, Guthrie B. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet. 2012;380:37–43. doi: 10.1016/S0140-6736(12)60240-2.
    1. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016;23:1060–1065. doi: 10.1016/j.cmet.2016.05.011.
    1. Beaudart C, Zaaria M, Pasleau F, Reginster JY, Bruyère O. Health outcomes of sarcopenia: a systematic review and meta-analysis. PLoS ONE. 2017;12:e0169548. doi: 10.1371/journal.pone.0169548.
    1. Buffel du Vaure C, Ravaud P, Baron G, Barnes C, Gilberg S, Boutron I. Potential workload in applying clinical practice guidelines for patients with chronic conditions and multimorbidity: a systematic analysis. BMJ Open. 2016;6:e010119. doi: 10.1136/bmjopen-2015-010119.
    1. Cefalu WT, Kaul S, Gerstein HC, Holman RR, Zinman B, Skyler JS, Green JB, Buse JB, Inzucchi SE, Leiter LA, Raz I, Rosenstock J, Riddle MC. Cardiovascular Outcomes trials in type 2 diabetes: where do we go from here? Reflections from a diabetes care editors’ expert forum. Diabetes Care. 2018;41:14–31. doi: 10.2337/dci17-0057.
    1. Cherubini A, Oristrell J, Pla X, Ruggiero C, Ferretti R, Diestre G, Clarfield AM, Crome P, Hertogh C, Lesauskaite V, Prada GI, Szczerbinska K, Topinkova E, Sinclair-Cohen J, Edbrooke D, Mills GH. The persistent exclusion of older patients from ongoing clinical trials regarding heart failure. Arch Intern Med. 2011;171:550–556. doi: 10.1001/archinternmed.2011.31.
    1. Coller BS. Translational research: forging a new cultural identity. Mt Sinai Med J. 2008;75:478–487. doi: 10.1002/msj.20064.
    1. Conroy SP, Westendorp RGJ, Witham MD. Hypertension treatment for older people-navigating between Scylla and Charybdis. Age Ageing. 2018
    1. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, Rolland Y, Schneider SM, Topinková E, Vandewoude M, Zamboni M; European Working Group on Sarcopenia in Older People Sarcopenia: european consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010;39:412–423. doi: 10.1093/ageing/afq034.
    1. Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, Cooper C, Landi F, Rolland Y, Sayer AA, Schneider SM, Sieber CC, Topinkova E, Vandewoude M, Visser M, Zamboni M; Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2 Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2018
    1. Cruz-Jentoft AJ, Carpena-Ruiz M, Montero-Errasquín B, Sánchez-Castellano C, Sánchez-García E. Exclusion of older adults from ongoing clinical trials about type 2 diabetes mellitus. J Am Geriatr Soc. 2013;61:734–738. doi: 10.1111/jgs.12215.
    1. Editorial So long to the silos. Nat Biotechnol. 2016;34:357. doi: 10.1038/nbt.3544.
    1. Hughes LD, McMurdo ME, Guthrie B. Guidelines for people not for diseases: the challenges of applying UK clinical guidelines to people with multimorbidity. Age Ageing. 2013;42:62–69. doi: 10.1093/ageing/afs100.
    1. Kent DM, Kitsios G. Against pragmatism: on efficacy, effectiveness and the real world. Trials. 2009;10:48. doi: 10.1186/1745-6215-10-48.
    1. Kilsby AJ, Sayer AA, Witham MD. Selecting potential pharmacological interventions in sarcopenia. Drugs Aging. 2017;34:233–240. doi: 10.1007/s40266-017-0444-z.
    1. Le Lain R, Ignaszewski C, Klingmann I, Cesario A, de Boer WI; SPRINTT Consortium SPRINTT and the involvement of stakeholders: strategy and structure. Aging Clin Exp Res. 2017;29:65–67.
    1. Mackenzie IS, Ford I, Walker A, Hawkey C, Begg A, Avery A, Taggar J, Wei L, Struthers AD, MacDonald TM, ALL-HEART study group Multicentre, prospective, randomised, open-label, blinded end point trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART study. BMJ Open. 2016;6:e013774. doi: 10.1136/bmjopen-2016-013774.
    1. Malmstrom TK, Morley JE. SARC-F: a simple questionnaire to rapidly diagnose sarcopenia. J Am Med Dir Assoc. 2013;14:531–532. doi: 10.1016/j.jamda.2013.05.018.
    1. Marzetti E, Cesari M, Calvani R, Msihid J, Tosato M, Rodriguez-Mañas L, Lattanzio F, Cherubini A, Bejuit R, Di Bari M, Maggio M, Vellas B, Dantoine T, Cruz-Jentoft AJ, Sieber CC, Freiberger E, Skalska A14, Grodzicki T, Sinclair AJ, Topinkova E, Rýznarová I, Strandberg T, Schols AMWJ, Schols JMGA, Roller-Wirnsberger R, Jónsson PV, Ramel A, Del Signore S, Pahor M, Roubenoff R, Bernabei R1, Landi F; SPRINTT Consortium The “Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies” (SPRINTT) randomized controlled trial: case finding, screening and characteristics of eligible participants. Exp Gerontol. 2018;113:48–57. doi: 10.1016/j.exger.2018.09.017.
    1. Mayhew AJ, Amog K, Phillips S, Parise G, McNicholas PD, de Souza RJ,, Thabane L, Raina P. The prevalence of sarcopenia in community-dwelling older adults, an exploration of differences between studies and within definitions: a systematic review and meta-analyses. Age Ageing. 2018
    1. McMurdo ME, Witham MD, Gillespie ND. Including older people in clinical research. BMJ. 2005;331:1036–1037. doi: 10.1136/bmj.331.7524.1036.
    1. Morley JE. Pharmacologic options for the treatment of sarcopenia. Calcif Tissue Int. 2016;98:319–333. doi: 10.1007/s00223-015-0022-5.
    1. Pinedo-Villanueva R, Westbury LD, Syddall HE, Sanchez-Santos MT, Dennison EM, Robinson SM, Cooper C. Health care costs associated with muscle weakness: a UK population-based estimate. Calcif Tissue Int. 2018
    1. Reiter R, Iglseder B, Treschnitzer W, Alzner R, Mayr-Pirker B, Kreutzer M, Pirich C, Kässmann H, Dovjak P, Reiss J. Quantifying appendicular muscle mass in geriatric inpatients: performance of different single frequency BIA equations in comparison to dual X-ray absorptiometry. Arch Gerontol Geriatr. 2019;80:98–103. doi: 10.1016/j.archger.2018.10.010.
    1. Roberts H, Khee TS, Philip I. Setting priorities for measures of performance for geriatric medical services. Age Ageing. 1994;23:154–157. doi: 10.1093/ageing/23.2.154.
    1. Rosenberg IH. Sarcopenia: origins and clinical relevance. J Nutr. 1997;127:990S–991S. doi: 10.1093/jn/127.5.990S.
    1. Sayer AA, Robinson SM, Patel HP, Shavlakadze T, Cooper C, Grounds MD. New horizons in the pathogenesis, diagnosis and management of sarcopenia. Age Ageing. 2013;42:145–150. doi: 10.1093/ageing/afs191.
    1. Scottish Government. Realistic prescribing—polypharmacy guidance. 3rd Edition 2018. . Accessed 28 Nov 2018
    1. Shen Y, Chen J, Chen X, Hou L, Lin X, Yang M. Prevalence and associated factors of sarcopenia in nursing home residents: a systematic review and meta-analysis. J Am Med Dir Assoc. 2018
    1. Studenski SA, Peters KW, Alley DE, Cawthon PM, McLean RR, Harris TB, Ferrucci L, Guralnik JM, Fragala MS, Kenny AM, Kiel DP, Kritchevsky SB, Shardell MD, Dam TT, Vassileva MT. The FNIH sarcopenia project: rationale, study description, conference recommendations, and final estimates. J Gerontol A Biol Sci Med Sci. 2014;69:547–558. doi: 10.1093/gerona/glu010.
    1. Thompson R, Robertson A, Lochmüller H. Natural history, trial readiness and gene discovery: advances in patient registries for neuromuscular disease. Adv Exp Med Biol. 2017;1031:97–124. doi: 10.1007/978-3-319-67144-4_5.
    1. Townsley CA, Selby R, Siu LL. Systematic review of barriers to the recruitment of older patients with cancer onto clinical trials. J Clin Oncol. 2005;23:3112–3124. doi: 10.1200/JCO.2005.00.141.
    1. Volpato S, Bianchi L, Cherubini A, Landi F, Maggio M, Savino E, Bandinelli S, Ceda GP, Guralnik JM, Zuliani G, Ferrucci L. Prevalence and clinical correlates of sarcopenia in community-dwelling older people: application of the EWGSOP definition and diagnostic algorithm. J Gerontol A Biol Sci Med Sci. 2014;69:438–446. doi: 10.1093/gerona/glt149.
    1. Witham MD, George J. Clinical trial design for older people–time for a rethink. QJM. 2014;107:15–16. doi: 10.1093/qjmed/hct178.

Source: PubMed

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