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A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia

Abstract

Background

Sarcopenia, the age-related loss of muscle mass [defined as appendicular LBM/Height2 (aLBM/ht2) below peak value by>1SD], strength and function, is a major contributing factor to frailty in the elderly. MK-0773 is a selective androgen receptor modulator designed to improve muscle function while minimizing effects on other tissues.

Objectives

The primary objective of this study was to demonstrate an improvement in muscle strength and lean body mass (LBM) in sarcopenic frail elderly women treated with MK-0773 relative to placebo.

Design

This was a randomized, double-blind, parallel-arm, placebo-controlled, multicenter, 6-month study. Participants were randomized in a 1:1 ratio to receive either MK-0773 50mg b.i.d. or placebo; all participants received Vitamin D and protein supplementation.

Setting

General community.

Participants

170 Women aged ≥65 with sarcopenia and moderate physical dysfunction.

Measurements

Dual energy X-ray absorptiometry, muscle strength and power, physical performance measures.

Results

Participants receiving MK-0773 showed a statistically significant increase in LBM from baseline at Month 6 vs. placebo (p<0.001). Participants receiving both MK-0773 and placebo showed a statistically significant increase in strength from baseline to Month 6, but the mean difference between the two groups was not significant (p=0.269). Both groups showed significant improvement from baseline at Month 6 in physical performance measures, but there were no statistically significant differences between participants receiving MK-0773 and placebo. A greater number of participants experienced elevated transaminases in the MK-0773 group vs. placebo, which resolved after discontinuation of study therapy. MK-0773 was generally well-tolerated with no evidence of androgenization.

Conclusions

The MK-0773-induced increase in LBM did not translate to improvement in strength or function vs. placebo. The improvement of strength and physical function in the placebo group could be at least partly attributed to protein and vitamin D supplementation.

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References

  1. Baumgartner RN, Koehler KM, Gallagher D, Romero L, Heymsfield SB, Ross RR, et al. Epidemiology of sarcopenia among the elderly in New Mexico. Am J Epidemiol 1998 Apr 15;147(8):755–763.

    Article  CAS  PubMed  Google Scholar 

  2. Evans WJ, Campbell WW. Sarcopenia and age-related changes in body composition and functional capacity. J Nutr 1993 Feb;123(2 Suppl):465–468.

    CAS  PubMed  Google Scholar 

  3. Janssen I, Heymsfield SB, Ross R. Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability. J Am Geriatr Soc 2002 May;50(5):889–896.

    Article  PubMed  Google Scholar 

  4. Ryall JG, Schertzer JD, Lynch GS. Cellular and molecular mechanisms underlying age-related skeletal muscle wasting and weakness. Biogerontology 2008 Aug;9(4):213–228.

    Article  CAS  PubMed  Google Scholar 

  5. Chevalier S, Gougeon R, Nayar K, Morais JA. Frailty amplifies the effects of aging on protein metabolism: role of protein intake. Am J Clin Nutr 2003 Sep;78(3):422–429.

    CAS  PubMed  Google Scholar 

  6. Kamel HK, Maas D, Duthie EH, Jr. Role of hormones in the pathogenesis and management of sarcopenia. Drugs Aging 2002;19(11):865–877.

    Article  CAS  PubMed  Google Scholar 

  7. Larsson L, Yu F, Hook P, Ramamurthy B, Marx JO, Pircher P. Effects of aging on regulation of muscle contraction at the motor unit, muscle cell, and molecular levels. Int J Sport Nutr Exerc Metab 2001 Dec;11Suppl:S28–S43.

    PubMed  Google Scholar 

  8. Morais JA, Chevalier S, Gougeon R. Protein turnover and requirements in the healthy and frail elderly. J Nutr Health Aging 2006 Jul;10(4):272–283.

    CAS  PubMed  Google Scholar 

  9. Roth SM, Metter EJ, Ling S, Ferrucci L. Inflammatory factors in age-related muscle wasting. Curr Opin Rheumatol 2006 Nov;18(6):625–630.

    Article  CAS  PubMed  Google Scholar 

  10. Roubenoff R. Catabolism of aging: is it an inflammatory process? Curr Opin Clin Nutr Metab Care 2003 May;6(3):295–299.

    PubMed  Google Scholar 

  11. Zadik Z, Chalew SA, McCarter RJ, Jr., Meistas M, Kowarski AA. The influence of age on the 24-hour integrated concentration of growth hormone in normal individuals. J Clin Endocrinol Metab 1985 Mar;60(3):513–516.

    Article  CAS  PubMed  Google Scholar 

  12. Muscaritoli M, Anker SD, Argiles J, Aversa Z, Bauer JM, Biolo G, et al. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) “cachexia-anorexia in chronic wasting diseases” and “nutrition in geriatrics”. Clin Nutr 2010 Apr;29; 1(2):154–159.

    Article  Google Scholar 

  13. Doherty TJ. Invited review: Aging and sarcopenia. J Appl Physiol 2003 Oct;95(4):1717–1727.

    CAS  PubMed  Google Scholar 

  14. Hughes VA, Frontera WR, Wood M, Evans WJ, Dallal GE, Roubenoff R, et al. Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health. J Gerontol A Biol Sci Med Sci 2001 May;56(5):B209–B217.

    Article  CAS  PubMed  Google Scholar 

  15. Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 2004 May;89(5):2085–2098.

    Article  CAS  PubMed  Google Scholar 

  16. Dobs AS, Nguyen T, Pace C, Roberts CP. Differential effects of oral estrogen versus oral estrogen-androgen replacement therapy on body composition in postmenopausal women. J Clin Endocrinol Metab 2002 Apr;87(4):1509–1516.

    Article  CAS  PubMed  Google Scholar 

  17. Gelfand MM, Wiita B. Androgen and estrogen-androgen hormone replacement therapy: a review of the safety literature, 1941 to 1996. Clin Ther 1997 May;19(3):383–404.

    Article  CAS  PubMed  Google Scholar 

  18. Isidori AM, Giannetta E, Pozza C, Bonifacio V, Isidori A. Androgens, cardiovascular disease and osteoporosis. J Endocrinol Invest 2005;28(10 Suppl):73–79.

    CAS  PubMed  Google Scholar 

  19. Davis SR. The therapeutic use of androgens in women. J Steroid Biochem Mol Biol 1999 Apr;69(1–6):177–184.

    Article  CAS  PubMed  Google Scholar 

  20. Miller KK. Androgen deficiency in women. J Clin Endocrinol Metab 2001 Jun;86(6):2395–2401.

    Article  CAS  PubMed  Google Scholar 

  21. Braunstein GD. Androgen insufficiency in women: summary of critical issues. Fertil Steril 2002 Apr;77Suppl 4:S94–S99.

    Article  PubMed  Google Scholar 

  22. Slayden SM. Risks of menopausal androgen supplementation. Semin Reprod Endocrinol 1998;16(2):145–152.

    Article  CAS  PubMed  Google Scholar 

  23. Shabsigh R, Katz M, Yan G, Makhsida N. Cardiovascular issues in hypogonadism and testosterone therapy. Am J Cardiol 2005 Dec 26;96(12B):67M–72M.

    Article  CAS  PubMed  Google Scholar 

  24. Kilbourne EJ, Moore WJ, Freedman LP, Nagpal S. Selective androgen receptor modulators for frailty and osteoporosis. Curr Opin Investig Drugs 2007 Oct;8(10):821–829.

    CAS  PubMed  Google Scholar 

  25. Bhasin S, Jasuja R. Selective androgen receptor modulators as function promoting therapies. Curr Opin Clin Nutr Metab Care 2009 May;12(3):232–240.

    Article  CAS  PubMed  Google Scholar 

  26. Schmidt A, Kimmel DB, Bai C, Scafonas A, Rutledge S, Vogel RL, et al. Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology. J Biol Chem 2010 May 28;285(22):17054–17064.

    Article  CAS  PubMed  Google Scholar 

  27. Marcantonio E.E., Witter R.E., Ding Y., Xu Y., Klappenbach J., Wang Y., et al. A 12-Week pharmacokinetic and pharmacodynamic study of two selective androgen receptor modulators (SARMs) in postmenopausal subjects. Endocrine Reviews Supplement 1[31(3)], S872. 2010. Ref Type: Abstract

    Google Scholar 

  28. Fielding RA, LeBrasseur NK, Cuoco A, Bean J, Mizer K, Fiatarone Singh MA. High-velocity resistance training increases skeletal muscle peak power in older women. J Am Geriatr Soc 2002 Apr;50(4):655–662.

    Article  PubMed  Google Scholar 

  29. Bean JF, Kiely DK, LaRose S, Alian J, Frontera WR. Is stair climb power a clinically relevant measure of leg power impairments in at-risk older adults? Arch Phys Med Rehabil 2007 May;88(5):604–609.

    Article  PubMed  Google Scholar 

  30. Suzuki T, Bean JF, Fielding RA. Muscle power of the ankle flexors predicts functional performance in community-dwelling older women. J Am Geriatr Soc 2001 Sep;49(9):1161–1167.

    Article  CAS  PubMed  Google Scholar 

  31. Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG, et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol 1994 Mar;49(2):M85–M94.

    Article  CAS  PubMed  Google Scholar 

  32. Guralnik JM, Ferrucci L, Simonsick EM, Salive ME, Wallace RB. Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability. N Engl J Med 1995 Mar 2;332(9):556–561.

    Article  CAS  PubMed  Google Scholar 

  33. Brach JS, Kriska AM, Newman AB, VanSwearingen JM. A new approach of measuring muscle impairment during a functional task: quadriceps muscle activity recorded during chair stand. J Gerontol A Biol Sci Med Sci 2001 Dec;56(12):M767–M770.

    Article  CAS  PubMed  Google Scholar 

  34. Abellan vK, Rolland Y, Andrieu S, Bauer J, Beauchet O, Bonnefoy M, et al. Gait speed at usual pace as a predictor of adverse outcomes in community-dwelling older people an International Academy on Nutrition and Aging (IANA) Task Force. J Nutr Health Aging 2009 Dec;13(10):881–889.

    Article  Google Scholar 

  35. Studenski S, Perera S, Patel K, Rosano C, Faulkner K, Inzitari M, et al. Gait speed and survival in older adults. JAMA 2011 Jan 5;305(1):50–58.

    Article  CAS  PubMed  Google Scholar 

  36. Haley SM, Coster WJ, Andres PL, Ludlow LH, Ni P, Bond TL, et al. Activity outcome measurement for postacute care. Med Care 2004 Jan;42(1 Suppl):I49–I61.

    PubMed  Google Scholar 

  37. Haley SM, Coster WJ, Andres PL, Kosinski M, Ni P. Score comparability of short forms and computerized adaptive testing: Simulation study with the activity measure for post-acute care. Arch Phys Med Rehabil 2004 Apr;85(4):661–666.

    Article  PubMed  Google Scholar 

  38. Jette AM, Tao W, Norweg A, Haley S. Interpreting rehabilitation outcome measurements 1. J Rehabil Med 2007 Oct;39(8):585–590.

    Article  PubMed  Google Scholar 

  39. Sharkey JR. Diet and health outcomes in vulnerable populations. Ann N Y Acad Sci 2008;1136:210–217.

    Article  PubMed  Google Scholar 

  40. Dillon EL, Sheffield-Moore M, Paddon-Jones D, Gilkison C, Sanford AP, Casperson SL, et al. Amino acid supplementation increases lean body mass, basal muscle protein synthesis, and insulin-like growth factor-I expression in older women. J Clin Endocrinol Metab 2009 May;94(5):1630–1637.

    Article  CAS  PubMed  Google Scholar 

  41. Paddon-Jones D, Sheffield-Moore M, Urban RJ, Sanford AP, Aarsland A, Wolfe RR, et al. Essential amino acid and carbohydrate supplementation ameliorates muscle protein loss in humans during 28 days bedrest. J Clin Endocrinol Metab 2004 Sep;89(9):4351–4358.

    Article  CAS  PubMed  Google Scholar 

  42. Parise G, Yarasheski KE. The utility of resistance exercise training and amino acid supplementation for reversing age-associated decrements in muscle protein mass and function. Curr Opin Clin Nutr Metab Care 2000 Nov;3(6):489–495.

    Article  CAS  PubMed  Google Scholar 

  43. Solerte SB, Gazzaruso C, Schifino N, Locatelli E, Destro T, Ceresini G, et al. Metabolic effects of orally administered amino acid mixture in elderly subjects with poorly controlled type 2 diabetes mellitus. Am J Cardiol 2004 Apr 22;93(8A):23A–29A.

    Article  CAS  PubMed  Google Scholar 

  44. Janssen HC, Samson MM, Verhaar HJ. Vitamin D deficiency, muscle function, and falls in elderly people. Am J Clin Nutr 2002 Apr;75(4):611–615.

    CAS  PubMed  Google Scholar 

  45. Parfitt AM, Gallagher JC, Heaney RP, Johnston CC, Neer R, Whedon GD. Vitamin D and bone health in the elderly. Am J Clin Nutr 1982 Nov;36(5 Suppl):1014–1031.

    CAS  PubMed  Google Scholar 

  46. Sato Y, Iwamoto J, Kanoko T, Satoh K. Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial. Cerebrovasc Dis 2005;20(3):187–192.

    Article  CAS  PubMed  Google Scholar 

  47. Holick MF. Optimal vitamin D status for the prevention and treatment of osteoporosis. Drugs Aging 2007;24(12):1017–1029.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Dimitris A. Papanicolaou.

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Papanicolaou, D.A., Ather, S.N., Zhu, H. et al. A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia. J Nutr Health Aging 17, 533–543 (2013). https://doi.org/10.1007/s12603-013-0335-x

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  • DOI: https://doi.org/10.1007/s12603-013-0335-x

Key words

  • Sarcopenia
  • aging
  • lean body mass
  • muscle
  • selective androgen receptor modulator