Orthopaedic Related Conditions Literature Review Louis Cheung Department of Orthopaedics & Traumatology The Chinese University of Hong Kong From: mydesultoryblog.com
General Facts of Skeletal Muscles 40 45% of body weight Maximal force production proportional to physiologic cross sectional area Fibril is composed of repeating units of sarcomeres (a contractile unit) Composed of slow twitch fiber (type I) and fast twitch fibers (type IIA, type IIB) [Einhorn. Orthopaedic Basic Science. ISBN:089203176X]
General Facts of Skeletal Muscles Pathological difference between sarcopenia and disused muscle atrophy: Sarcopenia: muscle fiber type II dominant Disused muscle atrophy: muscle fiber type I dominant Difference between sarcopenia and cachexia: Sarcopenia: multifactorial geriatric syndrome Cachexia: complex metabolic syndrome associated with underlying illness and characterized by loss of muscle mass with or without loss of fat mass Cause behind the loss of muscle mass may be indistinguishable clinically [Roland. Curr Opin Clin Nutr Metab Care. 2011]
[Roland. Curr Opin Clin Nutr Metab Care. 2011]
Epidemiology of Sarcopenia IOF: sarcopenia appears after 40 years and accelerates after 75 years [www.iofbonehealth.org] Prevalence in USA: 22.6% in women, 26.8% in men over 64 years, up to 31% and 52.9% over 80 years [Iannuzzi Sucich, J Gerontol A Biol Sci Med Sci, 2002] Prevalence in HK: 7.5% in women, 12.3% in men aged over 70 years [Lau. J Gerontol A Biol Sci Med Sci. 2005] Prevalence in suburb dwelling Chinese: 11.5% in women, 6.4% in men [Han. J Gerontol A Biol Sci Med Sci. 2015]
Muscle Bone Relationship Two theories of muscle bone relationship [Girgis. Calcif Tissue Int. 2015] Mechanostat theory Muscle exerts the required mechanical force to stimulate growth of bone Muscle takes leading role, as muscle development happens before bone gain in puberty Cross talk theory (newer) Muscle mass proportional to bone mass at remote sites Muscle flaps improve open fracture healing Hormonal influence, e.g. myostatin, FGF2, IL6, MMP2 Activity of muscle secreted factors that acts on bone (myokines), and vice versa.
Muscle Bone Relationship: Sarcopenia Osteoporosis Sarcopenia significantly associated with osteoporosis (by hip BMD) in 2,400 Japanese women (age: 40 88yr) [Miyakoshi. J Bone Miner Metab. 2013] Sarcopenia 9% Normal Sarcopenia 18% Osteopenia Sarcopenia 30% Osteoporosis Nonsarcopenic 91% Nonsarcopenic 82% Nonsarcopenic 70%
Muscle Bone Relationship: Sarcopenia Osteoporosis Sarcopenic women had OR=12.9 of having osteoporosis, OR=2.732 of having fractures, OR=2.1 of having higher risk of falls in 590 Finnish postmenopausal women (age: 65 72yr) [Sjoblom. Maturitas. 2013] In 679 European men (age: 40 79yr), men with RASM (relative appendicular skeletal muscle mass) <7.26kg/m 2 had significantly lower BMD. Men with sarcopenia more likely to have osteoporosis at OR=3.0 [Verschueren. Osteoporos Int. 2013]
Relationship of Sarcopenia and Fragility Fractures Prevalence of sarcopenia in fragility hip fracture patients in HK: 73.6% in males, 67.7% in females (by AWGS standard) 20.8% in males, 12.4% in females (by EWGSOP standard) [Ho. Hong Kong Med J. 2015] Sarcopenia associated with increased fracture risk (HR=1.87); combined osteoporosis and sarcopenia significantly increase risk of fractures (HR=3.49) [Yu. J Am Med Dir Assoc. 2014] Sarcopenia more common in females with hip and vertebral fractures and in men with hip and ankle fractures; is an independent risk factor for hip and ankle fractures in men and hip fractures in women [Hong. PloS One. 2015]
Relationship of Sarcopenia and Fragility Fractures [Hong. PloS One. 2015]
Relationship of Sarcopenia and Fragility Fractures 357 with hip fracture vs. 2511 without hip fracture: Sarcopenia, older age and lower BMD associated with occurrence of hip fracture (OR=1.476, OR=1.103, OR=0.082 respectively) [Hida. Geriatr Gerontol Int. 2013] 64% of hip fracture women and 95% hip fracture men had sarcopenia in New Mexico; adjusted OR = 10.54 [Di Monaco. Arch Gerontol Geriatr. 2012] 58% of hip fracture patients were sarcopenic; 74% were osteoporotic. Adjusted OR of osteoporosis of sarcopenic women = 1.80. [Di Monaco. Arch Gerontol Geriatr. 2011]
Sarcopenic Obesity and Frailty Decrease in resting metabolic rate (RMR) increased risk of fat deposition Obesity and sarcopenia/frailty may interact with respect to metabolic risk. [Buch. Exp Gerontol. 2016] Muscle mass loss and fat accumulation in muscle in elderly, with or without obesity, may explain some of the functional and metabolic defects in frail, sarcopenic population. Mechanism of interaction involves hormonal dysregulation and inflammatory pathways. [Berton. Nutr Rev. 2012]
Interventions for Sarcopenia Resistance exercise High quality protein intake Leucine HMB (beta hydroxybeta methylbutyrate) [Berton. Nutr Rev. 2012]
Interventions for Sarcopenia [Bowen. J Cachexia Sarcopenia Muscle. 2015]
Interventions for Sarcopenia Enhance muscle protein synthesis Increase lean mass in relation to fat mass 1.0 1.5g/kg of protein per day (recommended dietary allowance) [Morley. J Am Med Dir Assoc. 2010; American Society for Parental and Enteral Nutrition] HMB: a metabolite of branched chain amino acid leucine Improve muscle quality by upregulation of anabolic signaling and attenuation of proteolysis [Berton. Nutr Rev. 2012]
Interventions for Sarcopenia [Cruz Jentoft. Age Ageing. 2014] Leucine inhibits proteolysis and stimulates protein synthesis independently of insulin. Aged muscle less sensitive to leucine at physiological concentration but still able to respond if sufficiently large amount.
Interventions for Sarcopenia [Kim. JAGS. 2012] Randomized controlled trial 155 women aged 75y with sarcopenia Exercise + amino acid supplement group (E+AAS); Exercise group (E); Amino acid supplementation group (AAS); Health education (HE) for 3 months Exercise: 60min comprehensive exercise twice/week AAS: 3g leucine rich essential amino acid mixture twice/day
Interventions for Sarcopenia Walking speed significantly increased in all groups Leg muscle mass increased in E+AAS and E groups Knee extension strength increased in E+AAS group only by 9.3% Odds ratio for leg muscle mass and knee extension strength improvement = 4.89 (E+AAS vs. HE)
Myostatin Antagonists Myostatin (Growth Differentiation Factor 8, GDF 8) A member of transforming growth factor (TGF ) Negative regulator of skeletal muscle growth Myostatin null mice have twice the muscle mass of normal mice Increased expression with weightless and unloading From: http://www.sp.uconn.edu From: quest.mda.org
Myostatin Antagonists Bimagrumab (BYM338) Monoclonal antibody developed by Novartis to treat muscle loss and weakness Receive breakthrough to treat sporadic inclusion body myositis (sibm, inflammatory muscle disease) in 2013 Currently entering Phase II development Binding to type II activin receptors Show an increase in appendicular muscle mass and handgrip strength but gait speed is improved only in those with low baseline reading [Cesari. J Frailty Aging. 2015]
Myostatin Antagonists Myostatin Blocker (PF 06252616) Antibody based drug developed by Pfizer Healthy volunteers receiving 10mg drug by infusion every 2 weeks shows a statistically significant increase in muscle mass and volume None of side effects in Phase I study Phase II will focus on Duchenne Muscular Dystrophy Other companies development ACE 031 (decoy receptor) by Acceleron/Shire (side effect nosebleed and stopped?!) MYO 029 by Wyeth (no improvement?!) From: http://community.parentprojectmd.org/profiles/ blogs/pfizer myostatin blocker trial set to launch From: quest.mda.org
Selective Androgen Receptor Modulators (SARMs) SARMs A class of androgen receptor ligand binding to androgen receptor Display tissue specific activation of androgenic signaling LGD 4033 (Ligandrol) [Basaria. J Gerontol A Biol Sci Med Sci. 2013] Developed by Ligand Pharmaceuticals (USA) Non steroid, long elimination half life Well tolerated by young men; increased lean body mass and leg press strength Fat mass did not change significantly MK 0773 [Papanicolaou. J Nutr Health Aging. 2013] Developed by MSD Phase IIA sarcopenia clinical trial: increased lean body mass; no significant improvement in strength or function
Bring home Messages Sarcopenia is different from cachexia and disused muscle atrophy. Sarcopenia is associated with osteoporosis and fracture risk. Obesity and sarcopenia/frailty may interact with respect to metabolic risk. Combined exercise and nutrient supplement therapy is a more promising approach to resist against sarcopenia, where nutrient is recommended to be high quality protein, esp. leucine. Myostatin antagonist is a relatively potent drug under development to resist against sarcopenia for the time being.
Thank You