J Nutr Health Aging. 2018;22(6):664-675 © The Author(s) ROLE OF ORAL NUTRITIONAL SUPPLEMENTS ENRICHED WITH Β-HYDROXY-Β-METHYLBUTYRATE IN MAINTAINING MUSCLE FUNCTION AND IMPROVING CLINICAL OUTCOMES IN VARIOUS CLINICAL SETTINGS 1 2 2 3 2 A. SANZ-PARIS , M. CAMPRUBI-ROBLES , J.M. LOPEZ-PEDROSA , S.L. PEREIRA , R. RUEDA , 4 5 6 M.D. BALLESTEROS-POMAR , J.M. GARCIA ALMEIDA , A.J. CRUZ-JENTOFT 1. Nutrition Unit, Universitary Hospital Miguel Servet, Zaragoza, Spain; 2. Abbott Nutrition, Research and Development, Granada, Spain; 3. Abbott Nutrition, Research & Development, Columbus, OH, USA; 4. Complejo Asistencial Universitario de León; León, Spain; 5. Hospital Virgen de la Victoria de Málaga, Spain; 6. Geriatric Department, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain. Corresponding author: Alejandro Sanz-Paris, Nutrition Unit, Universitary Hospital Miguel Servet, Isabel the Catholic 1-3, Zaragoza 50009, Spain. firstname.lastname@example.org Abstract: Aging and disease-related malnutrition are well associated with loss of muscle mass and function. Muscle mass loss may lead to increased health complications and associated increase in health care costs, especially in hospitalized individuals. High protein oral nutritional supplements enriched with β-hydroxy-β- methylbutyrate (HP-ONS+HMB) have been suggested to provide benefits such as improving body composition, maintaining muscle mass and function and even decreasing mortality rates. The present review aimed to examine current evidence on the effect of HP-ONS+HMB on muscle-related clinical outcomes both in community and peri-hospitalization patients. Overall, current evidence suggests that therapeutic nutrition such as HP-ONS+HMB seems to be a promising tool to mitigate the decline in muscle mass and preserve muscle function, especially during hospital rehabilitation and recovery. Key words: Sarcopenia, malnutrition, oral nutritional supplements, disease, aging, HMB, muscle wasting. Introduction instance, progressive muscle decline can be a consequence of aging-related muscle dysfunction such as anabolic Maintaining skeletal muscle mass and function is important resistance, insulin resistance, reduced blood flow, impaired for sustaining health through the lifespan. Muscle comprises regenerative capacity, as well as mitochondrial dysfunction about 30-40 % of the body weight and is considered a key (6) (Fig. 1). Finally, some endocrine mechanisms such as tissue for physical movement and posture, as well as for vital thyroid dysfunction and reduced anabolic hormones may also functions including chewing, swallowing, and breathing (1). lead to muscle loss. Muscle loss has been associated with Besides its relevant role in structural maintenance of the body, negative health outcomes such as augmented risk of falls, muscle has been recognized as an important active metabolic which is associated with potential fractures, and impaired and homeostatic organ acting as the main reservoir for proteins activities of daily living (ADLs) (3), metabolic disorders, and serving as the main tissue for glucose disposal by the body negative hospitalization outcomes such as infections, health (2). Given these essential roles of muscle in overall well-being, complications and increased length of stay (LOS), mobility- it is not surprising that decline in muscle mass and function disability, and even mortality (7, 8) (Fig. 1). Even, it has leads to increased risk of mobility-disability (3), infections or been suggested that potential differences may exist in effects even mortality (4). of low muscle relative to either body mass or height on During the last decade, cumulative research has been cardiometabolic health in middle-aged and older adults (9). focused on the clinical causes and consequences of muscle Muscle loss can also occur as a result of malnutrition, mass and strength loss due to aging and/or associated with when nutritional intake is not optimal resulting in both pathological conditions in older adults. Muscle loss combined ‘over’ or ‘under’ nutrition. Of special interest is disease with strength or functional loss is currently defined as related malnutrition (DRM) that refers to ‘under nutrition’ ‘Sarcopenia’ (5). The European working group on sarcopenia characterized by a deficit of energy, protein and other in older people has suggested sub-categories of sarcopenia nutrients, loss of appetite, and disease-related catabolism. based on cause. This includes “primary” sarcopenia due to age- Additionally, it is known that impaired immunity because of related muscle loss and “secondary” sarcopenia that comprises; malnutrition predisposes to infections and decreases the ability a) disuse-related sarcopenia as a result of hospitalization or of the body to recover from infections. Thus, the combined physical inactivity, b) disease-related sarcopenia that includes effect of DRM and loss of muscle mass due to hospitalization- acute loss of muscle mass and strength due to acute or chronic related immobilization can cause severe functional decline disease, and c) nutrition-related sarcopenia resulting from (10), which has a negative impact on subsequent clinical and inadequate dietary intake of energy and/or protein (5). Multiple economic outcomes, such as high rate of non-elective hospital contributing factors are involved in loss of muscle mass. For readmission (8, 11). Published online January 4, 2018, http://dx.doi.org/10.1007/s12603-018-0995-7 Received May 5, 2017 Accepted for publication August 9, 2017 664 J Nutr Health Aging Volume 22, Number 6, 2018 THE JOURNAL OF NUTRITION, HEALTH & AGING© Figure 1 cachexia, acquired immune deficiency syndrome, sepsis, and Common causes and consequences of muscle mass and function endotoxemia (17, 19, 20). Recently, HMB has been added to loss high protein ONS as a means to target muscle loss in context of an optimized nutrition supplement that provides macro and micronutrients to meet the daily requirements of patients with nutritional insufficiencies/deficiencies. Administration of these high protein HMB-enriched oral nutritional supplements (HP-ONS+HMB) has shown promise in helping adults maintain muscle mass and function in hospital and community settings (4, 21-23). Therefore, the purpose of this review is to summarize and discuss the current evidence that examined nutritional support, mainly through HP-ONS+HMB on muscle function and clinical outcomes in adults with, or at risk of, malnutrition, and both in community and peri-hospitalization settings. Methods PubMed was used to search for relevant articles from the index date to August 2017. Keywords used in the search are summarized as follows: ‘HMB’ or ‘beta-hydroxy-beta- methylbutyrate’ and (oral nutrition supplements, enteral nutritional supplementation, nutritional intervention, replacement, therapy, treatment, effects or administration) and (muscle building, muscle breakdown, muscle function, DRM is a frequent problem in all health care settings, muscle strength, grip, muscle loss, muscle wasting, or including hospitals, care homes, and sheltered housing being sarcopenia, bed rest, disuse atrophy, or malnutrition, disease high prevalent in older individuals and in rehabilitation settings related malnutrition) and (body composition, free fat mass, (12). Therefore, lifestyle interventions that address both fat mass, muscle mass, lean body mass) and (amino acid malnutrition and associated-muscle loss is of great importance. supplementation, amino acid metabolite) and (aged, aging, Several approaches have been evaluated as potential older or elderly). strategies to mitigate muscle loss, such as exercise and/or therapeutic nutrition, and pharmaceutical interventions such Role of ONS in clinical practice as myostatin inhibitors, testosterone and selective androgen receptor modulators. Resistance exercise has well established Sarcopenia and malnutrition frequently coexist especially benefits on preserving muscle (13). Thus, exercise in in older adults who are hospitalized or those with chronic combination with therapeutic nutrition has also shown some disease (DRM). The coexistence of both conditions can promising results as an effective approach to target muscle loss further aggravate disease prognosis and negatively impact in older adults (13). clinical outcomes. Malnutrition is a condition that often goes Oral nutritional supplements (ONS) containing high levels of unrecognized especially in the hospital although, it has been proteins, essential amino acids, and branched chain amino acids associated with negative clinical and economical outcomes have also been reported to support muscle mass maintenance such as increased LOS, health costs, complications, readmission in different patient settings (14), although the optimal levels rates, and mortality rates (8). In fact, although malnutrition to meet patients’ needs remain uncertain (15). In particular, prevalence may be very high ranging from 8% to 62%, ingestion of protein sources enriched with Leucine (Leu) is depending on clinical setting and population type, in an eleven- thought to offer benefits in the preservation of muscle mass and year retrospective study, which analyzed data from 44 million function during aging and illness (14, 16). adult impatient episodes, only 1.6% of the population received Of special relevance is a Leu metabolite, β-hydroxy-β- ONS intervention (24). methylbutyrate (HMB), which exerts its effects through Prevention and treatment of malnutrition include dietary protective, anticatabolic mechanisms, and has been shown to advice to increase the protein and energy content of the diet, directly influence protein synthesis (17) and mitochondrial food fortification, or nutrient supplementation via ONS (25, dynamics in skeletal muscle (18). HMB has been shown to 26). In clinical practice, this is usually addressed by adding benefit muscle mass and strength in various clinical populations commercially available ONS to standard diet after systematic such as chronic obstructive pulmonary disease (COPD), cancer assessment of the nutritional status and nutritional requirements 665 J Nutr Health Aging Volume 22, Number 6, 2018 ROLE OF ORAL NUTRITIONAL SUPPLEMENTS ENRICHED WITH Β-HYDROXY-Β-METHYLBUTYRATE (energy, proteins and micronutrients) of the patients to ensure the control after meta-analysis (1.76 Kgf (95% Confidence an optimized intervention to address specific nutritional needs Interval 0.36-3.17), p=0.014, n=219). These findings are (27, 28). consistent with conclusions from other systematic reviews Evidence is still limited on the clinical effectiveness of including different types of HP-ONS (34, 39). However, dietary advice (29). Also results from nutritional interventions long-term population studies are still needed to conclusively studies in malnourished populations are mixed possibly due to demonstrate the efficacy of HP-ONS in improving muscle and variations in study design, inclusion criteria, and composition functional outcomes. of the nutritional intervention (27), factors that may have In conclusion, evidence for HP-ONS on mitigating contributed to the failure of some studies to show significant sarcopenia outcomes is still weak (13). effects. In addition, many nutrition intervention studies target hospital outcomes such as LOS, episode cost, and readmission HMB alone or combined with other amino acids probability which requires large sample size, which is not always reachable (24). Several systematic reviews and meta-analyses have However, a number of systematic reviews and meta- evaluated the potential role of HMB supplementation, either analyses consistently indicate clinical benefits of using ONS on alone or in combination with other amino acids, in improving outcomes, including dietary intake, body composition, disease muscle quality and function both in older adults with sarcopenia complications, mortality and LOS (30-33). and under pathological conditions (14, 17, 40). On the other hand, a cumulative body of evidence suggests Recently, a systematic review of the clinical evidence that ONS enriched with specific nutrients, and administrated focused on oral supplementation with amino acids and as a sole source of nutrition or in addition to normal diet amino acid metabolites (included HMB) in patients under could have a positive impact on adults under pathological critical illness or other similar muscle wasting illness (COPD, conditions, especially among hospitalized patients. In fact, chronic heart failure, age-related muscle wasting (sarcopenia) several recent systematic reviews and meta-analysis have or disuse atrophy (bed-rest) was performed by Wandrag et shown a potential beneficial effect of ONS, especially those al. (14). Results from four studies including intensive care containing high protein levels (with ≥20% of total energy from unit patients revealed that despite the fact that the studies protein; HP-ONS), on clinical outcomes in elderly people were classified as moderate and low quality with limitations, at risk of malnutrition (34, 35). Protein is key for driving HMB supplementation seemed to improve nitrogen balance in muscle anabolism and provides the amino acid building blocks patients, and the addition of Arginine (Arg) and/or Glutamine needed to rebuild muscle (36). Muscle protein synthesis is (Gln) appeared to counterbalance any benefit of HMB alone. significantly diminished in the elderly and chronic disease Beneficial effects were also reported in a recently published populations (37). Based on current reviewed evidence on the systematic review and meta-analysis of RCTs conducted by benefits of protein intake in treating age-related decline in Wu et al. (40), which aimed to investigate whether HMB muscle mass, strength, and functional abilities, the European supplementation had significant effects on body composition society for clinical nutrition and metabolism recently increased and muscle strength in healthy older adults and those with the protein recommendations for healthy elderly (1-1.2 g pathological conditions with a mean age of ≥ 65 years. Six protein/Kg body weight/day) and malnourished or at risk of studies were identified to be included in the meta-analysis malnutrition elderly (1.2-1.5 g protein/Kg body weight/day) showing that supplementation of HMB alone or in combination (38). Therefore, dietary interventions consisting of HP-ONS with other amino acids increased muscle mass gain in the during sarcopenia and illness-associated muscle wasting have intervention groups compared to the control groups (standard been currently proposed as potential nutritional strategies to mean difference=0.352 kg; 95% CI: 0.11, 0.594; Z value=2.85; mitigate muscle loss and related outcomes (16, 34). In this p=0.004). Yet, there were no differences in fat mass changes line, a meta-analysis including 36 randomized control trials between groups (standard mean difference=-0.08 kg, p=0.511). (RCTs) (n=3,790) revealed that a range of clinical, functional This review also found that out of the 9 RCTs that evaluated and nutritional benefits and economic implications was favored muscle strength and functionality outcomes in response to in patients at hospital or community setting (mean age 74 HMB, two of the studies (40, 41) reported improvements years) receiving HP-ONS with no loss of appetite or reduction in the aforementioned outcomes. The effect of a 12 week in normal food intake as compared to control group (35). A supplementation with a combination of HMB (2 g/d), Arg (5 major finding was a significant overall reduction (19%) in a g) and Lysine (Lys) (1.5 g) in elderly sedentary women (~76.7 range of complications together with significant increases in years) was examined by Flakoll et al. (41), which found that hand grip strength (HGS), mean total energy, protein intakes, at the end of the study, HGS was significantly greater in the body weight, and mid-arm muscle circumference. Interestingly, HMB-supplemented group than in the placebo group (p=0.04). HP-ONS was found to be effective in improving muscle Further, there was a 17% improvement in the get-up-and-go strength with 5 out of 6 RCTs reporting significant mean performance time in the HMB-supplemented group versus the changes in HGS that were greater in the HP-ONS group than placebo group (p=0.002). 666 J Nutr Health Aging Volume 22, Number 6, 2018 THE JOURNAL OF NUTRITION, HEALTH & AGING© Table1 Summary of studies using HP-ONS+HMB in community dwelling older adults Outcomes Study Population Design N Duration Body composition Strength Functionality Others Cramer et al (2016) Age ≥65 years with Prospective, randomized, 330 24 weeks NSD between groups In severe sarcopenia: - - malnutrition and double-blinded, controlled, for Total lean muscle lowest leg strength at sarcopenia 2-treatment parallel inter- mass in all sarcopenia baseline vention groups at 12 and 24 EXP: in mild-moderate CTRL: HP-ONS (n=165) weeks sarcopenia and normal EXP: HP-ONS+HMB (1.5 In severe sarcopenia: ↓ grip strength ↑ leg stren- g CaHMB) (n=165), 2 ser- lowest muscle quality at gth from baseline to 12 vings/day baseline weeks as compared to EXP: sarcopenia and CTRL normal grip strength ↑ leg strength from group improved muscle baseline over 24 weeks, quality to a greater NSD between groups extent than CTRL from ↑ Grip strength in baseline to 12 weeks severe and moderate NSD between groups at sarcopenia (normal gait 24 weeks speed) from baseline to 12 weeks, NSD between groups Berton et al (2015) Female, mean age Randomized, double-blind, 65 8 weeks NSD for BW, FFM, EXP: ↑ PT isokinetic NSD between EXP: product 69.5±5.3 years placebo controlled, 2 group FM, and ASSMI flexion and extension, ↑ groups for total consumption com- parallel design between groups PT isometric strength, SPPB scores pliance was 96±6% CTRL: Exercise + no treat- EXP: ↑ muscle density ↑ HG endurance vs. EXP: ↑ 6-Minute ment/placebo (not specified) vs. CTRL CTRL Walking Test vs. (n=33) Trend for improvement NSD for HG strength CTRL EXP: Exercise + HP- in fat:muscle ratio between groups ONS+HMB (1.5 g CaHMB) (p=0.07) (n=32), 1 serving/day de Luis et al (2015) Age >65 years with Open-label, crossover 35 12 weeks EXP: ↑ BMI, ↑ BW, EXP: ↑ HG strength EXP: ↑ Sf 36 QoL No events of diarrhea, recent weight loss EXP: HP-ONS+HMB (1.5 g ↑ FFM, ↓ FM from (right and left) NSD in all other nausea, cramps, CaHMB), 2 servings/day baseline In sub analysis: Signi- QoL measures abdominal distention In sub analysis: Signi- ficant changes only (physical function, or vomiting ficant changes only remained in the >3.4% bodily pain, vitality, remained in the >3.4% weight improvement social functioning, weight improvement group role emotional) group In sub analysis: Significant changes only remained in the >3.4% weight improvement group ASSMI, Appendicular Skeletal Muscle Mass Index; BMI, Body Mass Index; BW, Body Weight; CaHMB, Calcium β-hydroxy-β-methylbutyrate; CTRL, Control; EXP, Experimental; FFM, Fat Free Mass; FM, Fat Mass; HG, Hand Grip; HP-ONS+HMB, High Protein-Oral Nutritional Supplement + β-hydroxy-β-methylbutyrate; NSD, Non-Significant Difference; PT, Peak Torque; QoL, Quality of Life; SPPB, Short Physical Performance Battery; ↑ or ↓: statis- tically significant increase or decrease. J Nutr Health Aging Volume 22, Number 6, 2018 ROLE OF ORAL NUTRITIONAL SUPPLEMENTS ENRICHED WITH Β-HYDROXY-Β-METHYLBUTYRATE A more recent study by Stout et al. (42) in older adults also weight loss over time for the HMB group (p=0.06). These found improvements in physical performance in response to findings are clinically relevant since patients who undergo total HMB supplementation. This study was a double-blind, placebo knee arthroplasty have been reported to have a 20% to 30% controlled trial carried out in two phases. Each phase included decline in muscle strength and walking ability, even at 1 year 54 ambulatory males and females (aged >65 years). Phase I was after surgery. Therefore, preservation of leg strength could lead a non-exercise phase where participants were supplemented to an improved walking ability thereby enhancing ADLs and with HMB (3 g/d) or placebo and phase II was the exercise improving quality of life (QoL). phase where participants were supplemented with HMB (3 Studies showing muscle inactivity due to extended bed-rest g/d) or placebo in combination with progressive resistance (e.g. during hospitalization) have shown to induce rapid muscle training (RT) (3 days a week). For Phase I, body composition atrophy and loss of strength and power especially in the elderly. analysis revealed a significant increase from baseline in total Healthy older subjects have been reported to lose ~1 kg of lean and leg lean mass within the HMB group (but not placebo) tissue from the lower extremities after 10 days of bed-rest, at 3 and 6 months, with a trend (p=0.09) favoring HMB over with an associated ~16% decline in isokinetic knee extensor placebo for leg lean mass at 6 months. Also, the HMB group strength . Loss of muscle mass is a key factor in the elderly had significantly greater leg strength and muscle quality than in relation to loss of functional capacity, as well as hospital the placebo group at the end of 6 months and greater fat mass morbidity and mortality. Deutz et al. (45) recently evaluated loss at 24 weeks. For Phase II, RT had a significant benefit on the effect of HMB (3 g/d) versus placebo control in healthy lean mass, strength and function in both groups, reinforcing the older adults (n=19) put on 10 days of complete bed-rest. Bed- benefits of progressive RT. Thus, these findings supported a rest caused a significant decrease in total LBM (2.05 ± 0.66 kg; benefit of HMB on muscle mass, strength and muscle quality p=0.02, paired t-test) in the control group, whereas treatment in the absence of RT, and reinforced the benefits of RT on with HMB prevented this decline over bed-rest (0.17 ±0.19 improving body composition and muscle functionality. kg; p=0.23, paired t-test). A statistically significant difference Another previously published systematic review of (p=0.02, ANOVA) between treatment groups for change in randomized trials examined the clinical literature on LBM over bed-rest was reported. the effectiveness of HMB supplementation in healthy and Altogether, these findings suggest that supplementation of pathological conditions (17). Notably, the authors concluded HMB alone or in combination with other amino acids may be a that most of selected studies exhibited a beneficial effect of valuable nutritional therapy to help maintain muscle mass and HMB either alone or in combination with other amino acids functionality in healthy older adults or hospitalized patients as (Arg and Gln or Arg and Lys) in mitigating loss of muscle mass well as during recovery/rehabilitation. and function in both healthy older adults and in patients with different pathological conditions. HMB-enriched ONS in community dwelling older adults Several studies have examined the effect of HMB in combination with other amino acids on postoperative The associated loss of muscle mass with aging has been rehabilitation. Reduced muscle strength has been observed recognized as a major health concern related to a decline during postoperative recovery in patients with osteoarthritis in physical function, lower QoL and mortality. Recent after total knee arthroplasty. Nishizaki et al. (43) investigated publications have shown that supplementation with the effect of supplementation with a combination of HMB HP-ONS+HMB resulted in favorable muscle health outcomes (3g), Arg (14 g), and Gln (14 g) versus placebo control on in community dwelling older adults (Table 1). postoperative recovery of quadriceps strength in patients aged Berton et al. (23) aimed at evaluating whether 65-80 years (n=23) after total knee arthroplasty. Postoperative HP-ONS+HMB given as 1 serving/day for 8 weeks together rehabilitation in these patients consisted of strength-training with a mild fitness program could improve physical and range-of-motion exercises, starting in bed (postoperative performance, muscle strength and body composition day 1), followed by walking training on subsequent days of parameters. This open labeled RCT was conducted in a rehabilitation. Muscle strength (knee extension) of the operated group of healthy community dwelling women (aged ≥ 65 and non-operated was measured on postoperative days 14, 28, years) attending a mild fitness program including mainly and 42. Whereas the control group showed a significant loss of aerobic exercise and some resistance exercise. Participants muscle strength on day 14 (p=0.02), the HMB group attenuated in the control group were encouraged not to take any muscle strength decline for the operated-side knee over pre- and supplementation that increases their physical performance, post-operative periods. There was no significant difference however, diet specifications were not provided. No between groups in muscle cross sectional area (measured by significant group differences were observed over 8 weeks computerized tomography) before surgery and 42 days post- for the primary outcomes such as short physical performance surgery. The duration of rehabilitation was similar for both battery scores or balance test scores. The greatest benefits groups, with a comparable LOS (19.1±3.7 days for the HMB related to HP-ONS+HMB supplementation were observed vs. 18.9±3.3 days for the control), but there was a trend for for the secondary outcomes such as improved hand-grip 668 J Nutr Health Aging Volume 22, Number 6, 2018 THE JOURNAL OF NUTRITION, HEALTH & AGING© endurance (delta=21.41±16.28 s; p=0.02) and peak torque PT, muscle quality, grip strength, and gait speed from baseline (PT) isokinetic flexion (delta = 1.56±1.56 Nm; p=0.03), with no differences between groups. Similarly, both groups extension (delta=3.32±2.61 Nm; p=0.03) and PT isometric significantly increased leg strength from baseline over 24 strength (delta=9.74±3.90 Nm; p=0.02), while no changes were weeks (p<0.001), with no treatment differences. However, observed for HGS. Notably, 6-minute walking test improved when stratified for sarcopenia severity, early benefits (12 from the baseline to the follow-up (delta=7.67±8.29 m; p=0.04) weeks) on leg strength was observed with HP-ONS+HMB in supplemented group. There were no significant changes in supplementation over control in the non-severe sarcopenia body weight (BW), fat free mass (FFM), abdominal fat mass group (normal grip strength) (p=0.032). In addition, in this (FM) or appendicular skeletal muscle mass index (ASMMI) group muscle quality improved to a greater extent than the between groups. However, HP-ONS+HMB group did show control group (p=0.027) from baseline to 12 weeks. By 24 significant increases in muscle density at radius and tibia weeks, both groups showed improvements in leg strength and sites as compared to control (p=0.03), as well as a trend for MQ with no treatment differences. improvement in fat: muscle ratio (p=0.07).Since SPPB at This study points to the overall benefit of supplementing BL was >11 (fully functional), it is not surprising that this malnourished-sarcopenic individuals with HP-ONS for outcome did not change at the end of the intervention period, improving muscle outcome, even in that absence of an exercise due to low sensitivity of the measure to detect minor changes program. In addition, it shows that there are early benefits in functional status. Overall, this study points to the beneficial to be seen with supplementation of HP-ONS+HMB on mild- effect of HP-ONS+ HMB in context of a mild fitness program moderate sarcopenic subpopulations as early as 12 weeks into on clinically relevant measures like isometric and isokinetic intervention. These results also point to the need for early strength, and 6-minute walking test since impairment in these intervention in order to achieve benefits on muscle-related outcomes is mainly associated with fall risks, low bone mineral outcomes in older sarcopenic adults. density, hip fractures, and functional limitations in ADLs. Overall, these three studies indicate that in elderly Likewise, an open labeled study performed by de Luis et al. community-dwelling patients the consumption of  investigated the effect of a HP-ONS+HMB (2 servings HP-ONS+HMB may be useful for improving muscle related- per day) on muscle strength and QoL in elderly patients (>65 functional outcomes and QoL. However, additional well years) with recent weight loss (>5% during previous 3 months) controlled studies in a larger population are warranted to fully over a 12-week period. Overall, this study showed that the validate the findings of these published studies. 35 patients receiving the HP-ONS+HMB reported significant benefits in anthropometric parameters such as increased body HMB-enriched ONS in patients in peri-hospitalization mass index (BMI), weight, and FFM (p>0.05) and increases setting in blood biochemical variables including prealbumin (1.5±4.1 mg/dl). The physical and general health domain, as part of the Use of HP-ONS+HMB can also lead to significant clinical, Short Form-36 Health Survey, significantly (p<0.05) improved, functional and nutritional benefits in individuals with, or at risk as well as the right and left HGS. Sub-analysis of two groups of, malnutrition in hospital setting. It is estimated that 30-50% (‘greater than’ and ‘less than’ 3.4% weight improvement) of hospitalized patients are malnourished and even short LOS revealed significant (p<0.05) improvements in body may have direct clinical consequences such as loss of LBM composition (2 Kg gain in lean mass), strength, and muscle accompanied with an accelerated muscle function decline function in the ‘greater than’ 3.4 % weight improvement’ (10). In addition, chronic diseases such as cancer and COPD subgroup. Notably, subjects with a greater weight gain can lead to severe muscle loss. Several published studies have (percentage of weight improvement >3.4%) consumed on been identified that examined the effect of HP-ONS+HMB average more HP-ONS+HMB (1.86+0.82 units/day) than on muscle function and metabolism in patients with different subjects with a smaller weight gain (<3.4%) (1.25+0.78 units/ pathologies under peri-hospitalization conditions (Table 2). day). This study however has some important limitations such It has been reported that adequate nutrition reduces as the open label design, the lack of an isocaloric control immobilization and hospitalization in orthopedic patients with group, and a small sample size. Nevertheless, this study does malnutrition through an improvement in wound healing, muscle demonstrate the clinical benefits of consuming HP-ONS+HMB mass and muscle strength (48). In a recent RCT, Ekinci et in a population undergoing weight loss. It remains to be seeing al. (21) evaluated the effects of HP-ONS+HMB over and if the observed benefits are due to caloric intake versus the above standard postoperative nutrition (experimental) versus specific composition of the ONS consumed. standard postoperative nutrition alone (control) on muscle A recent double-blinded RCT by Cramer et al. (47) strength and mobilization in malnourished women aged 65-94 evaluated the effects of two HP-ONS on malnourished and years who underwent hip fracture surgery. This study found sarcopenic older adults. Subjects received 2 servings/day of that 2 servings per day of a HP-ONS+HMB, added to the HP-ONS+HMB or HP-ONS (control group) for 24 weeks. standard postoperative nutrition plan for 30 days was able Overall, both ONS groups showed improvement in isokinetic to significantly increase HGS as compared to control group, 669 J Nutr Health Aging Volume 22, Number 6, 2018 ROLE OF ORAL NUTRITIONAL SUPPLEMENTS ENRICHED WITH Β-HYDROXY-Β-METHYLBUTYRATE Table 2 Summary of studies using HP-ONS+HMB in patients in peri-hospitalization setting Outcomes Study Population Design N Duration Body composition Strength Functionality Others Malafarina et al Mean age 85.4±6.3 Multi-center rando- 92 30 days EXP: No change in FM, NSD in HG NSD for gait speed EXP: ↑ protein, ↑ Vitamin (2017) years with a hip mized open-label MM and aLM strength and grip work index D ↑ prealbumin fracture admitted to CTRL: ↓ BW, ↓ MM and NSD for Barthel No change in LOS and rehabilitation CTRL: standard ↓ aLM. No change in FM score rehabilitation days diet (n=43) Good product adherence EXP: HP- (>80%) ONS+HMB (1.5 Predictive factors for g CaHMB), 2 Δ-aLM: ONS, Functional servings/day + stan- Ambulation Categories dard diet (n=49) prior to fracture, and Bar- thel score prior to fracture Olveira et al (2016) Normally nourished, Prospective, 30 12 weeks (follow EXP: ↑ BMD and ↑ Mid- EXP: ↑ maximal - EXP: mean age 56.1±13 randomized, pa- up at week 24) Arm Muscle Circumfe- and mean HG stren- ↑aseline years with non-cystic rallel-group rence from baseline at gth from baseline to fibrosis bronchiectasis CTRL: Pulmonary 12-24 weeks 12-24 weeks ↑ myostatin from baseline rehabilitation only ↑ BW, ↑ FFM (total), ↑ CTRL: ↑ mean at 24 weeks (no ONS) (n=15) FFM arms and ↑ FFM HG strength from EXP: Pulmonary trunk, and ↑ FFMI at 12 baseline to 12-24 ↑ prealbumin from base- rehabilitation +HP- weeks (p<0.01) from weeks line to 12-24 weeks ONS+HMB (1.5 g baseline CaHMB) (n=15), 1 Between group ↑ protein intake from serving/day NSD for FFM legs analysis was not baseline to 12 weeks. NSD performed/ reported at 24 weeks Between group analysis was not performed/ NSD for energy intake reported from baseline Ekinci et al (2016) Older female, age 65- Randomized 75 30 days NSD for BW and BMI EXP: ↑ Muscle EXP: ↑ % mobile EXP: Shorter wound-hea- 94 years at nutritional controlled between groups and from strength on day 30 patients on days ling period than CTRL risk with a hip fracture CTRL: standard baseline 15 and 30 (81.3%) admitted to orthopedic postoperative nutri- NSD in C-reactive compared to CTRL clinics tion (n=37) protein, arm circumfe- (26.7%) EXP: HP- rence, triceps skinfold ONS+HMB (1.5 thickness, and calf g CaHMB), 2 circumference servings/day + stan- dard postoperative nutrition (n=38 J Nutr Health Aging Volume 22, Number 6, 2018 THE JOURNAL OF NUTRITION, HEALTH & AGING© Table 2 (continued) Outcomes Study Population Design N Duration Body composition Strength Functionality Others Deutz et al (2016) Age ≥65 years, hospi- Prospective, rando- From admission to EXP: ↑ BW at day 30. - - NSD in primary com- talized malnourished mized, double- hospital discharge, Although NSD: changes posite endpoint (90-day (SGA class B or C) blinded, controlled, and from hospital in BW were consistent- postdischarge incidence two-group, parallel discharge to 90 ly higher compared to of death or nonelective design, multicenter days post-discharge CTRL readmission) PLACEBO: sup- 90 days post- EXP: ↓ 50% of 90-day plement (ready to discharge mortality rate drink beverage + Number needed to SOC) (n=324) treat=20.3 (95% Confi- EXP: SOC + HP- dence interval: 10.9, ONS+HMB (1.5 g 121.4) CaHMB) (n=328), Improved odds of better 2 servings/day nutritional status at day 90 NSD for LOS and activi- ties of daily living Lopez et al (2015) Age 62. 5 years with Pilot, open-label, 29 2 months EXP: % LBM remained - - - Abstract COPD and/or involun- prospective, ran- stable and ↓ in CTRL tary weight loss domized, pre/post (NSD) treatment response NSD for BMI, % weight in 2 treatment arms loss, tricipital skinfold CTRL: HP-ONS thickness, CA, dyna- EXP: HP- mometry, average REE, ONS+HMB (1.5 calculated REE or forced g CaHMB), 2 expiratory volume-one servings/day second Garcia-Almeida et Mean age 59.7±15 Prospective, cros- 25 3 months EXP: ↑ LBM, ↑ BW EXP: ↑ muscle - At discharge: 96% were al (2015) Abstract years with severe sover strength SGA grade C and 4% malnutrition (96% were EXP: HP- grade B grade SGA-C) after ONS+HMB (1.5 At month 3: 8% were prolonged hospitali- g CaHMB), 2 SGA grade C, 12% B, and zation servings/day 80% A EXP: ↓ C-reactive protein ↑ albumin levels aLM, Appendicular Lean Mass; BMD, Bone Mineral Density; BMI, Body Mass Index; BW, Body Weight; COPD, Chronic Obstructive Pulmonary Disease; CA, Circumference Arm; CaHMB, Calcium-β-hydroxy-β-methylbutyrate; CTRL, Control; EXP, Experimental; FFM, Fat Free Mass; FFMI, Fat Free Mass Index; FM, Fat mass; HG, Hand Grip; HP-ONS+HMB, High-Protein-Oral Nutritional Supplement + β-hydroxy-β-methylbutyrate; LBM, Lean Body Mass; LOS, Length Of Stay; MM, Muscle Mass; NSD, Non-Significant Dif ference; QoL, Quality of Life; REE, Resting Energy Expenditure; SGA, Subjective Global Assessment SOC, Standard-Of-Care. ↑ or ↓: statistically significant increase or decrease. J Nutr Health Aging Volume 22, Number 6, 2018 ROLE OF ORAL NUTRITIONAL SUPPLEMENTS ENRICHED WITH Β-HYDROXY-Β-METHYLBUTYRATE (8.63±3.83 Kgf vs 6.40±3.86 Kgf; p=0.026), but not muscle maximal strength), mid-arm muscle circumference, and QoL mass. In addition, would-healing period was significantly (physical functioning scale) at both 12 and 24 weeks (p<0.01) shorter in the experimental versus control group (14.56±2.80 in HP-ONS+HMB treated group. These results showed the days vs. 15.93±2.18 days; p<0.05) and the immobilization benefits of the adjunctive use of a HP-ONS+HMB with an period was also reduced (81.3%; 26/32 of treated patients exercise rehabilitation program in improving strength and QoL were mobile on day 30 vs. 26.7%; 8/30 in control group; in patients. p=0.001) without changes to BMI. However, hospitalization The effect of HP-ONS+HMB has been explored in other time was not significantly changed in the first 30 days clinical outcomes together with muscle strength assessment. and no significant differences were detected in C-reactive Conflicting results exist regarding the role of HP-ONS in protein, arm circumference, triceps skinfold thickness, and hospital readmission (35) and mortality (34). Few oral nutrition calf circumference. Although important limitations included interventional studies exist in hospitalized populations with the lack of placebo control and assessment of dietary intake different pathologies aimed at evaluating impact on clinical was based on the patient’s declaration, these results suggest outcomes such as LOS or mortality. While some systematic that HP-ONS+HMB may benefit accelerated wound healing, reviews have suggested that readmission and mortality can increased mobilization and muscle strength in older adults after be significantly attenuated through using HP-ONS other orthopedic surgery. systematic reviews and meta-analysis have not (33, 50). There A multicenter randomized trial conducted by Malafarina et are a number of reasons leading to inconsistencies in these al. in 2017 (49) assessed whether HP-ONS+HMB improved studies namely low patients number, variability in the disease muscle mass and nutritional markers in elderly patients with hip status of the patients studied or other important methodological fracture. Ninety-two elderly patients (mean age 86 ±6 years) limitations. The NOURISH (Nutrition effect On Unplanned with hip fracture admitted to rehabilitation facilities received Readmissions and Survival in Hospitalized patients) study standard diet plus two servings per day of HP-ONS+HMB or represents one of the largest (n=622) RCT conducted so far standard diet only together with rehabilitation therapy (assisted in the nutrition field to evaluate readmission and survival. In mobility and physical exercise once a day for five days a this study Deutz et al. (19) explored the benefits of adding week) for 30 days. Weight, muscle mass and appendicular HP-ONS+HMB therapy to standard of care versus a placebo lean mass (aLM) were stable in supplemented patients, whilst control added to standard of care alone on various outcomes these parameters decreased in the control group, with a such as hospital readmissions, nutritional indices, morbidity and significant difference between groups (p<0.001 and p=0.020, mortality in malnourished, hospitalized older adults (≥ 65 years) respectively). Interestingly, fat mass did not change in both with various comorbidities such as pneumonia, congestive heart groups and more weight loss was observed in the control failure, acute myocardial infarction, and COPD (4). Although group (p<0.001). The predictive factors for Δ-aLM were ONS no significant differences were detected between groups for the (p=0.006), Functional Ambulation Categories (FAC) score primary composite endpoint (90-day of first readmission and/ prior to fracture (p<0.001) and Barthel index (BI) prior to or death and 90-day readmission rate), the 90-day mortality rate fracture (p=0.007). Supplemented patients showed higher significantly decreased with HP-ONS+HMB when compared to intake of protein (p=0.007) and increased blood concentration the placebo group, 4.8% versus 9.7% (p=0.018), respectively, of 25(OH)D (p<0.001) as compared to control group. In with a relative risk of 0.49 (95% confidence interval, 0.27 to addition, greater percentage of supplemented patients showed 0.90). This lack of significant difference in readmission rate functional recovery (68%) as compared to control group (59%), could be explained by the higher mortality rate in the placebo although the difference was not significant (p=0.265). This group, which could contribute to similar readmission rates study concluded that supplementing the standard diet with a observed in the 2 groups. In addition, while other efficacy HP-ONS+HMB resulted in muscle mass preservation, and variables such as mean total LOS and ADL were similar improved body composition in elderly patients with hip fracture between treatments, the proportion of patients categorized as admitted to rehabilitation unit. SGA-A (normally-nourished) increased over the study peaking Efficacy of HP-ONS+HMB combined with exercise has at day 90 with 45.5% in the HP-ONS+HMB group compared been assessed by Olveira et al (18) in non-malnourished with 30% in the placebo group. non-cystic fibrosis bronchiectasis patients under pulmonary An open-label prospective randomized study conducted rehabilitation (n=30; aged 18-80 years). Here the effects of by Lopez et al. (51) assessed the effect of a HP-ONS+HMB pulmonary rehabilitation with or without HP-ONS+HMB on muscle mass. HP-ONS+HMB was administrated to supplementation (1 serving/day) were compared over a 24 week malnourished COPD patients (n=13; 62.5 years) and was period. Patients who received pulmonary rehabilitation plus compared to control patients who consumed a HP-ONS for 2 HP-ONS+HMB showed improved FFM index at 12 weeks, months. Results from this study indicated that the percentage and improved trunk FFM but not appendicular FFM at 12 and change from baseline of LBM remained stable in the 24 weeks (p≤0.05). A significant increase from baseline was HP-ONS+HMB group and declined in the control group at the reported for bone mineral density (BMD), HGS (mean and expense of fat mass, as measured by bioelectric impedance 672 J Nutr Health Aging Volume 22, Number 6, 2018 THE JOURNAL OF NUTRITION, HEALTH & AGING© analysis. No statistical differences at month 1 and month 2 specialized intervention. from baseline were detected for BMI, percentage of weight loss, tricipital skinfold thickness, circumference arm (CA), grip Concluding remarks strength, average and calculated resting energy expenditure (REE) or forced expiratory volume-one second for both groups. Overall, due to the scarce number of RCTs using ONS, Althought promising, the full publication of this study needs to limited evidence exists on the benefits of ONS in improving be reported to critically assess the data. body composition and functionality in malnourished A relationship between improved nutritional status and populations in different clinical settings. However, there is a enhanced muscle function in malnourished hospitalized older cumulative body of evidence suggesting that a ‘therapeutic’ patients has been also reported. In a recent published abstract, ONS enriched with specific nutrients could have a positive Garcia-Almeida et al. (49) conducted a prospective single impact on adults under catabolic conditions, especially arm, open label study in 50 adults (average age 59.7±15 years) among hospitalized patients. These specific nutrients such with severe malnutrition (96% withgrade SGA-C), consuming as HMB have shown promising effects on maintenance of 2 servings of HP-ONS+HMB for 3 months after prolonged muscle mass and strength in various clinical settings. It has hospitalization. This study showed improvements in their been suggested that HP-ONS+HMB may be a promising nutritional status such that the population on the whole moved nutritional approach to maintain or improve muscle mass and from 96% SGA-C and 4% SGA-B upon hospitalization to function in adults under different health and disease conditions. 8% SGA-C, 12% SGA-B and 80% SGA-A upon discharge. Furthermore, in hospitalized patients, supplementation with a A correlation between gains in lean mass and increased total HP-ONS+HMB formula was linked to significant improvement energy intake diet was also observed, as well as increased in patient-related clinical outcomes. Therefore, combination serum albumin levels and improved muscle function at the end of HP-ONS+HMB with standard of care programs may be a of study. Althought promising, the full publication of this study promising tool to improve muscle health in clinical practice, needs to be reported. Also, the lack of a placebo control and especially during patient rehabilitation and recovery (Fig. the open label design of this study warrents consideration when 2). Nevertheless, there is still a need for more RCTs using making conclusions on the benefits of the HP-ONS+HMB HP-ONS+HMB administration in various clinical settings to intervention in this study. fully understand the scope of the benefits that supplementation could provide under various catabolic conditions. Clinical relevance of HP-ONS+HMB Figure 2 Although the number of publications are limited, there is an Lifestyle interventions to enhance muscle health evolving literature pointing to the benefits of supplementing with HP-ONS+HMB to address muscle-related problems that develop with aging, chronic disease and/or immobilization, in addition to improving nutritional status especially in patients with or at risk of malnutrition. The combination of improving nutritional status along with muscle outcomes such as body composition, strength and mobility appear to translate to clinically relevant outcomes such as improved recovery time from hip surgery (21), improvements in the patients QoL (22) and even reduction in mortality (4). A couple of studies have combining exercise along with HP-ONS+HMB resulting in better clinical outcomes such as improved mobility (23), strength and QoL (22), than seen with just exercise alone, pointing to benefits of multimodal intervention whenever feasible. Importantly, HP-ONS+HMB formula also contains key ingredients that have been shown to significantly improve muscle-related outcomes such as calcium and vitamins D (52- 55). The combination of all these micronutrients with HMB and other macronutrients such as high-quality protein levels seems to be a promising nutritional intervention to improve recovery of muscle mass and function in older adults. There however remains a need for more well-controlled studies using HP-ONS+HMB in various clinical populations to identify the populations that will benefit the most from this 673 J Nutr Health Aging Volume 22, Number 6, 2018 ROLE OF ORAL NUTRITIONAL SUPPLEMENTS ENRICHED WITH Β-HYDROXY-Β-METHYLBUTYRATE Author Contributions: A.S.P. formulated the review topic. M.C.R performed the 2013;29:29-36. literature review and A.S.P, M.C.R, S.L.P and A.J.C.J. wrote the manuscript. J.M.L.P., 20. Cruz-Jentoft AJ. Beta-hydroxy-beta-methyl butyrate (HMB): From experimental data to R.R.C., M.D.B.P. and J.M.G.A. revised the manuscript and M.C.R. edited drafts of this clinical evidence in sarcopenia. Curr Protein Pept Sci. 2017;18:1-5. review. All authors read and approved the final manuscript. 21. Ekinci O, Yanik S, Terzioglu Bebitoglu B, Yilmaz Akyuz E, Dokuyucu A, Erdem S. Effect of Calcium beta-Hydroxy-beta-Methylbutyrate (CaHMB), Vitamin D, and Conflicts of Interests: M.C.R., J.M.L.P., S.L.P. and R.R. are employed by Abbott Protein Supplementation on Postoperative Immobilization in Malnourished Older Adult Nutrition. A.J.C.J. has received speaker and research funds from Abbott Nutrition. Patients With Hip Fracture: A Randomized Controlled Study. Nutr Clin Pract. 2016:1- Ethical standard: I declare that the review comply with the current laws of the country 22. Olveira G, Olveira C, Dona E, Palenque FJ, Porras N, Dorado A, et al. Oral supplement in which it was performed” enriched in HMB combined with pulmonary rehabilitation improves body composition and health related quality of life in patients with bronchiectasis (Prospective, Open Access: This article is distributed under the terms of the Creative Commons Randomised Study). Clin Nutr. 2016;35:1015-22. Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), 23. Berton L, Bano G, Carraro S, Veronese N, Pizzato S, Bolzetta F, et al. Effect of Oral which permits use, duplication, adaptation, distribution and reproduction in any medium Beta-Hydroxy-Beta-Methylbutyrate (HMB) Supplementation on Physical Performance or format, as long as you give appropriate credit to the original author(s) and the source, in Healthy Old Women Over 65 Years: An Open Label Randomized Controlled Trial. provide a link to the Creative Commons license and indicate if changes were made. PLoS One. 2015;10:e0141757. 24. 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