HMB + Vitamin D Supplements for Frailty

(HMB Trial)

Overseen By John A Batsis, MD

Age: 65+

Sex: Any

Trial Phase: Academic

Sponsor: University of North Carolina, Chapel Hill

Must not be taking: Antiobesity medications

Disqualifiers: Dementia, Untreated psychiatric disorders, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

25 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators aim to conduct a 12-week, single-arm, pre/post-intervention of b-hydroxy-methylbutyrate in persons aged 65 to 85 years to assess feasibility and acceptability of the intervention and study procedures, secondary outcomes of physical function and changes in multi-omics patterns, and exploratory outcomes that will allow the team to describe physical function phenotype. The investigators' primary outcomes are the: feasibility of the study procedures (including safety), feasibility of the intervention delivery, and acceptability of study procedures and measures. Secondary outcomes include: Objective and subjective physical function measures that predict disability including the 30-second sit-to-stand, knee strength, isokinetic strength, grip strength, gait speed, 400-m walk test, Pittsburgh Fatiguability, PROMIS global health-10, social support, anthropometry, National Institutes of Health (NIH) Cognitive toolbox, Automated Self-Administered 24-hour Dietary Assessment (ASA-24), Community Healthy Activities Model Programs (CHAMPS), Ultrasound Imaging, Magnetic Resonance Imaging (MRI), Changes in untargeted metabolomic profile data based on qualitative or semiquantitative analysis of the most probable detectable metabolites in laboratory samples , Discover potential metabolites that explain changes in physical function using a discovery science, precision medicine approach (discovery science approach that is exploratory)

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those taking weight loss medications. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the treatment HMB + Vitamin D supplements for frailty?

Research shows that HMB supplements can improve muscle strength and physical performance in older adults, and when combined with Vitamin D, they may enhance muscle function and strength, especially in those with low Vitamin D levels. ^{1 2 3 4 5}

Is it safe to take HMB and Vitamin D supplements for frailty?

Research shows that taking HMB and Vitamin D supplements is generally safe for both young and older adults, with no serious side effects reported in studies. ^{1 3 6 7 8}

How does the HMB + Vitamin D treatment for frailty differ from other treatments?

The HMB + Vitamin D treatment is unique because it combines Beta-hydroxymethyl butyrate (HMB), which may help with muscle health, with Vitamin D, which is linked to improved physical performance and muscle function. This combination targets frailty by potentially addressing muscle mass and strength, areas not specifically targeted by other treatments. ^{9 10 11 12 13}

Research Team

John A Batsis, MD

Principal Investigator

University of North Carolina, Chapel Hill

Eligibility Criteria

This trial is for English-speaking adults aged 65 to 85 who are patients at UNC Geriatrics Medicine clinic and have chronic conditions as defined by Medicare. It's not for those with dementia, life-threatening illnesses, certain psychiatric diagnoses, recent heart failure hospitalization, advanced cancer on treatment, severe liver or kidney disease, advanced COPD or high Vitamin D levels.

Inclusion Criteria

A University of North Carolina at Chapel Hill (UNC) Geriatrics Medicine clinic patient

I am between 65 and 85 years old and speak English.

Chronic medical conditions based on the 21 Medicare multiple chronic conditions

Exclusion Criteria

Individuals with life-threatening or untreated psychiatric diagnosis that would interfere with study participation

My severe COPD stops me from participating fully.

Individuals unwilling/unable to provide consent

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive beta-hydroxymethyl butyrate (HMB) with vitamin D3 for 12 weeks to assess feasibility and acceptability of the intervention and study procedures.

12 weeks

Weekly visits (in-person or virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including changes in physical function and multi-omics patterns.

4 weeks

Treatment Details

Interventions

• Beta-hydroxymethyl butyrate supplement
• Matching Beta-hydroxymethyl butyrate supplement without Vitamin D
• Vitamin D supplement

Trial Overview The study tests a Beta-hydroxymethyl butyrate supplement with and without Vitamin D over 12 weeks in older adults. It aims to see if the supplements are feasible and acceptable to take while looking at their effects on physical function and changes in biological markers related to health.

Participant Groups

Group I: Participants with Weakness Experimental Treatment 3 Interventions

Participants will take beta-hydroxymethyl butyrate (HMB) with vitamin D3 for 12 weeks. Those participants with vitamin D3 levels \> 80 ng/dL will be provided intervention capsules without vitamin D3.

Beta-hydroxymethyl butyrate supplement is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Beta-hydroxy-beta-methylbutyrate for:

• Dietary supplement for muscle health and recovery

Approved in European Union as Beta-hydroxy-beta-methylbutyrate for:

• Dietary supplement for muscle health and recovery

Approved in Canada as Beta-hydroxy-beta-methylbutyrate for:

• Dietary supplement for muscle health and recovery

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

North Carolina Translational and Clinical Sciences Institute

Collaborator

Trials

61

Recruited

4,600+

Findings from Research

In a study involving 80 healthy older women, 1.5 g of calcium HMB supplementation for 8 weeks significantly improved muscle strength and physical performance, particularly in isokinetic and isometric strength, as well as endurance, without any serious adverse effects reported.

While there were no significant changes in the Short Physical Performance Battery (SPPB) scores, the HMB group showed notable improvements in specific strength measures and walking distance, suggesting targeted benefits of HMB supplementation in enhancing muscle function in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Oral Beta-Hydroxy-Beta-Methylbutyrate (HMB) Supplementation on Physical Performance in Healthy Old Women Over 65 Years: An Open Label Randomized Controlled Trial. Berton, L., Bano, G., Carraro, S., et al.[2018]

In a study of 1290 older adults, lower plasma levels of beta-hydroxy-beta-methylbutyrate (HMB) were significantly associated with frailty, indicating that HMB may play a role in muscle health as people age.

The research suggests that HMB levels decrease with age and are inversely related to frailty status, supporting the idea that HMB supplementation could be beneficial for frail older individuals with low HMB levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association between endogenous plasma beta-hydroxy-beta-methylbutyrate levels and frailty in community-dwelling older people. Molina-Baena, B., Carnicero, JA., Pereira, SL., et al.[2023]

Supplementation with calcium β-hydroxy-β-methylbutyrate (HMB) and vitamin D3 significantly improved lean body mass and muscle strength in older adults (over 60 years) who were not exercising, with notable benefits observed at 6 months and 3 months respectively.

The study, which involved 117 participants over 12 months, found that HMB+D supplementation enhanced physical functionality, as measured by a composite functional index, even in non-exercisers, indicating its potential as a beneficial intervention for maintaining muscle health in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Effects of Calcium β-Hydroxy-β-Methylbutyrate and Vitamin D3 Supplementation on Muscular Function in Older Adults With and Without Resistance Training: A Randomized, Double-blind, Controlled Study. Rathmacher, JA., Pitchford, LM., Khoo, P., et al.[2021]

HMB supplementation has been shown to increase lean body mass and preserve muscle strength and function in older adults aged 60 and above with sarcopenia or frailty, based on a review of three randomized controlled trials involving 203 subjects.

The systematic review followed PRISMA guidelines and highlighted that HMB is effective in combating muscle loss in this population, suggesting it could be a beneficial intervention for maintaining physical health in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effect of β-hydroxy-β-methylbutyrate (HMB) on Sarcopenia and Functional Frailty in Older Persons: A Systematic Review. Oktaviana, J., Zanker, J., Vogrin, S., et al.[2020]

In a 12-week study involving 70 pre-frail older adults, supplementation with high protein oral nutrition shakes containing 3g of β-hydroxy-β-methylbutyrate (HP-HMB) significantly increased mid-thigh muscle cross-sectional area compared to a control group, indicating improved muscle mass.

The HP-HMB group also showed significant improvements in physical performance, as evidenced by better scores in functional tests, and a reduction in intramuscular adiposity, suggesting that HP-HMB supplementation can enhance both muscle health and overall physical function in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral Nutritional Supplement with β-hydroxy-β-methylbutyrate (HMB) Improves Nutrition, Physical Performance and Ameliorates Intramuscular Adiposity in Pre-Frail Older Adults: A Randomized Controlled Trial. Peng, LN., Cheng, YC., Yu, PC., et al.[2021]

HMB is effective in reducing exercise-induced muscle damage and enhancing recovery in both trained and untrained individuals, especially when taken close to workouts and for at least two weeks prior to exercise.

Daily consumption of 38 mg per kg of body mass can lead to increased muscle hypertrophy, strength, and power, and HMB is safe for both young and elderly populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB). Wilson, JM., Fitschen, PJ., Campbell, B., et al.[2021]

The study found that the calcium salt form of HMB (CaHMB) has significantly higher relative bioavailability compared to the free acid form (FAHMB) when administered orally, with increases of 49%, 54%, and 27% for different doses.

After intravenous administration, CaHMB also showed an 80% greater bioavailability than FAHMB, suggesting that CaHMB may be more effective in enhancing muscle protein synthesis and preventing muscle loss due to its better absorption and lower systemic clearance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The relative bioavailability of the calcium salt of β-hydroxy-β-methylbutyrate is greater than that of the free fatty acid form in rats. Shreeram, S., Johns, PW., Subramaniam, S., et al.[2023]

The study demonstrated that administering a daily enteral supplement of 3g of HMB in the ICU is feasible, with 84.3% adherence to the prescribed regimen among 50 participants over 28 days.

While there was a trend suggesting that HMB may help reduce muscle loss compared to placebo, the results were inconclusive, indicating that further research is needed to confirm its efficacy in preventing muscle wasting after traumatic injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-hydroxy-beta-methylbutyrate supplementation and functional outcomes in multitrauma patients: A pilot randomized controlled trial. Wittholz, K., Fetterplace, K., Karahalios, A., et al.[2023]

Vitamin D plays a crucial role not only in bone health but also in muscle function, potentially influencing the development of frailty in older adults through its effects on muscle mass and strength.

Interventional studies suggest that vitamin D supplementation can positively impact frailty status by improving physical performance, although more rigorous research is needed to confirm a direct causal relationship.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hypovitaminosis D and frailty: Epiphenomenon or causal? Wong, YY., Flicker, L.[2018]

In a study of 688 older adults with low vitamin D levels, high-dose vitamin D supplementation (≥1000 IU/d) did not significantly prevent frailty compared to a lower dose of 200 IU/d.

Interestingly, participants taking 2000 IU/d had nearly double the risk of worsening frailty, while those on 4000 IU/d showed a lower risk of developing frailty, suggesting that higher doses may have varying effects on frailty outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of vitamin D supplementation on frailty in older adults at risk for falls. Cai, Y., Wanigatunga, AA., Mitchell, CM., et al.[2022]

Higher serum levels of 25-hydroxyvitamin D (25OHD) are significantly associated with a reduced risk of frailty, with a pooled risk estimate showing that for every 25 nmol/L increase in 25OHD, the risk of frailty decreases by about 12%.

The analysis included data from 10 studies with a total of 6 cross-sectional and 4 prospective cohort studies, suggesting a linear relationship between vitamin D levels and frailty risk, indicating that maintaining adequate vitamin D levels may be important for preventing frailty in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low 25-hydroxyvitamin D levels and the risk of frailty syndrome: a systematic review and dose-response meta-analysis. Ju, SY., Lee, JY., Kim, DH.[2019]

In a study involving 25,871 older adults, neither vitamin D3 nor omega-3 fatty acid supplementation showed any significant effect on preventing or reducing frailty over a median follow-up of 5 years.

The results indicate that routine supplementation with vitamin D3 or omega-3 fatty acids is not effective for frailty prevention in generally healthy older adults, suggesting that these supplements should not be recommended for this purpose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Vitamin D3 and Omega-3 Fatty Acid Supplementation on Risk of Frailty: An Ancillary Study of a Randomized Clinical Trial. Orkaby, AR., Dushkes, R., Ward, R., et al.[2023]

In a study of 1005 older adults (444 men and 561 women), low levels of vitamin D (25(OH)D <50 nmol/L) were significantly associated with increased odds of frailty in men (OR = 4.94), but not in women (OR = 1.43), indicating a sex-specific relationship.

Parathyroid hormone (PTH) appears to mediate the relationship between vitamin D levels and certain aspects of frailty, particularly in men, suggesting that addressing vitamin D insufficiency may be more critical for preventing frailty in older men.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of low vitamin D levels with the frailty syndrome in men and women. Shardell, M., Hicks, GE., Miller, RR., et al.[2021]

References

1. United States pubmed.ncbi.nlm.nih.gov

Effect of Oral Beta-Hydroxy-Beta-Methylbutyrate (HMB) Supplementation on Physical Performance in Healthy Old Women Over 65 Years: An Open Label Randomized Controlled Trial. [2018]

2. Germany pubmed.ncbi.nlm.nih.gov

Association between endogenous plasma beta-hydroxy-beta-methylbutyrate levels and frailty in community-dwelling older people. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Long-term Effects of Calcium β-Hydroxy-β-Methylbutyrate and Vitamin D3 Supplementation on Muscular Function in Older Adults With and Without Resistance Training: A Randomized, Double-blind, Controlled Study. [2021]

4. France pubmed.ncbi.nlm.nih.gov

The Effect of β-hydroxy-β-methylbutyrate (HMB) on Sarcopenia and Functional Frailty in Older Persons: A Systematic Review. [2020]

5. France pubmed.ncbi.nlm.nih.gov

Oral Nutritional Supplement with β-hydroxy-β-methylbutyrate (HMB) Improves Nutrition, Physical Performance and Ameliorates Intramuscular Adiposity in Pre-Frail Older Adults: A Randomized Controlled Trial. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB). [2021]

7. United States pubmed.ncbi.nlm.nih.gov

The relative bioavailability of the calcium salt of β-hydroxy-β-methylbutyrate is greater than that of the free fatty acid form in rats. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Beta-hydroxy-beta-methylbutyrate supplementation and functional outcomes in multitrauma patients: A pilot randomized controlled trial. [2023]

9. Ireland pubmed.ncbi.nlm.nih.gov

Hypovitaminosis D and frailty: Epiphenomenon or causal? [2018]

10. England pubmed.ncbi.nlm.nih.gov

The effects of vitamin D supplementation on frailty in older adults at risk for falls. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Low 25-hydroxyvitamin D levels and the risk of frailty syndrome: a systematic review and dose-response meta-analysis. [2019]

12. United States pubmed.ncbi.nlm.nih.gov

Effect of Vitamin D3 and Omega-3 Fatty Acid Supplementation on Risk of Frailty: An Ancillary Study of a Randomized Clinical Trial. [2023]

13. United States pubmed.ncbi.nlm.nih.gov

Association of low vitamin D levels with the frailty syndrome in men and women. [2021]