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In the body

Moved to Wikipedia:Featured article candidates/Beta-Hydroxy beta-methylbutyric acid/archive2 § Comments by Doc James

Follow-up from FAC

Moved from Wikipedia:Featured article candidates/Beta-Hydroxy beta-methylbutyric acid/archive2 § Arbitrary section break2
The content in this tab has been moved again; it's now located at Wikipedia:Featured article candidates/Beta-Hydroxy beta-methylbutyric acid/archive3#Comments by Doc James.
Please continue this discussion there.

The review you are using comes to three sentences of conclusions

"HMB contributed to preservation of muscle mass in older adults." which says it help keep mm mass, does not comment on those with sarcopenea.

"HMB supplementation may be useful in the prevention of muscle atrophy induced by bed rest or other factors." A decrease of uncertainty

"Further studies are needed to determine the precise effects of HMB on muscle strength and physical function in older adults." Means it is unclear if HMB affects str or function. Doc James (talk · contribs · email) 03:04, 17 December 2016 (UTC)

IMO before we should be uneqivacally recommending this stuff in WP's voice I would like to see (1) government sources supporting benefit (2) specific reviews supporting benefit (which we have some of) and (3) general reviews supporting benefit. I do not see us as having either 1 or 3. Doc James (talk · contribs · email) 03:09, 17 December 2016 (UTC)
2017 general review on sarcopinea says "A recent meta-analysis revealed some benefit of using a combined approach of dietary supplements and exercise, but the findings were inconsistent among various populations." PMID:27886695
Based on this 2015 review [1] "The main message is that enhanced benefits of exercise training, when combined with dietary supplementation, have been shown in some trials – indicating potential for future interventions, but that existing evidence is inconsistent." Doc James (talk · contribs · email) 03:30, 17 December 2016 (UTC)
@Doc James: I've used more or less the exact wording from the meta-analysis' actual conclusion, as opposed to the abstract, in the lead in this edit. The body of the article already stated the part of the sentence that I added to the lead. This link will take you to the full text of the meta-analysis if you want to read the full conclusion.
  • "Further studies are needed to determine the precise effects of HMB on muscle strength and physical function in older adults." Means it is unclear if HMB affects str or function. Yes, I agree that what you stated is what that sentence means. The article didn't contradict this assertion before and it still doesn't now. The body of the article repeated that same assertion using different language at the time that you wrote this comment. I added the statement to the lead since you mentioned it.
  • IMO before we should be uneqivacally recommending this stuff in WP's voice I would like to see (1) government sources supporting benefit (2) specific reviews supporting benefit (which we have some of) and (3) general reviews supporting benefit. - we are not and have not been recommending anything. The article makes statements about efficacy in older adults based upon a meta-analysis. In the body of the article only, it states that the authors of two reviews have recommended it. If there are reviews that do not recommend it, we can state that too.
    Re (1): why can't we just state that no governmental health agencies have endorsed the use of HMB?
    Re (3): what is a "general review"?
  • Based on this 2015 review [2] "The main message is that enhanced benefits of exercise training, when combined with dietary supplementation, have been shown in some trials – indicating potential for future interventions, but that existing evidence is inconsistent." - this is consistent with what the meta-analysis states about the combination of exercise+HMB: "While effects on muscle mass were consistent, outcomes for muscle strength and physical performance varied in different reports. Perhaps resistance exercise in combination with HMB treatment is a potent stimulus for muscle improvement. Further studies are needed to investigate the combination of HMB and exercise for improving muscle strength and physical performance." Both reviews appear to support the assertion that "the effects of HMB combined with exercise on muscle strength and performance require further research in older adults", so would you like to see this statement added?
  • 2017 general review on sarcopinea says "A recent meta-analysis revealed some benefit of using a combined approach of dietary supplements and exercise, but the findings were inconsistent among various populations." PMID:27886695 - this review cites this review which did not conduct a meta-analysis (quote from methodology: The studies were not graded for quality; no attempt at a meta-analysis was made.) but cited this meta-analysis when stating "A meta-analysis of findings from randomized controlled trials has shown that protein supplementation during an exercise training program increases gains in muscle mass and strength, in younger (<50 years) and older (≥50 years) adults16 – much less is known about the combined effects of exercise training and supplementation with other dietary components that have been linked to sarcopenia." That meta-analysis doesn't mention HMB anywhere. Seppi333 (Insert 2¢) 08:37, 17 December 2016 (UTC)
I'm ok with the changes you made relative to medical foods. Since the efficacy for sarcopenia has been such a major point of conflict, I think we should use language which is as close to the source as possible without creating a copyvio from paraphrasing too closely. Seppi333 (Insert 2¢) 19:36, 19 December 2016 (UTC)
@Doc James: Can you respond to my questions from above? Also, please let me know if you think Jytdog's and my changes to the first three sentences in the lead resolve the issues you had with the efficacy and the medical food statements. Seppi333 (Insert 2¢) 19:39, 19 December 2016 (UTC)
Jytdog's use of "may" is much better than "can" based on my reading of the evidence. We have the concern that this stuff has not actually been studied in people with sarcopenia, we have the issue of the small number of peoples in the trials, and than we have the issue of other sources using more tentative language. Doc James (talk · contribs · email) 19:42, 19 December 2016 (UTC)
Have moved the marketing claims to the 4th paragraph.[3] Likely just needs one reference rather than 4 as all supported by PR Newswire Doc James (talk · contribs · email) 19:47, 19 December 2016 (UTC)
I've removed the link to sarcopenia in the lead sentence since you feel that this is an issue. Seppi333 (Insert 2¢) 19:48, 19 December 2016 (UTC)
That was not my issue and this does not address my concerns[4] Doc James (talk · contribs · email) 19:48, 19 December 2016 (UTC)
You said We have the concern that this stuff has not actually been studied in people with sarcopenia. I've removed sarcopenia from the lead and simply indicated it's people with age-related muscle loss, which is supported by the title of the meta-analysis and the demographics included in the meta-analysis. The modified sentence is almost identical to the sentence in the conclusion of the meta-analysis, with superficial wording differences. Why is that sentence still an issue? It's clearly not an overstatement of efficacy per the meta-anaylsis. Edit: the article says "HMB can inhibit the loss of lean body mass in individuals experiencing age-related muscle loss"; the meta-analysis says "Overall, this meta-analysis indicates that HMB can prevent lean body mass loss in older adults." What the meta-analysis says is stronger than what the article says because prevent means "completely avoid", whereas inhibit just means "reduce". I'm not okay with downplaying the efficacy anymore than that.Seppi333 (Insert 2¢) 19:51, 19 December 2016 (UTC)
Entire conclusion from the meta-analysis

From [5]:

5. Conclusion
Overall, this meta-analysis indicates that HMB can prevent lean body mass loss in older adults. But the effects of HMB on muscle strength and physical function appears to vary in different populations. Additional well-designed clinical studies are necessary to confirm the effectiveness of HMB in the prevention of loss of muscle strength and physical function.

@Doc James: What is your concern with that sentence, specifically, if the population samples included in the RCTs from that meta-analysis (link here) wasn't the issue? Seppi333 (Insert 2¢) 00:00, 20 December 2016 (UTC)
  • Seppi, above you wrote: " I've removed sarcopenia from the lead and simply indicated it's people with age-related muscle loss". That is not any change in meaning, right? Jytdog (talk) 01:54, 20 December 2016 (UTC)
@Jytdog: sarcopenia and age-related muscle loss aren't entirely synonymous. Sarcopenia is a medical diagnosis that involves the loss of lean body mass, whereas the loss of muscle mass associated with age is simply a phenomenon that typically starts to occur in the late 30s or mid-40s and accelerates with each additional decade. Before that point, the human body is on average in an anabolic state, and muscle growth tends to occur annually even without exercise. After that age range, the body is on average in a catabolic state, and muscle mass tends to decline on an annual basis. The meta-analysis included studies in which the samples contained primarily healthy older adults who did not have a diagnosis of sarcopenia. Some of the participants may have been sarcopenic, but to my knowledge none were diagnosed as such.
The fact that the participants in most of the studies were not diagnosed with sarcopenia is one of the issues that Doc James correctly pointed out earlier. We shouldn't say that the meta-analysis applies to adults diagnosed with sarcopenia. Its conclusion really only applies to older adults in general, almost all of whom experience annual losses in muscle mass if they don't perform resistance exercise on a regular basis. Seppi333 (Insert 2¢) 02:24, 20 December 2016 (UTC)

New reviews

Checked for updates on November 9th, 2017 (my birthday, yay). Seppi333 (Insert 2¢) 05:33, 9 November 2017 (UTC)

Happy Birthday :-) Doc James (talk · contribs · email) 05:37, 9 November 2017 (UTC)
Thanks! Seppi333 (Insert 2¢) 06:12, 9 November 2017 (UTC)

1st

plus Added (partially) - more potential material to go through and add if deemed encyclopedic; see collapse tab below

  2. @Jytdog, Boghog, and Doc James: I just did a literature search and found one new review: PMID 28493406;[1] it was published online on May 10, 2017. Also, I contacted the corresponding author of this prospective systematic review a few weeks ago; he told me that it has been submitted to an academic journal and is currently being peer-reviewed, so I suspect that it will be published within the next 1–3 months. Once it's published, I intend to add a summary of its findings on the effects/efficacy of HMB in healthy individuals.

As for this[1] review, I intend to use it to cite existing statements and possibly add new material which is relevant to clinical uses (e.g., HMB supplementation in elderly/sarcopenic individuals). These are the sections from the review that are relevant to its clinical uses:

Excerpts of the sections on Elderly populations, Toxicity + adverse effects, and Conclusions

Elderly and effects of HMB supplementation

Sarcopenia, which is present in approximately 5 to 10% of persons over 65 years of age is associated with weakness, falls, and a decreased ability to respond to illness or injury.[60] Muscle wasting may be exacerbated during a period of disuse during a prolonged bed rest and by decreased food intake, particularly during an illness.

A hallmark of sarcopenia in elderly subjects is a decreased ability to increase muscle protein synthesis in response to anabolic signals such as food intake and resistance exercise. In other words, this condition suppresses the stimulatory effect of food and other signals on mRNA translation, the rate-controlling step for protein synthesis, which is primarily regulated by the mTOR signalling pathway. Such anabolic resistance of muscle to nutrients is probably due to oxidative stress and low-grade inflammation.

There is growing evidence that the severe decreases in the skeletal muscle mass and function that occur with ageing may be mitigated by HMB supplementation (Table 3). Based on the meta-analysis of seven randomized controlled trials, HMB supplementation can prevent the loss of lean body mass in older adults without causing a significant change in fat mass.[72] The rationale for HMB supplementation in ageing subjects is strongly supported by recent findings of a negative correlation between the HMB levels in blood plasma with age and the lower levels of KIC dioxygenase in the livers of old rats than in young rats.[73]
— [1]

 

Toxicity and adverse effects

Several studies have demonstrated that supplemental HMB is well tolerated and has no toxic effects.[11, 100, 117] However, although HMB is made naturally by the body, it is possible that the positive effects of HMB on the protein balance in muscle may exert some adverse effects in other tissues. Stimulation of protein synthesis and suppression of proteolysis by HMB decreases the release of various amino acids from muscles to the blood and may impair their availability in visceral tissues. Glutamine is of particular interest on the basis that it acts as an essential substrate for enterocytes and immune cells and its deficiency decreases protein synthesis in skeletal muscle.[118, 119] The plasma glutamine concentration is already low in many patients with critical illness, and a decreased glutamine level has been reported after HMB treatment.[22] Therefore, studies are needed to examine whether the positive effects of HMB on muscle mass in cachexia are associated with glutamine depletion and adverse effects in other tissues.

Conclusions

The reports summarized here indicate that HMB provides a number of benefits to subjects involved in strength-power and endurance sports. The effects on muscle mass and strength, particularly during resistance training, are likely related to the suppression of proteolysis and a positive effect on protein synthesis. Its benefits in aerobic performance are probably more associated with improved mitochondrial biogenesis and fat oxidation. Favourable effects on the recovery from exercise-induced damage may be related to the role of HMB as a precursor of cholesterol, which modulates membrane fluidity and affects ion channels, and membrane excitability.

Studies have demonstrated that HMB can prevent the development of sarcopenia in elderly subjects and that the optimal action of HMB on muscle growth and strength occurs when it is combined with exercise. Unfortunately, exercise is performed only by a small percentage of elderly subjects. Several studies suggest that HMB supplementation is ineffective in healthy sedentary subjects.

Studies performed under in vitro conditions and animal studies suggest that HMB may be effective as a treatment for muscle wasting in various forms of cachexia. However, clinical reports are rare, and most of them examined the therapeutic potential of combinations of various agents. It was therefore not possible to determine, which of the supplements was effective. Further studies examining the effects of HMB administered alone are needed to reach a conclusion regarding the specific effectiveness of HMB in attenuating muscle wasting in a range of catabolic conditions. Although most of the endogenous HMB is produced in the liver and impaired HMB production may be assumed to occur in liver disease, there are no reports regarding the metabolism of HMB and the effects of its supplementation in subjects with liver disease.
— [1]

 

Also, check for new pharmacology content to add from these sections of the review:

  • Effects on protein metabolism in skeletal muscle
  • Effects on leucine metabolism
  • Effects on cholesterol metabolism
  • Exercise performance and effects of HMB supplementation
For myself: unrelated excerpt on an animal study

Apart from the benefits to muscle, there are other effects of HMB that may be beneficial to old people. HMB ameliorated the effects of ageing in the dendritic tree of the pyramidal neurons in the medial prefrontal cortex of both male and female rats and improved the working and cognitive flexibility in old-age rats.[74, 75]
— [1]

Most of the quoted material above is already covered to some extent in the article at the moment, but the commentary from this review isn't reflected in the current article text. Should new content be added, or should this reference just be appended to existing text that it supports? Do any of you have any proposed revisions to the article in mind? @Doc James: I'm directing that last question mainly at you since you took issue with how some of the medical statements were worded during the most recent FAC nomination. Seppi333 (Insert 2¢) 04:27, 3 June 2017 (UTC)

2nd

  2. "A systematic review on β-hydroxy-β-methylbutyrate free acid supplementation suggests improvements in measures of muscle recovery, performance, and hypertrophy following resistance training."[2]

@Boghog, Jytdog, and Doc James: The "#Upcoming systematic review" was finally published in an academic journal in September.[2] Boghog, do you think we should renominate the article for FA or continue with GAN once I add coverage of this review and the other reviews listed below to the article? Seppi333 (Insert 2¢) 04:48, 9 November 2017 (UTC)

FYI: I'm waiting to get ref #5 below (PMID 28554316) from WP:RX before I update the article with the content from all of the reviews cited in this section (i.e., the ones in #Section reflist). Seppi333 (Insert 2¢) 01:13, 19 November 2017 (UTC)

3rd–8th

  2. Pharmacological targeting of exercise adaptations in skeletal muscle: Benefits and pitfalls – October 2017 review.[3]
  4. The Potential of β-Hydroxy-β-Methylbutyrate as a New Strategy for the Management of Sarcopenia and Sarcopenic Obesity – October 2017 review.[4] plus Added
  6. Beta-hydroxy-beta-methyl butyrate (HMB): From experimental data to clinical evidence in sarcopenia – May 2017 review[5]
  8. What factors influence protein synthesis and degradation in critical illness? – March 2017 review.[6]
  10. Ergogenic Aids in Sports – February 2017 review (in Spanish - would probably only cite material covered in the abstract if this review is used).[7]
  12. Efficacy and Safety of Leucine Supplementation in the Elderly – December 2016 review.[8]

Seppi333 (Insert 2¢) 05:19, 9 November 2017 (UTC) – Updated 06:12, 9 November 2017 (UTC)

Yes this ref says "Clinical trials performed in older adults confirm that HMB can attenuate the progression of sarcopenia in elderly subjects." So basically it may slow muscle loss.[6]
This review is a little more cautious concluding "However, heterogeneous methodological approaches preclude solid conclusions, and more studies are needed to confirm the role of HMB as a promising agent to treat sarcopenia."[7]
So definitely promising and appears safe but not yet definite. Doc James (talk · contribs · email) 05:44, 9 November 2017 (UTC)
@Doc James: I had to contact Dr. Alfonso Cruz-Jentoft via email to obtain his review article (i.e., the one that you mentioned was a little more cautious in your reply immediately above) since no one at WP:RX had access to the journal in which he published his review. You can read his review and its conclusions here. Seppi333 (Insert 2¢) 18:22, 17 December 2017 (UTC)
Quotation from PMID 28554316 about HMB's pharmacodynamics

- HMB increases myofibrillar protein synthesis by upregulation via the mTOR pathway.

- HMB modulates protein degradation by inhibiting the ubiquitin-proteasome proteolytic pathway in muscle cells. Ubiquitin is induced by immobilization and by catabolic conditions, inducing proteasome expression through the activation of nuclear factor kappa B (NK-κB), thus promoting muscle wasting. HMB may inhibit the activity of NK-κB, attenuating muscle loss in wasting conditions.

- The integrity of cell membranes depends on cholesterol synthesis from acetyl-CoA. HMB is converted to ß-hydroxyß- methylglutaryl-coenzyme A (HMG-CoA), which is turned into cholesterol by the HMG-coenzyme A reductase, the rate-limiting enzyme to cholesterol synthesis. Thus, HMB supplementation may stabilize cell membranes. HMB itself seems to be a component of cell membranes.

- HMB may prevent cell apoptosis and enhance muscle satellite cell survival.

- HMB increases proliferation and differentiation of muscle stem cells, via the MAPK/ERK and PI3K/Akt pathways.

- HMB up-regulates transcription and expression of the IGF-I gene in skeletal muscle and liver. IGF exerts an anabolic action and causes hypertrophy of skeletal muscle fibers.

Pharmacodynamics and pharmacokinetics of HMB-CA in humans in vivo

  2. This is a primary source which examines the same pharmacodynamic and pharmacokinetic parameters for HMB-CA as the ones that were examined in the study on HMB-FA and leucine which is currently cited in the article – October 2017 primary study.[9] Seppi333 (Insert 2¢) 06:12, 9 November 2017 (UTC)
  4. Already cited in the article (this is the study on HMB-FA and leucine that was mentioned immediately above).[10]

Section reflist

References

  1. ^ a b c d e Holeček M (May 2017). "Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions". Journal of Cachexia, Sarcopenia and Muscle. 8 (4): 529–541. doi:10.1002/jcsm.12208. PMC 5566641. PMID 28493406.
  2. ^ a b Silva VR, Belozo FL, Micheletti TO, Conrado M, Stout JR, Pimentel GD, Gonzalez AM (September 2017). "β-hydroxy-β-methylbutyrate free acid supplementation may improve recovery and muscle adaptations after resistance training: a systematic review". Nutrition Research. 45: 1–9. doi:10.1016/j.nutres.2017.07.008. hdl:11449/170023. PMID 29037326. HMB's mechanisms of action are generally considered to relate to its effect on both muscle protein synthesis and muscle protein breakdown (Figure 1) [2, 3]. HMB appears to stimulate muscle protein synthesis through an up-regulation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), a signaling cascade involved in coordination of translation initiation of muscle protein synthesis [2, 4]. Additionally, HMB may have antagonistic effects on the ubiquitin–proteasome pathway, a system that degrades intracellular proteins [5, 6]. Evidence also suggests that HMB promotes myogenic proliferation, differentiation, and cell fusion [7]. ... Exogenous HMB-FA administration has shown to increase intramuscular anabolic signaling, stimulate muscle protein synthesis, and attenuate muscle protein breakdown in humans [2].
  3. ^ Weihrauch M, Handschin C (October 2017). "Pharmacological targeting of exercise adaptations in skeletal muscle: Benefits and pitfalls". Biochemical Pharmacology. 147: 211–220. doi:10.1016/j.bcp.2017.10.006. PMC 5850978. PMID 29061342.
  4. ^ Rossi AP, D'Introno A, Rubele S, Caliari C, Gattazzo S, Zoico E, Mazzali G, Fantin F, Zamboni M (October 2017). "The Potential of β-Hydroxy-β-Methylbutyrate as a New Strategy for the Management of Sarcopenia and Sarcopenic Obesity". Drugs & Aging. 34 (11): 833–840. doi:10.1007/s40266-017-0496-0. PMID 29086232. S2CID 4284897. Clinical trials performed in older adults confirm that HMB can attenuate the progression of sarcopenia in elderly subjects. HMB supplementation results in an increase in skeletal muscle mass and strength in the elderly and its effect is even greater when combined with physical exercise.
  5. ^ Cruz-Jentoft AJ (May 2017). "Beta-hydroxy-beta-methyl butyrate (HMB): From experimental data to clinical evidence in sarcopenia". Current Protein & Peptide Science. 18 (7): 668–672. doi:10.2174/1389203718666170529105026. PMID 28554316. HMB is widely used as an ergogenic supplement by young athletes.
  6. ^ Di Girolamo FG, Situlin R, Biolo G (March 2017). "What factors influence protein synthesis and degradation in critical illness?". Current Opinion in Clinical Nutrition and Metabolic Care. 20 (2): 124–130. doi:10.1097/MCO.0000000000000347. PMID 28002075. S2CID 3480306.
  7. ^ omitted - not planning to use this review
  8. ^ Borack MS, Volpi E (December 2016). "Efficacy and Safety of Leucine Supplementation in the Elderly". The Journal of Nutrition. 146 (12): 2625S – 2629S. doi:10.3945/jn.116.230771. PMC 5118760. PMID 27934654. No serious side effects have been reported with leucine, EAA, or HMB supplementation; and the health risks associated with these supplements are few and predictable.
  9. ^ Wilkinson DJ, Hossain T, Limb MC, Phillips BE, Lund J, Williams JP, Brook MS, Cegielski J, Philp A, Ashcroft S, Rathmacher JA, Szewczyk NJ, Smith K, Atherton PJ (October 2017). "Impact of the calcium form of β-hydroxy-β-methylbutyrate upon human skeletal muscle protein metabolism". Clinical Nutrition (Edinburgh, Scotland). 37 (6): 2068–2075. doi:10.1016/j.clnu.2017.09.024. PMC 6295980. PMID 29097038. Ca-HMB led a significant and rapid (<60 min) peak in plasma HMB concentrations (483.6 ± 14.2 μM, p < 0.0001). This rise in plasma HMB was accompanied by increases in MPS (PA: 0.046 ± 0.004%/h, CaHMB: 0.072 ± 0.004%/h, p < [0.001]) and suppressions in MPB (PA: 7.6 ± 1.2 μmol Phe per leg min-1, Ca-HMB: 5.2 ± 0.8 μmol Phe per leg min-1, p < 0.01). ... During the first 2.5 h period we gathered postabsorptive/fasted measurements, the volunteers then consumed 3.42 g of Ca-HMB (equivalent to 2.74 g of FA-HMB) ... It may seem difficult for one to reconcile that acute provision of CaHMB, in the absence of exogenous nutrition (i.e. EAA's) and following an overnight fast, is still able to elicit a robust, perhaps near maximal stimulation of MPS, i.e. raising the question as to where the additional AA's substrates required for supporting this MPS response are coming from. It would appear that the AA's to support this response are derived from endogenous intracellular/plasma pools and/or protein breakdown (which will increase in fasted periods). ... To conclude, a large single oral dose (~3 g) of Ca-HMB robustly (near maximally) stimulates skeletal muscle anabolism, in the absence of additional nutrient intake; the anabolic effects of Ca-HMB are equivalent to FA-HMB, despite purported differences in bioavailability (Fig. 4).
  10. ^ Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ (June 2013). "Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism" (PDF). The Journal of Physiology. 591 (11): 2911–2923. doi:10.1113/jphysiol.2013.253203. PMC 3690694. PMID 23551944. The stimulation of MPS through mTORc1-signalling following HMB exposure is in agreement with pre-clinical studies (Eley et al. 2008). ... Furthermore, there was clear divergence in the amplitude of phosphorylation for 4EBP1 (at Thr37/46 and Ser65/Thr70) and p70S6K (Thr389) in response to both Leu and HMB, with the latter showing more pronounced and sustained phosphorylation. ... Nonetheless, as the overall MPS response was similar, this cellular signalling distinction did not translate into statistically distinguishable anabolic effects in our primary outcome measure of MPS. ... Interestingly, although orally supplied HMB produced no increase in plasma insulin, it caused a depression in MPB (−57%). Normally, postprandial decreases in MPB (of ~50%) are attributed to the nitrogen-sparing effects of insulin since clamping insulin at post-absorptive concentrations (5 μU ml−1) while continuously infusing AAs (18 g h−1) did not suppress MPB (Greenhaff et al. 2008), which is why we chose not to measure MPB in the Leu group, due to an anticipated hyperinsulinaemia (Fig. 3C). Thus, HMB reduces MPB in a fashion similar to, but independent of, insulin. These findings are in-line with reports of the anti-catabolic effects of HMB suppressing MPB in pre-clinical models, via attenuating proteasomal-mediated proteolysis in response to LPS (Eley et al. 2008).

Small additional concerns

Some small additional concerns. I don't think these are enough to prevent a successful GA nomination, and they have been discussed with Seppi333 during the nomination and we have reached a loggerheads. I note these with a view to a (1) FA nomination and (2) MEDRS compliance:

  1. I still think some work could be done paring down references
  2. I think information relating to the lack of effects of overdose should be included in text
  3. I am concerned that primary sources are used to make medical claims, which is not something recommended by our WP:MEDRS
    • "One clinical trial with Juven for AIDS also demonstrated improvements in immune status, as measured by a reduced HIV viral load relative to controls and higher CD3+ and CD8+ cell counts"
    • "The efficacy of Juven for the treatment of cancer cachexia was also examined in a phase 3 clinical trial which found a strong trend (i.e., p=.08) for an improvement in lean body mass relative to controls"
  4. I do not think that the article needs so many notes (I think most could be removed without damaging the article's integrity)

It would be useful if a third editor could comment on these; Seppi333 makes some good points and it may be useful if a third or fourth editor could offer their opinion on the above. Have a lovely festive season, --Tom (LT) (talk) 22:53, 25 December 2017 (UTC)

@Tom (LT): Re: "The efficacy of Juven for the treatment of cancer cachexia was also examined in a phase 3 clinical trial which found a strong trend (i.e., p=.08) for an improvement in lean body mass relative to controls"
Given that this is a primary study showing a non-statistically significant trend, and the cited systematic review essentially says it's useless, this should probably be removed. PriceDL (talk) 00:11, 26 December 2017 (UTC)
Generally speaking, I am never been in favor of removing references because there are too many and need to be pared down. Sure, some refs may not be MEDRS and removed, but medical topics need to be rich with references and if ten superscripted numerals aren't appropriate in the 'reader's' of the article, retain the references in the wiki-markup view. These references can then be 'reactivated' as other references become outdated. Perhaps I am sensitive to the referencing issues brought up, but there is no need to remove them just because there are too many. Best Regards, Barbara (WVS) ✐  ✉ 15:02, 2 March 2018 (UTC)

Conjugate base

There appears to be disagreement on whether Beta-Hydroxy beta-methylbutyrate should be described like an alternate name of Beta-Hydroxy beta-methylbutyric acid in the lead. While the two are closely related (They're each other's conjugate acid/base.), I think that the article needs to recognize that they're not exactly the same molecule. Care to differ or discuss with me? The Nth User 02:10, 1 June 2018 (UTC)

The current version is fine with me. Seppi333 (Insert 2¢) 21:18, 1 June 2018 (UTC)
I still think that saying that the two conjugates are the same as each other is a simple factual error. Besides prominence of the subject, the case would be exactly the same if Wikipedia said that water was the same as hydronium or hydroxide. Care to differ or discuss with me? The Nth User 02:57, 2 June 2018 (UTC)
@The Nth User: I completely understand what you're saying. Strictly from a chemistry viewpoint, the two compounds are different in many ways. From a pharmacological/molecular biological, medical, and even biochemical viewpoint though, the two are entirely interchangeable since their pharmacological/cellular properties/effects (e.g., the signaling cascades that they trigger in humans, the resulting effects on muscle protein synthesis/breakdown in humans in vivo, and their presumed biomolecular targets), clinical properties/effects (e.g., effects on lean body mass, recovery time, muscle strength/power, etc. in humans in vivo), and metabolic properties/effects (i.e., biosynthesis and metabolism, due to the fact that these compounds are readily converted to one another in the body, dependent upon the pH of the biofluid compartment where they're distributed) are equivalent; in other words, for the purpose of describing each of those aspects, the acid and base are interchangeable and simultaneous reference to both via the abbreviation "HMB" is desirable/merited.
I've done my best to balance the fact that they're not equivalent from a chemical viewpoint but are from most other viewpoints by including coverage of both chemical structure diagrams in the drugbox (i.e., the two are very prominently displayed in the drugbox, which makes it abundantly clear that there's a structural difference between them in one of the acid's two hydroxyl groups and a difference in their molecular formulas). I also stopped using the catch-all abbreviation "HMB" in the Beta-Hydroxy beta-methylbutyric acid#Chemistry section and instead used the expanded names of the conjugate acid and base to differentially cover their chemical properties. That's literally the only section of the article where doing this was actually necessary because the vast majority of assertions elsewhere in the article apply simultaneously to both the acid and the base. If you have a better idea about how to go about doing this, let me know. I'm open to modifying the coverage of the distinction in the lead provided that it doesn't create ambiguity about the equivalence of the pharmacological, medical, and biochemical properties. Seppi333 (Insert 2¢) 01:44, 10 June 2018 (UTC)
Actually, what I said above wasn't completely accurate; differential coverage of HMB-Ca and HMB-FA was necessary in a few sections of the article since the calcium moiety in HMB-Ca modifies the pharmacokinetic properties (i.e., uptake/distribution) and slightly modifies the magnitude of the clinical and cellular/pharmacodynamic effects of the compound relative to HMB-FA (i.e., pure β-hydroxy β-methylbutyric acid). Even so, there are many statements in the article that cover aspects of those topics where differential coverage of HMB-Ca and HMB-FA was/is not necessary. Seppi333 (Insert 2¢) 01:48, 10 June 2018 (UTC)
@Seppi333: The article now is fine. I just wanted a clarification that they were two separate chemicals at the top. But if anything good came out of this, I got the idea for conjugate acid and base parameters to be added to Template:Chembox. Care to differ or discuss with me? The Nth User 18:43, 16 June 2018 (UTC)

Citing a new chemistry claim

β-Hydroxy β-methylbutyric acid is a member of the carboxylic acid family of organic compounds and like them, it is a weak acid.

@EdChem: Would you happen to know of a source that can be used to cite this statement? Seppi333 (Insert 2¢) 09:56, 17 April 2018 (UTC)

Is a citation needed? The diagram of the molecule in the infobox shows a carboxyl group. Care to differ or discuss with me? The Nth User 02:12, 1 June 2018 (UTC)
The only claim in that sentence that really needs a citation is the assertion that carboxylic acids are weak acids. "β-Hydroxy β-methylbutyric acid is a monocarboxylic β-hydroxy acid" is cited in the previous paragraph. Seppi333 (Insert 2¢) 21:18, 1 June 2018 (UTC)
The weak acid article supports the general pattern that carboxylic acids are weak, and the enumeration of the strong acid general types and specific examples does not include any. But surprisingly, neither acid strength (target of the weak acid redirect) nor carboxylic acid actually directly cite this specific pattern of this functional group! So "like them" is still not strictly WP:V. DMacks (talk) 05:07, 7 June 2018 (UTC)
@DMacks: So, do you think this statement should be rephrased to something along the lines of the following sentence?
"β-Hydroxy β-methylbutyric acid is a weak acid and a member of the carboxylic acid family of organic compounds."
If it's rephrased in that manner, the only thing that needs to be cited is the assertion that HMB is a weak acid. I might be able to find a citation for that assertion own my own. Seppi333 (Insert 2¢) 01:22, 10 June 2018 (UTC)
"Weak acid" is a mechanical definition based on the pKa. The pKa value is given and cited in the previous section. So maybe the "weak acid" detail should be moved to there rather than where it is now if we are stating a bare fact rather than making a "chemical structure" explanation? So in the second-level "Chemistry" section:
β-hydroxy β-methylbutyric acid is a weak acid, having a pKa 4.4. Its refractive index...
and then later in the "Chemical structure" section:
β-hydroxy β-methylbutyric acid is a member of the carboxylic acid family of organic compounds. It is a structural analog...
DMacks (talk) 02:39, 10 June 2018 (UTC)
That sounds reasonable. I'll make the change. Seppi333 (Insert 2¢) 19:41, 11 June 2018 (UTC)

@Seppi333: I don't really think any citation was needed as the fact that it is a carboxylic acid and a weak acid is utterly uncontroversial and unlikely to be challenged by anyone. Nevertheless, I also agree with DMacks that the pKa value confirms that it is a weak acid, and the form of words proposed and implemented from your discussion is accurate. Sorry for the delay in responding. EdChem (talk) 12:04, 20 July 2018 (UTC)

No problem. It probably wouldn't be challenged, but article content in FAs needs to be verifiable. Seppi333 (Insert 2¢) 02:04, 21 July 2018 (UTC)

Long and repetitive introduction

Most of the content in the introduction is repeated literally word-for-word in the article body. In my revisions I removed all the duplicate info], repeated word for word in the body. I read other bioactive chemical pages and they don’t have the extreme repetitiveness of this article. The intro almost reads as an advertisement for HMB, let your customers read the article first. Anyway, I saw no reason given for undoing my copyedits, why were they removed? Dogshu (talk) 13:04, 29 August 2018 (UTC)

@Dogshu: sorry for the delayed reply. The lead/intro section of an article is supposed to summarize the body of the article. Article leads should not contain any information which is not stated in the body, with exception for very basic facts about the article topic (e.g., synonyms, topical scope, etc.). Consequently, a well-written article lead should be fairly redundant with the body and adhere to WP:SUMMARYSTYLE. Seppi333 (Insert 2¢) 23:05, 30 August 2018 (UTC)
@Seppi333:Yes it should be redundant. However entire sections of the intro are repeated verbatim in the body. My revision preserved the references to the content without repeating whole sections verbatim. I know I’m a newb though, and accept your decision, unless anyone else dissents. I am curious however if those that want all the information up front in the intro, making it sound like a miracle drug, have ties to the food supplement industry and are thus biased. Dogshu (talk) 02:18, 31 August 2018 (UTC)
@Dogshu: Hmm. Well, the sentences in the lead don't necessarily have to differ from the body, but I suppose "good writing" entails at least a little variation when assertions are restated. This reminds me of a general question that I asked about redundant article content when I was a new editor (User talk:Seppi333/Archive 1#Content Redundancy Q), although IIRC the issue that led to me asking that had more to do with restated assertions within different sections of the article's body. Anyway, when I wrote this article, I basically just either summarized several paragraphs of text from the body in 1-2 sentences or copy/pasted the key points and contextual facts from every section of the body. That said, if you want to superficially rephrase the duplicate sentences in the lead section so that they're not verbatim duplicates of the text in the article's body, that would be completely fine with me.
As for the efficacy of this drug, this article's lead currently states a direction of an effect without quantifying how large the effects are (AKA the magnitude or effect size); more clinical research needs to be conducted in resistance-trained individuals (i.e., people who perform strength/resistance training on a regular basis), endurance athletes, and untrained athletes before a meta-analysis can be performed to determine the effect size of HMB supplementation for each population group. Based upon current evidence, the effect of HMB on muscle mass tends to be smaller in individuals who perform strength training on a regular basis relative to untrained groups. That said, the effect size in older adults has been estimated by a meta-analysis of clinical trials and is included in a note within the body of this article (see beta-Hydroxy beta-methylbutyric acid#cite note-36), but this content isn't covered in the article's lead section; based upon the estimated standard mean difference and the weighted average duration listed in that note, daily HMB supplementation in older adults appears to produce an annual increase in skeletal muscle mass by ~1.5 pounds on average. That's a rather notable fact since sedentary older adults lose muscle mass on an annual basis, and some lose much more. Seppi333 (Insert 2¢) 00:44, 2 September 2018 (UTC)
Addendum: I included the note I mentioned above at the end of the corresponding sentence in the lead in this edit. Seppi333 (Insert 2¢) 00:48, 2 September 2018 (UTC)

Updates - recent (post-FA) reviews and meta-analyses

From this search:


Meta-analyses from 2018

  • PMID 29249685; meta-analysis: performance-enhancement literature  High Priority plus Added
  • PMID 29676656; meta-analysis + systematic review: healthy adults - presumably mostly athletes (effect on exercise-induced muscle damage)  High Priority plus Added

Systematic reviews from 2018

  • PMID 29300431 - systematic review: elderly/clinical  High Priority
  • PMID 29941852 - systematic review: clinical population - post-surgical recovery  High Priority

Other reviews from 2017–2018

  • PMID 28683706 - review by Cruz-Jentoft that I missed earlier  High Priority

Add these when time permits:

  1. PMID 29345167 - review: athletes
  2. PMID 29804584 - (narrative?) review: elderly ("aging neuromuscular junction")
  3. PMID 30237683 - sports pharmacology review
  4. PMID 29182451 - review: athletes
  5. PMID 29045254 - review


Seppi333 (Insert 2¢) 21:36, 23 October 2018 (UTC)

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