Talk:Β-Hydroxy β-methylbutyric acid

Reviews and CC-BY-2.0/CC-BY-4.0 diagrams
Most of these articles are currently available here. The file names reflect the ref names defined in the source code below.  Seppi  333  (Insert 2¢) 19:05, 23 May 2016 (UTC)
 * 1) February 2013 review, indicates the impracticality of obtaining a 3 gram dose through diet
 * 2) Skeletal muscle homeostasis, 2016 review (Available for free at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843955/)
 * 3) July 2010 review of various HMB-induced biomarker changes/athletic effects
 * 4) Medical use in sarcopenia, November 2014 systematic review
 * 5) Tentatively supports a more general statement about attentuating muscle damage in pathological states, December 2013 systematic review
 * 6) Supplementation in older adults, September 2015 meta-analytic systematic review
 * 7) Prevalence of use, pharmacodynamics, availability, and sports testing status, April 2015 performance-enhancing drugs review
 * 8) Newest review on HMB: medical use in muscle wasting and sarcopenia, April 2016 review
 * 9) Athletic performance-related effects of HMB, 2011 review
 * 10) HMB for cancer cachexia, 2013 review
 * 11) Effects of amino acid derivatives, 2015 review
 * 12) Review with background info on molecular signaling cascades in protein synthesis/degradation, September 2015 review
 * 13) HMB's clinical evidence in older adults, May 2016 review (Available for free at http://www.mdpi.com/2072-6643/8/5/295/htm)
 * 14) Nutrition supplements for athletes, February 2014 review
 * 15) HMDB entry
 * 16) Sarcopenia, July 2015 review
 * 17) HMB's in vivo intracellular pharmacodynamics in human skeletal muscle, 2013 primary study using muscle biopsies - cited by
 * 18) HMB in animals, June 2015 review,
 * 19) Sarcopenia, May 2016 review
 * 20) Very strong statements of efficacy for medical use, June 2016 review; (note: this review explicitly states that HMB ingestion can improve every core symptom of sarcopenia and other forms of muscle wasting: the loss of muscle mass, function, and strength):
 * This review supports the following statements:
 * 1) *HMB is a potent stimulator of MPS and a potent inhibitor of MPB.
 * 2) *HMB potently inhibits and may reverse muscle loss in sarcopenic individuals and even in hypercatabolic disease states such as cachexia.
 * 3) *Ingestion of HMB results in demonstrable muscle mass accretion.
 * 4) *Ingestion of HMB can improve measures of muscle strength in sarcopenic individuals.
 * 5) *Consumption of HMB with dietary protein can improve muscle function, resulting in functional muscle performance improvements.
 * 6) *The overall treatment of muscle wasting conditions should include dietary supplementation with HMB.
 * 7) *Ingestion of HMB and consumption of a high protein diet combined with regular resistance exercise is recommended for individuals that are at risk of developing or currently experiencing sarcopenia.
 * 8) July 2014 review; Covers trials involving Juven for various medical conditions w/ positive (AIDS-induced wasting, cancer cachexia) and negative findings (post-gastric bypass, rheumatoid arthritis) and an interesting trial involving Juven vs HMB alone vs placebo, where HMB alone significantly improved nitrogen balance relative to Juven or placebo.

 Seppi  333  (Insert 2¢) 20:36, 29 April 2016 (UTC)
 * Thanks for posting those sources! I cannot believe how crappy that 2013 review is.  Disturbing.  Am going to open a discussion at WT:MED about it. Jytdog (talk) 18:16, 30 April 2016 (UTC)
 * I've only read (mostly) through half of these, but it appears that the reviews that describe HMB's effects in general (i.e., not solely in the context of a pharmacotherapy for sarcopenia/muscle wasting) - - draw the same or even stronger conclusions about its effects in humans compared to the ISSN review. I'll probably end up relying on the newer reviews for supporting statements about clinical effects, so using this source to independently support such statements won't be an issue.


 * Also, I'm considering taking this article to FA status since its primary clinical/therapeutic effect is unique and improving the article won't be too much work compared to other drug articles that I've worked on; there's only a handful of reviews and a few database refs from which to collate information on the compound, so finding all the relevant information to satisfy the comprehensiveness criterion won't be difficult (researching/revising amphetamine for FA took over a year; this would probably take ~1 month). With that in mind, if you have any feedback on the other sources or any other suggestions, I'd be interested to hear it.  Seppi  333  (Insert 2¢) 16:51, 20 May 2016 (UTC)

Hey, sorry to bother you again with this request, but would you be willing to send me these 5 reviews? They're paywalled and I don't have access. I'd really appreciate it.  Seppi  333  (Insert 2¢) 22:28, 23 May 2016 (UTC)
 * I sent them all except which my library doesn't get. Jytdog (talk) 00:30, 24 May 2016 (UTC)
 * I appreciate it. Hopefully I can get that last one from WP:RX.  Seppi  333  (Insert 2¢) 05:08, 24 May 2016 (UTC)

December 2016
 Seppi  333  (Insert 2¢) 19:15, 5 December 2016 (UTC)
 * Review of HMB's effects on skeletal muscle, pharmacodynamics, and pharmacokinetics from January 2016
 * Systematic review on supplements for cachexia from 2016

Recent preclinical research

 * Covers HMB's effects on protein synthesis in brain cells, neurite outgrowth, and age-related dendritic remodeling in the brain of various nonhuman animals:
 * Evidence that HMB is a (non-protein small molecule) neurotrophic factor in the brain of nonhuman animals (mice - in vitro/rats - in vivo)
 * Increases protein synthesis in the mouse brain (in vitro) and pig brain (in vivo)

 Seppi  333  (Insert 2¢) 03:19, 28 May 2016 (UTC)

mTOR signaling cascades
Leaving this here for personal reference.  Seppi  333  (Insert 2¢) 08:51, 1 June 2016 (UTC) Updated 00:42, 27 August 2016 (UTC)
 * Has a detailed mTOR signaling cascade diagram
 * Discusses and includes a diagram of signaling cascades involved in MPS/MPB hosted here temporarily

Metabolic pathway links

 * HMB-CoA HMDB entry
 * HMB-CoA KEGG entry
 * 3-Hydroxyisovaleryl-CoA ⇔ 3-Methylcrotonyl-CoA + H2O –
 * 3-Hydroxyisovaleryl-CoA ⇔ 3-Hydroxyisovalerate – "unclear reaction"
 * alpha-Ketoisocaproate + O2 ⇒ 3-Hydroxy-3-methylbutyrate + CO2 – ; 4-hydroxyphenylpyruvate dioxygenase = KIC dioxygenase per

Should be able to write a comprehensive biosynthesis/metabolism section using these 5 refs:
 * 1) (covers α-KIC → HMB reaction)
 * 2) (covers most of the metabolic pathway; has another diagram)
 * 3) (covers HMB-CoA → HMB)
 * 4)  (covers most of the metabolic pathway; includes the same metabolic pathway graphic as the ISSN review)
 * 5) ISSN review - (review with the article's current metabolic pathway graphic)

 Seppi  333  (Insert 2¢) 00:10, 7 June 2016 (UTC)

FAC-related references

 * WADA and NCAA refs
 * allowed by WADA and the NCAA
 * WADA banned substances list
 * Physical/Chemical properties and classification refs
 * Chemical taxonomy - http://www.hmdb.ca/metabolites/HMDB00754#taxonomy (already defined as )
 * Parent compounds and the relationship between the acid/base


 * Primary clinical research involving Juven (3 g HMB + 14 g arginine + 14 g glutamine)
 * - 2002 trial of Juven for cancer cachexia
 * - 2002 trial examining the effect of Juven on collagen deposition
 * - 2007 trial examining the effects of Juven in critically ill trauma patients.
 * - 2008 Phase 3 clinical trial of Juven w/o exercise for cancer cachexia
 * - 2015 trial of Juven for postoperative recovery of quadriceps muscle strength after total knee arthroplasty
 * - 2016 trial with Juven examining the effect on vascular endothelial function in older adults after 6 months


 * Reviews covering clinical trials with Juven
 * - 2013 review that probably covers the phase 3 + other trials w/ Juven for cachexia (need to obtain this review)
 * - 2014 review of Juven for diabetic foot ulcers
 * / - covers the effects of Juven on lean body mass+immune function in individuals w/ AIDS and lean body mass in individuals w/ cancer cachexia
 * / - relevant section quoted below



 Seppi  333  (Insert 2¢) 00:55, 25 August 2016 (UTC)

Upcoming systematic review
"Beta-hydroxy-beta-methylbutyrate free acid improves resistance training-induced muscle mass and function: a systematic review" - anticipated completion (publication?) date: September 2016
 * Research question: What is the effect of HMB-FA on resistance training-induced muscle mass and function?
 * Primary outcomes:
 * Effects on skeletal muscle in sedentary, active and recreationally-trained subjects and HMB-supplemented compared with placebo.
 * Change in lean mass from baseline to final intervention.
 * Change in strength and biochemical parameters from baseline to final intervention.

 Seppi  333  (Insert 2¢) 11:45, 31 July 2016 (UTC)

Comment about safety
I'd like to start off by stating that I hope my commenting here does not turn away any potential GA reviewers since I believe these concerns can be addressed quickly, so much so that I'm tempted to go ahead and make them myself rather than post here, but I believe the prose will be more consistent if these changes are made by those who have written the majority of the article already.

In the opening there is a stand-alone sentence discussing HMB's safety in "young or old individuals", but to me that is a little unclear. The first source cited for that statement says "Chronic consumption of HMB is safe in both young and old populations", so I looked through it to see what they consider young. It appears they are referring to young adults as later in the paper they state that no research has been carried out on infants and very little research has been carried out on adolescents. Additionally no research appears to have been carried out on pregnant women.

With this in mind I would suggest further clarifying in the lead the lower bound of the age of individuals for which HMB supplementation appears safe. In addition the description of its safety in humans in the side effects section should be qualified so that it excludes human sub-populations that HMB hasn't been well studied in. Lastly the first sentence of that section implies that safety for animals in general has been established—"the safety profile of HMB in humans and animals"—this should be reworded/expanded to convey either which animals it has been found to be safe for, and/or to describe how animal models have been used to help establish the safety profile in humans. M. A. Bruhn (talk) 05:13, 3 August 2016 (UTC) On a related note, the only thing I could probably put into an OD section is the LD50 for rodent species; since LD50 in non-human animals seldom accurately reflects the LD50 for humans, I decided to forego the overdose section altogether.
 * I agree that this should be clarified.
 * I think specifying "young adults and older adults" should adequately address the ambiguity in the current phrasing. I actually wasn't aware that any clinical testing with the compound had been conducted on individuals who are younger than 18.
 * I imagine that based upon the current wording, one might infer that its safety status has been shown to be analogous to a US pregnancy category A drug; this isn't true, since as far as I know there hasn't been any RCT testing with HMB supplementation on pregnant women. While it's very likely true that the compound isn't teratogenic, we can't say this and it shouldn't be implied without an appropriate citation.  I'll add a clause stating that no clinical testing has been conducted with supplemental HMB in pregnant women.
 * I'd intended to add data on toxicity testing in animal models earlier but later decided to forego it since I figured most people would be interested in clinical information in humans. If you think it's worth adding, I'd be happy to include this.  IIRC, animal testing has involved daily doses of 15 g in rats for a duration of 1+ months w/o adverse effects, but I'll need to double check that. (edit: the doses given to rats were actually much higher based upon  and )   I'll add the information about the animal, dose/dosage, and duration of testing to the article sometime today or tomorrow when I find the review that covers it. As for humans, clinical testing has involved 3 g daily doses for up to a year w/o adverse effects and 6 g daily doses for a couple of months w/o adverse effects in young adults.  This would probably also be worth mentioning in the side effects section, so I'll include this as well when I add the information on animal testing.
 * I'll start working on making these changes now. Please let me know if you have any other suggestions for improvement; I'd be happy to act on them. Also, feel free to edit the article yourself and make any changes that you know are supported by references. I don't bite.  Seppi  333  (Insert 2¢) 06:02, 3 August 2016 (UTC)
 * I'm going to add the information on high-dose animal testing a little later since I need to log off for now. I think I've addressed most of the issues you've raised here, so let me know what you think when you get a chance.  Seppi  333  (Insert 2¢) 07:23, 3 August 2016 (UTC)
 * Those changes have mostly addressed everything for me. The only concern I have is with the ambiguity of "animals". From the context it can be reasonably inferred by the average reader to refer to animals commonly used in research to predict effects in humans, but not all readers might make inference. Although it's unlikely that someone's going to believe it's referring to coral reefs and bumble bees, the statement as it is presently worded is grammatically stating that HMB is safe for animals in general. I think it just needs to be slightly reworded so that instead stating "The safety profile of HMB in ... animals has been well-established...” it instead more explicitly conveys that the animals which HMB appears safe in are animals used to gauge safety for humans. Maybe something along the lines of "The safety profile of HMB in adult humans has been well-established by medical reviews looking at a combination of randomized controlled trials in humans as well as extensive animal testing." I haven't read the medical reviews so I don't know if this is a good characterization or not.
 * I agree that data on animal models is probably irrelevant to add. I said that information on safety of specific animals could be added just on the off chance that there was information that was useful in it of itself, for instance if there had been any research on using HMB supplementation to bulk up livestock. But if that's not the case then there wouldn't seem to be a reason to make any specific mention of animal testing except in cases where it introduces something that human testing hasn't covered, such as with the pregnant pigs. I think making an OD section just for the LD50 might be giving it undue weight. I notice that the chem infoboxes have an LD50 parameter but the drug infoboxes do not, so perhaps that is an indication that LD50's for drugs shouldn't be presented in the infoboxes either. I'm neither for or against addition of such information, and think you should just do what you prefer.
 * I'll let you know if I see anything else or feel free to do it myself. Thanks and good luck with your editing.M. A. Bruhn (talk) 08:35, 3 August 2016 (UTC)
 * I used your proposed wording, which was accurate, and indicated that most of the animal testing has involved lab rats, pigs, chickens, and turkeys. Edit: the review on HMB supplementation in animals  states that "the utility of HMB supplementation in animals has been shown in numerous studies, which have demonstrated enhanced body weight gain and carcass yield in slaughter animals", but I'm going to look for other sources that cover its use in livestock for this purpose before covering it in the article since I don't know how common/notable this practice is.  Seppi  333  (Insert 2¢) 09:24, 3 August 2016 (UTC); edited at 14:17, 3 August 2016 (UTC)

How would you feel about the addition of this statement to the paragraph on pregnancy? ", Metabolic Technologies Inc., the company that grants licenses to include HMB in dietary supplements, advises pregnant and lactating women not to take HMB due to a lack of safety studies conducted with this population." I'm hesitant to add this, although I think it's notable since this is the company that grants licenses to allow the inclusion of HMB in dietary supplements. The reference is a primary source for the statement, but the statement itself is advisement as opposed to a medical claim.  Seppi  333  (Insert 2¢) 02:45, 23 August 2016 (UTC)
 * Edit: I decided to add this material to a newly created "Contraindications" section, since IMO this content is most appropriate there.  Seppi  333  (Insert 2¢) 04:19, 23 August 2016 (UTC)
 * I'm not sure how I feel about this source's inclusion. Companies will produce statements instructing consumers not to use their products in certain ways simply because 1) they want to avoid liability and 2) they know their consumers will ignore them anyways (like with consumers using Q-tips to clean their ears). When you first posted I spent some time trying to find a more MEDRS compliant source to use instead, I found several RS sources, but no MEDRS though. If it is qualified as "Company X says Y" then it isn't really an issue of accuracy (since they do indeed state this) so much as weight. I'm not sure if it is undue weight or not. If this were a drug then it would be easy to find alternative sources, but since it is a supplement our options are limited. I suppose I am leaning more towards its inclusion, but would prefer it if a better source could replace it. M. A. Bruhn (talk) 06:42, 29 August 2016 (UTC)
 * fwiw I think that Seppi is trying like crazy to cover all the sections in MEDMOS and cover the things we usually cover; for medicines we usually give the formal pregnancy category. A drug label will generally give the information as to whether the drug has been tested in pregnant women, or not and the label will give the negative information.  In this case neither the label for Juven nor the label for the medical food Ensure discusses pregnancy.  Neither of the current FDA draft guidances on medical food (not this and not this discuss pregnancy categories, and I am ~guessing~ that this is because medical food is well, food.  Not something strange like a drug.
 * Because of all that, Seppi, I think there is no need to talk about the pregnancy thing; not until this is marketed as a drug (which I am guessing it never will be)
 * That said, I still think including the statement by the company, with attribution as suggested by M A Bruhn above, is a very good move. Jytdog (talk) 07:00, 29 August 2016 (UTC)
 * Yeah... I've been looking for medical sources that make a statement about HMB use during pregnancy or that cover a rather obvious drug interaction between HMB and rapamycin and/or mTOR inhibitors in general, but haven't really found suitable sources for either. In the case of the pregnancy statement in the article, I figure I can get away with that source since it doesn't really make any medical claims about HMB. It's basically just the company's advice, so I agree that it is more of a WP:DUE issue than a WP:RS/MEDRS issue.
 * As for the HMB/rapamycin interaction, their opposing effects on MTORC1 activation and protein synthesis is mentioned only in this primary source, which I can't use to cite a drug interaction.  Seppi  333  (Insert 2¢) 21:09, 29 August 2016 (UTC)

Page name
The page name doesn't seem to be the most obvious choice to be. Thinking about WP:NAMINGCRITERIA I might suggest as alternatives (in rough order of preference): Thoughts? If there is a decision for no change, then I think the last 2 terms should also be redirects here. Klbrain (talk) 18:38, 3 August 2016 (UTC)
 * HMB, on the grounds of Conciseness and Recognizability. It might then require the existing HMB to be moved to HMB (disambiguation)
 * beta-hydroxyisovaleric acid, on the grounds of Naturalness (MESH heading term)
 * 3-hydroxy-3-methylbutanoic acid, on the grounds of Precision (IUPAC name)
 * I'll respond to these in reverse order:
 * 3-hydroxy-3-methylbutanoic acid is neither more nor less precise than the current article name, both names only specify one molecule.
 * The main issue with beta-hydroxyisovaleric acid is that the common acronym, HMB, doesn't work for it. Additionally it seems that it isn't the preferred term in current literature.
 * There are specific naming guidelines based off of the topic. WP:NCMED gives the naming guidelines for medical articles and states "The article title should be the scientific or recognised medical name that is most commonly used in recent, high-quality, English-language medical sources". Furthermore it states that drugs should be titled based off their International Nonproprietary Name, although I'm fairly certain HMB does not have an INN, and the line between drug and supplement is blurry. The chemistry naming guidelines at WP:NCCHEM generally recommend this quoted section from the general naming conventions: "Generally, article naming should give priority to what the majority of English speakers would most easily recognize, with a reasonable minimum of ambiguity, while at the same time making linking to those articles easy and second nature". I think it might be best to look at other dietary supplements for guidance, and looking at other dietary supplement articles it appears using an acronym in place of the chemical name is not normally done, although perhaps a broader discussion should be had on the topic in a more general forum. M. A. Bruhn (talk) 20:46, 3 August 2016 (UTC)
 * The vast majority of literature that has been published on this compound from the past 20 years has used the terms "β-hydroxy β-methylbutyrate" [213 hits] or "β-hydroxy β-methylbutyric acid" [10 hits] (some sources also hyphenate "hydroxy-β"), depending on whether the study involved the conjugate base or acid. Prior to that, the 3- and β- "hydroxyisovalerate/hydroxyisovaleric acid" terms were more common. For comparison, the MESH name "beta-hydroxyisovaleric acid" gets only 8 results out of the 247 papers that are found from an unfiltered search using any of the MESH-indexed synonyms. The IUPAC name is seldom used in published literature.
 * Most commercial products contain the calcium salt of this compound and refer to it as "calcium hydroxymethylbutyrate", "calcium β-hydroxy β-methylbutyrate", or "calcium β-hydroxy β-methylbutyrate monohydrate" (again, some also hyphenate "hydroxy-β"), so I imagine that most of the incoming traffic to this article uses one of those terms. I'm more inclined to use the conjugate base as the page name since it's more prevalent in published literature, but it seems more common to use the acid than the base as the page title when there aren't separate articles for the conjugate acid/base forms of a compound (in this case, the acid/base forms of HMB should be covered in the same article). Consequently, I think the current page name is acceptable even though it's not the most common name. I'm open to renaming the article though.  Seppi  333  (Insert 2¢) 22:01, 3 August 2016 (UTC)

New sources
Thanks for doing a literature search and posting these sources here; I really appreciate it! I'll read through and use them to write new content when I get a chance later today or tomorrow.  Seppi  333  (Insert 2¢) 21:26, 9 September 2016 (UTC)
 * I've been busier than I expected off-wiki over the past few days. I should have time to follow-up on this tomorrow night.  Seppi  333  (Insert 2¢) 22:48, 12 September 2016 (UTC)
 * My bad for not doing this yet; I'm going to stop trying to give myself further deadlines that I can't meet due to how busy I've been this past week. I will, however, use the sources that you linked below to add content before I look for sources to cite for adding a statement on the calcium content of HMB-Ca.  Seppi  333  (Insert 2¢) 23:40, 16 September 2016 (UTC)
 * That's OK - the fitzpatrick book is already used and there is not much else here that is useful. I was mostly recording my work actually trying to track down sales.. Jytdog (talk) 23:43, 16 September 2016 (UTC)
 * Oh. Well, I'll still look through them anyway - might have something worth adding.  Also, one of the refs that you linked to at FAC mentioned something you might be interested in (see the bold+underlined text below). As of when this ref was published, all of MTI's products contained HMB, as stated in the quote.  As of now, they also sell or license one product which contains no HMB: an adenosine triphosphate (ATP) supplement which they call "betaATP".  Seppi  333  (Insert 2¢) 00:44, 17 September 2016 (UTC)
 * FWIW, based upon the prices of currently available HMB-Ca and HMB-FA supplements and the relative efficacy in primary studies between HMB-FA and HMB-Ca, I really doubt MTI is making close to $10,000,000 annually on HMB-FA alone.  Seppi  333  (Insert 2¢) 00:51, 17 September 2016 (UTC)

sources for extent of use of HMB
am looking for sources for this, will record what I find here. others are free to add of course...

This is really hard as MTI is a private company so have no obligation (and don't) report sales.


 * -- says that 10,300 athletes at the 2000 Summer Olympics were tested for doping, and of them, 2758 were surveyed about their use of supplements.  24 of them said they used HMB.  (for comparison, 1996 used some kind of vitamin)


 * (not a great ref, but guy who runs it seems to be not insignificant in world of lifers, see here).  Has a blog entry focused on primary sources  published in 2014 and the followup  published this July and their remarkable results, and writes: "A supplement that’s been around for a long time, but which isn’t all that popular, works better than steroids?".   "which isn't all that popular".   Not much but something.


 * again really slim. From 1999.  One of roundtable participants says: "HMB sales declined rapidly after it was introduced because it had no perceived effect on muscle mass and was expensive."  Same person also said: "Likewise, HMB has not lived up to its marketing hype as an anabolic agent"  Another, " Among athletes who want to gain muscle mass, protein and creatine supplements are popular, especially in football, wrestling, and track and field. HMB and the banned substances DHEA and the “andros” are used by few or none"

This is all I found in a google search 10 pages out. Will check my library... Jytdog (talk) 21:10, 9 September 2016 (UTC)

sources on business background and marketing

 * -- has a passage describing the origin of Metabolic Technologies. Also discusses the science a bit - says early research was hyped, and notes the 2009 review that found it had some benefit for people just starting a training regimen but not for people who have been at it longterm.


 * -- "hook" was launch of Ensure Muscle Health;  discusses that HMB is marketed to older/middle aged folks who want to start getting into shape, because that is who benefits the most (citing the 2009 review again)


 * - a trade rag, notes that HMB is marketed for horses but there is "little to no data to support its use in horses".

Same search as above. Jytdog (talk) 21:10, 9 September 2016 (UTC)

Mg of ionic calcium per gram of pure HMB from HMB-Ca
Need to find a WP:RS-quality source for this, since I think it's worth covering. Probably should be mentioned in the article since the navbox links here and most HMB-Ca brands don't appear to list this information on the supplement bottles.  Seppi  333  (Insert 2¢) 23:40, 16 September 2016 (UTC)

Placement of biosynthesis section
Biosynthesis is currently a subsection pharmacology/pharmacokinetics. Pharmacokinetics is what the body does to the drug, not how the body synthesizes it. Also some bugs and I assume many other "critters" synthesize HMB. Hence logically biosynthesis should not be a subsection of pharmacokinetics, but rather the chemistry (or possibly a new biochemistry) section. The reason I ask is that MC-CoA is used in the biosynthesis of a tetrasaccharide produced by Bacillus anthracis (anthrax  bacteria) and HMB itself has been used in the laboratory synthesis of this tetrasaccharide (see ). This new material would not be appropriate to add to the pharmacokinetics section but would be appropriate in a new biochemistry section. Thoughts? Boghog (talk) 09:13, 25 September 2016 (UTC)
 * I'm okay with moving it. I recognized that it wasn't really relevant to the PK section when I created it under that heading, but I put it there anyway simply because the HMB metabolism diagram also illustrates HMB biosynthesis.  Seppi  333  (Insert 2¢) 10:33, 25 September 2016 (UTC)

Expansion of chemistry section
With thanks to for supplying database searches, I have expanded the synthesis section. There are several more syntheses that could be added, but most of these are obscure reactions or reactions where HMB is a side product. Hence I question the notability of these. Also there were some early syntheses reported (and associated physical data of the synthesized HMB) based on an aldol condensation without dehydration between acetone and ethyl acetate. However I think this would be highly unlikely since the dehydration is the driving force for the reaction. As far as physical data, there is not much more that could (or should) be added. By far, the most notable aspect of HMB is that is a naturally produced metabolite and a food additive. Much less has been published about its chemistry. Hence per WP:DUE, it is appropriate that the chemistry section of this article is significantly shorter than some of the other sections. Boghog (talk) 09:35, 25 September 2016 (UTC)
 * you should probably post this in Nergaal's review section to discuss with him what should or could be added about to HMB's chemistry. He's the only reviewer who has commented on the chemistry section thus far.  Seppi  333  (Insert 2¢) 17:52, 26 September 2016 (UTC)

History → Synthesis section split
I split part of the material that you added to the history section to the synthesis section and re-added a slightly duplicate statement about its very first reported synthesis to the history section in this edit. Is that okay with you?  Seppi  333  (Insert 2¢) 16:52, 9 November 2016 (UTC)
 * Yes. I was thinking of doing something similar.  Thanks for taking care of that. Boghog (talk) 17:32, 9 November 2016 (UTC)

Follow-up from FAC
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 "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)


 * 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 "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.  Seppi  333  (Insert 2¢) 08:37, 17 December 2016 (UTC)


 * Just reade a few changes (diff) that i think reflect the refs and put the body and lead in harmony... calibration is very tricky here.    are there outstanding issues? Jytdog (talk) 08:42, 18 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.  Seppi  333  (Insert 2¢) 19:36, 19 December 2016 (UTC)
 * 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.  Seppi  333  (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. 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.  Seppi  333  (Insert 2¢) 19:48, 19 December 2016 (UTC)
 * That was not my issue and this does not address my concerns 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. Seppi  333  (Insert 2¢) 19:51, 19 December 2016 (UTC)

From :

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.

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?  Seppi  333  (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)
 * 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.  Seppi  333  (Insert 2¢) 02:24, 20 December 2016 (UTC)

New reviews
Checked for updates on November 9th, 2017 (my birthday, yay).  Seppi  333  (Insert 2¢) 05:33, 9 November 2017 (UTC)
 * Happy Birthday :-) Doc James  (talk · contribs · email) 05:37, 9 November 2017 (UTC)
 * Thanks!  Seppi  333  (Insert 2¢) 06:12, 9 November 2017 (UTC)

1st

 * 1)  I just did a literature search and found one new review: ; 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 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:





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

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.  Seppi  333  (Insert 2¢) 04:27, 3 June 2017 (UTC)

2nd

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

The "" was finally published in an academic journal in September. 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?  Seppi  333  (Insert 2¢) 04:48, 9 November 2017 (UTC)
 * FYI: I'm waiting to get ref #5 below 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 ).  Seppi  333  (Insert 2¢) 01:13, 19 November 2017 (UTC)

3rd–8th

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

 Seppi  333  (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.
 * 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."
 * So definitely promising and appears safe but not yet definite. Doc James  (talk · contribs · email) 05:44, 9 November 2017 (UTC)
 * 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.  Seppi  333  (Insert 2¢) 18:22, 17 December 2017 (UTC)

- 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

 * 1)  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.  Seppi  333  (Insert 2¢) 06:12, 9 November 2017 (UTC)
 * 2) </li> Already cited in the article (this is the study on HMB-FA and leucine that was mentioned immediately above).<ref name="Pharmacology of HMB-FA in humans in vivo">

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 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
 * 4) * "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"
 * 5) *"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"
 * 6) 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)


 * 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)

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.

Would you happen to know of a source that can be used to cite this statement?  Seppi  333  (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.  Seppi  333  (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)
 * 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.  Seppi  333  (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.  Seppi  333  (Insert 2¢) 19:41, 11 June 2018 (UTC)

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 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.  Seppi  333  (Insert 2¢) 02:04, 21 July 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.  Seppi  333  (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)
 * 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 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.  Seppi  333  (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.  Seppi  333  (Insert 2¢) 01:48, 10 June 2018 (UTC)
 * 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)

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)
 * 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.  Seppi  333  (Insert 2¢) 23:05, 30 August 2018 (UTC)
 * 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)
 * 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), 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.  Seppi  333  (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.  Seppi  333  (Insert 2¢) 00:48, 2 September 2018 (UTC)

Updates - recent (post-FA) reviews and meta-analyses
From this search:

Meta-analyses from 2018


 * ; meta-analysis: performance-enhancement literature
 * ; meta-analysis + systematic review: healthy adults - presumably mostly athletes (effect on exercise-induced muscle damage)

Systematic reviews from 2018


 * - systematic review: elderly/clinical
 * - systematic review: clinical population - post-surgical recovery

Other reviews from 2017–2018
 * - review by Cruz-Jentoft that I missed earlier

Add these when time permits:
 * 1)  - review: athletes
 * 2)  - (narrative?) review: elderly ("aging neuromuscular junction")
 * 3)  - sports pharmacology review
 * 4)  - review: athletes
 * 5)  - review

 Seppi  333  (Insert 2¢) 21:36, 23 October 2018 (UTC)

Lead breaks on mobile phones in desktop view
This is what the beginning of the article looks like in desktop view on my Huawei P20 Pro: https://i.imgur.com/zyevlQK.jpg

Is it necessary to put the conjugate base in a nowrap? The full, acid name is not in a nowrap. Cheers, Manifestation (talk) 10:49, 26 February 2019 (UTC)
 * That's a good point. I support nowrap or other methods to keep each beta with its next word, but no need to keep separate words together. I changed it to allow breaking at the whitespace, as the acid itself is, as you note. DMacks (talk) 15:34, 26 February 2019 (UTC)
 * Great! It works. Thanks a lot, Manifestation (talk) 16:25, 27 February 2019 (UTC)

Myoplex
This article mentions the supplement Myoplex three times: once in the lead, once under "Use", and once under "History". However, the brand under which the formulation was distributed, EAS, has been discontinued as of June 2018 by its parent, Abbott Laboratories (see here and here). Therefore, I assume Myoplex is no longer being produced. Many shops still have it in stock, but I guess they will run out eventually. Cheers, Manifestation (talk) 17:09, 27 February 2019 (UTC)
 * Removed it  Seppi  333  (Insert 2¢) 20:27, 1 August 2023 (UTC)

Sources of HMB
There is little to no information about where companies are sourcing HMB for human consumption. Where is the compound coming from? Animals? Plants? Mining? 2603:6011:5840:77:E883:6958:855B:D2FC (talk) 14:51, 29 May 2023 (UTC)
 * There’s an entire section on chemical synthesis …  Seppi  333  (Insert 2¢) 20:27, 1 August 2023 (UTC)

Source update
There are scores of very recent secondary reviews in PubMed, and yet most of the sourcing in the Uses section of this article are dated. Sandy Georgia (Talk)  13:39, 1 August 2023 (UTC)


 * Where is supplements purged, under what brand name. 67.4.0.15 (talk) 19:30, 1 August 2023 (UTC)


 * Might update it in a year or two. Seems fine right now.  Seppi  333  (Insert 2¢) 20:14, 1 August 2023 (UTC)