HMB 'Likely' Protects 'Muscle Quality' & 'Possibly' to 'Likely' Cuts Inflammation During 23-Day Intense Military Training

Unfortunately, the study at hand provides insufficient evidence to decide whether you should buy (free acid) HMB if you are about to participate in a military bootcamp.
The idea that HMB is the rather anticatabolic version of leucine, I've mentioned in previous articles, obviously occurred to an international group of scientists from the University of Central Florida, the Israel Defense Forces as well as associated universities, too (Hoffman. 2016).

In their recent study, the scientists examined whether HMB supplementation can attenuate muscle loss and the inflammatory response during highly intense, sustained military training. A study, of which Hoffman et al. point out, that it is "to the best of [their] knowledge" the first study to "have examined HMB supplementation in soldiers during intense military operations" (Hoffman. 2016).
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The authors examined the effect of 23-days of HMB supplementation on the immune and inflammatory response, and changes in muscle mass in combat soldiers during highly intense military training duringn which they consumed eiather with three servings (1 gram per serving) per day (at meal time | BetaTor®), or a placebo (PL) consisted of a similar amount of Litesse® polydextrose, reverse osmosis water, corn syrup, debittering agent, orange flavoring, stevia extract, citric acid, potassium sorbate, and xanthine gum powder (both sponsored by Metabolic Technologies Inc.):
  • During the 23-day study period all soldiers performed the same daily protocol. 
  • On days 1 – 10 soldiers were garrisoned on base and participated in the same advanced military training tasks that included combat skill development and conditioning. 
  • During days 11 – 17 soldiers were released for a week of rest and recovery. Upon reporting back for duty, soldiers were then subjected to a week (days 18 – 23) of extreme training with minimal recovery. 
  • On days 18 through 20, soldiers navigated 23.3 km per evening in difficult terrain carrying approximately 35 kg of equipment on their back (equating to approximately 40% of participant’s body mass). The duration of the navigational exercise lasted between 6 – 8 hours per evening. During daylight TED 
  • On day 21-23, the soldiers were subjected to excessive physical training that included 90-min of intense hand-to-hand combat (krav-maga training), 60-min of endurance training and an additional 60-min of resistance training. 
As the scientists point out, the soldiers slept of only 22.5 h (3.8 ±3.0 h per night) during the six days of intense training, which including two evenings of no sleep (days 18 and 22). Blood draws and magnetic resonance imaging (MRI) measures were conducted in a single day prior to (PRE) and approximately 18-hours following the final supplement consumption (on day 24) (POST). All
blood draws and MRI measures were performed at Soroka Medical Center.
Table 1: Circulating cytokine concentrations (pg/ml) and muscle damage markers in HMB and PL in response to intense military training (Hoffman. 2016) | All data are reported as means ± SD.
Due to injuries and compliance issues, only 13 of the 27 participants were included in the final analysis (HMB = 6 and PL = 7), and even those subjects consumed only 89.3 ± 6.8% of the possible servings. I doubt, however, that the scientists didn't observe significant interactions were observed between HMB and PL for body mass (F=3.36, p=0.094) from pre (72.6 ± 7.1 kg and 70.7 ± 6.6 kg, respectively) to post (71.7 ± 6.4 kg and 71.2 ± 6.9 kg, respectively).
Why is HMB-FA supposed to be better than calcium HMB (Ca-HMB)? While some people say that the producers make false marketing claims about the bioavailability of HMB-FA, the reality is that the patent holder's claim that "BetaTOR [HMB-FA] is more rapidly absorbed so you get a higher peak and sustained concentration in the blood" (Manufacturer claim) has been proven in both, rodent (Shreeram. 2014) and human studies (Fuller. 2011). The former, however, also reveal that the bioavailability, i.e. the amount of HMB that actually hits the circulation - or, as scientists say the area under the curve (AUC) from t = 0 to t = ∞ - is actually 49%, 54%, and 27% lower (with increasing doses reducing the difference) than for Ca-HMB (Shreeram. 2014). The often-heard claim that the AUC doesn't matter as much as the speed may be in analogy to the comparison of whey vs. steaks, where the speed at which whey protein is absorbed and its leucine content enters your bloodstream is supposed to make all the difference, but is as of yet unproven.
On the other hand, the scientists observed potentially meaningful effects of HMB on markers of inflammation. More specifically, HMB ingestion, based on magnitude analysis (see Table 1 for an overview of all results), ...
  • likely attenuated (78% likelihood effect) response compared with the effect of PL (a difference ± 90% CI of -38 ± 43.7 pg/ml between he Δ HMB – Δ PL)
  • likely (87.2% likelihood effect) attenuated the INFγ response compared with the effect of the placebo (a difference ± 90% CI of -42 ± 47.3 pg/ml between the Δ HMB – Δ PL)
  • possibly attenuated (74% likelihood effect) the IL-1ra response compared to PL (a difference ± 90% CI of -11 ± 18.9 pg/ml between the Δ HMB – Δ PL).
  • possibly (74.5% likelihood effect) attenuated the IL-6 response compared to PL (a difference ± 90% CI of -6.6 ± 11.2 pg/ml between the Δ HMB – Δ PL).
  • possibly attenuated (63% likelihood effect) the GM-CSF response compared with the effect of PL (a difference ± 90% CI of -8.1 ± 20.0 pg/ml between the Δ HMB – Δ PL).
  • likely decreased (80.5% likelihood effect) the IL-8 response compared to PL (a difference ± 90% CI of -6.7 ± 10.0 pg/ml between the Δ HMB – Δ PL).
  • very likely (92% likelihood effect) attenuated the TNF-α response compared to PL (a difference ± 90% CI of - 10.8 ± 7.2 pg/ml between the Δ HMB – Δ PL).
As the authors point out, "[t]he remaining cytokines demonstrated no significant pre and post changes between HMB and PL for IL-1b (F=0.04, p=0.84), and MCP-1(F=0.58, p=0.46) [and,  more importantly] the magnitude based inference analyses indicated that comparisons between HMB and PL on these inflammatory markers were unclear" (Hoffman. 2016).
Figure 1: There's a 77% chance the rel. increase in adductor magnus MRI muscle volume is significant (Hoffman. 2016). In view of the likely increased CK and LDH levels this could be a result of cell swelling in response to muscle damage.
Unfortunately, we have to eyeball the trend (F=4.30, p=0.062) towards HMB's effects on plasma CK with the same skepticism as the "likely", "possible" and even "very likely" effects on markers of inflammation. Ok, the fact that the increased CK levels in the HMB group were accompanied by "a likely increase (84% likelihood) in the LDH response compared to PL (a difference ± 90% CI of 53 ± 5.8 IU·L-1 between the ∆ HMB - ∆ PL)" (Hoffman. 2016), is what you'd expect in response to exercise. Usually, though, CK and LDH are considered markers of muscle damage and IIRC the scientists thought to demonstrate that HMB has a muscle protective effect.

To even complicate things, in previous studies both acute increases and chronic decreases in CK have been observed in studies by Wilson et al. (2009 | acute data) and Panton et al. (2000 | chronic data), respectively. Whether there was an increased muscle damage or whether HMB had protective effect as the "likely [...] increase muscle volume for the adductor magnus (77% likelihood [see Figure 1]) compared to PL" (Hoffman. 2016), the scientists appears to suggest, is thus impossible to say.
More HMB Free Acid Science: Now It's Also Good For High Intensity Interval Training (HIIT) Says the Latest Spon-sored Trial W/Out Calcium HMB Con-trol in Young Men & Women | more!
Bottom line: Even though I cannot debate that the scientists' magnitude analyses provide, as they say in the conclusion, "evidence that HMB supplementation may attenuate the inflammatory response to high intense military training, and maintain muscle quality" (Hoffman. 2016). The study is seriously under-powered (remember they had 14 dropouts).

Due to the high number of dropouts, it was more or less impossible to produce significant results. In a situation like that, the use of magnitude analyses to "save" the study makes sense, but reliability of the results is even lower than "likely" and "possibly" would suggest.

So why did I discuss the study, then? Well, let's say I sense that either Metabolic Technologies Inc., who are mentioned in the acknowledgements, which also declare that the authors have "no conflict of interests to report"(Hoffman. 2016), or licensees of HMB free acid are going to cite this study in write-ups and on product packages without mentioning words like "possibly" or "likely" or any of the other problems discussed above | Comment on Facebook
  • Fuller, John C., et al. "Free acid gel form of β-hydroxy-β-methylbutyrate (HMB) improves HMB clearance from plasma in human subjects compared with the calcium HMB salt." British journal of nutrition 105.03 (2011): 367-372.
  • Hoffman, Jay R., et al. "HMB attenuates the cytokine response during sustained military training." Nutrition Research (2016).
  • Panton, Lynn B., et al. "Nutritional supplementation of the leucine metabolite β-hydroxy-β-methylbutyrate (HMB) during resistance training." Nutrition 16.9 (2000): 734-739.
  • Shreeram, Sathyavageeswaran, et al. "The Relative Bioavailability of the Calcium Salt of β-Hydroxy-β-Methylbutyrate Is Greater Than That of the Free Fatty Acid Form in Rats." The Journal of nutrition 144.10 (2014): 1549-1555.
  • Wilson, J.M., et al. "Acute and timing effects of beta-hydroxy-beta-methylbutyrate (HMB) on indirect markers of skeletal muscle damage." Nutrition & metabolism 6.1 (2009): 1.
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