Topical All-Trans Retinoic Acid & Mortality / Lead Exposure, Aging, & Bone Loss

A clinical trial [Veterans Affairs Topical Tretinoin Chemoprevention Trial (VATTC)] of topical all-trans retinoic acid (tretinoin, Retin-A) had to be halted because the intervention arm experienced higher mortality. The authors indicate that a causal relationship is unlikely, but the finding is a bit troubling nonetheless. The increase in mortality was not attributable to any one specific cause of death.

https://jamanetwork.com/journals/jamadermatology/fullarticle/711869

"We considered the possibility that topical tretinoin applied to the face and ears might be a cause of death. One study that was published during our trial involved systemic administration of isotretinoin, a closely related compound. That trial found a significant interaction between the medication and smoking in their effect on mortality, with isotretinoin therapy associated with increased mortality among smokers.⁴ Studies involving a less closely related compound, beta carotene, have also suggested an increased risk of lung cancer and risk in smokers.^5,10-12 We looked for an interaction in our data with smoking, analogous to that found in the isotretinoin trial, but could not find one. ... A dose-response relationship between total number of tubes of cream used and frequency of use with risk of death was not present in our data, although we could not definitively rule out a threshold effect on the basis of our data. "

The study population was comprised of military veterans, mostly older males (mean age of 71). Veterans often have higher rates of toxic exposures related to their military service - lead exposure from ammunition, in particular. There may be some interaction with lead exposure - it is difficult to search on the topic since 'lead' is a homograph. I did manage to find an article on the effects of metal exposure on retinoid metabolism that looks interesting but of course it is paywalled: https://pubmed.ncbi.nlm.nih.gov/24291063/

To speculate even further, perhaps there is some relationship to aquaporin function, as both retinoic acid and lead impact aquaporin function. 

https://pubmed.ncbi.nlm.nih.gov/16203098/

Moreover, lead has myriad deleterious health impacts and mobilization of lead stored in bones occurs due to age-related bone resorption in both men and women.

https://pubmed.ncbi.nlm.nih.gov/11675263/ 

Increasing blood retinol levels would exacerbate the process; a study of oral retinol intake found:

"In both sexes, increasing retinol became negatively associated with skeletal health at intakes not far beyond the recommended daily allowance (RDA), intakes reached predominately by supplement users."

https://asbmr.onlinelibrary.wiley.com/doi/full/10.1359/jbmr.2002.17.8.1349

Could topical tretinoin increase blood retinoid levels? The VATCC study report states: 

"We also noted the published literature that described absorption of various formulations of percutaneously applied tretinoin of 1% to 8%^13-18 and that the current prescribing information of one formulation refers to absorption of up to 31% of the applied dose under certain circumstances.¹⁹ After application for at least 1 year in 1 study, absorption of less than 2% was noted.¹⁵ Several publications have noted that the amount of tretinoin absorbed does not significantly alter the endogenous levels of tretinoin and its metabolites; the concentration of absorbed tretinoin was estimated at about 1% of the endogenous concentration.^{14,17,18,20,21"} 

I looked up two human studies on the list and was dismayed by the small sample sizes (n=7, n=5, n=4):

https://pubmed.ncbi.nlm.nih.gov/9091507/

https://pubmed.ncbi.nlm.nih.gov/8113456/

The age of participants was not mentioned in the abstracts and of course I cannot access the full articles. Skin barrier function declines in the elderly and this may affect level of absorption. I was unable to find any studies on whether topical tretinoin use is associated with osteopenia or osteoporosis specifically in aged individuals.

The lack of dose response relationship in the VATCC study casts doubt on a causal relationship. However, the possibility that dosing levels were not accurately reported should be considered given that there may have been sharing of the tretinoin among household members as it is a popular cosmetic anti-aging topical and is relatively expensive without insurance, which typically does not cover cosmetic use. Also, if lead is indeed a factor, then body burden of lead would need to be taken into account.

It seems there is need for further investigation as there is an at least somewhat biologically plausible mechanism for harm in this particular population. 

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For those concerned about past lead exposure and possible mobilization due to bone loss associated with aging (and perhaps tretinoin use in later years?), Dr Greger of NutritionFacts has an informative series of videos on lead exposure and dietary and lifestyle approaches to mitigation. Here are some highlights (more available on the site):

The Effects of Low-Level Lead Exposure in Adults - this one covers lead exposure associated with firearms use

Can Vitamin C Help with Lead Poisoning?

Best Food for Lead Poisoning – Garlic

Can Saunas Detoxify Lead from the Body?

 

The Sheeky Science Show has video reviews on alpha-ketoglutarate (AKG) and spermidine for osteoporosis:

AKG prevents age-related bone loss?

Warmth prevents bone loss..!? Increased spermidine & Gut microbiome link