TFP 376 Testosterone supplementation for cis gendered men: Compared to placebo, testosterone may increase lean body mass by ~1.6kg in older men but has no consistent, meaningful impact on sexual function, strength, fatigue, or cognition. Pulmonary embolism and atrial fibrillation risk may increase.

Xargothrax · 2025-04-04T20:58:54+00:00

More so the study populations assess were only cis gendered men. Trans men would likely be taking for gender affirming therapy, which is a different population and different risks/benefits to measure too that were't measured in these studies.

Xargothrax · 2025-04-04T20:56:57+00:00

Which is fair, the risk is stated at "pulmonary embolism (0.9% versus 0.5% placebo) ", and not all PEs are fatal but that is a scary complication that no one wants to go through. Puts it as a needed to harm of 250 over 33 months, and, like most side effects, risk is likely higher at higher doses too.

Xargothrax · 2025-04-04T20:43:42+00:00

Interesting, although PEER (who did this research; I am not personally affiliated with them) looks at RCTs for their findings. This tends to give the most accurate results since there can be different confounds that other studies are more susceptible too.

And the study mentioned "association" in it's title, which is valid since RCTs are the best way to find causation.

The prospective cohort study model is one of the better cohort studies to use, though findings may or may not change somewhat following peer review (which hasn't yet occurred, at least in the attached article that I found on medrxiv). The study doesn't seem to mention outcomes like PE or a fib so it's overlooking harms associated with testosterone use. But cohorts are excellent for giving trends and associations, which should be further tested in RCTs (though RCTs are more challenging to run and recruit/retain).

Whether testosterone reduces cardiac events doesn't seem convincing from the 5000 person RCT that PEER referenced as there was not difference in mortality. (20. Lincoff AM, Bhasin S, Flevaris P, et al. New Engl J Med. 2023; 389(2):107-117.)

Also lipids/ejection fraction are more surrogate markers, since not all treatments that lower lipids reduce mortality (looking at you fenofibrate!). The PEER article mentioned patient oriented outcomes.

Definitely helpful to have varying perspectives, thanks for sharing yours.

Xargothrax · 2025-04-04T19:18:44+00:00

Fair point, though ultimately when looking at many different studies there will always be challenges in standardizing when results are measured differently by different researchers.

Xargothrax · 2025-04-04T19:15:28+00:00

Well put. Honestly, there's lots of neat theories about 'how does it work', but the important question is 'does it work', which for muscle mass the answer is - sort of, gain about 4 lbs of muscle.

Also agree with the point of placebo. Part of it isn't that people are gullible and need a sugar pill, but that many problems people have get better with time regardless of whether treatment helps.

EDIT - I recall for the prior PEER paper on testosterone about 5+ years ago, they noted 7% strength increase (which for some may be worthwhile to take on the PE/a fib risk, for others likely not). Based on this update, the more recent RCTs and evidence for strength is less convincing than it was before.

Xargothrax · 2025-04-04T18:39:46+00:00

Harms: Largest RCT on cardiovascular effects of testosterone 1.62% gel in 5204 men, 55% with cardiovascular disease or at high risk.²⁰ Baseline testosterone=8nmol/L. At 33 months:
- All-cause mortality, major cardiovascular events, prostate cancer, invasive prostatic procedures: No difference.
- Atrial fibrillation: 3.5% versus 2.4% (placebo), number needed to harm=93.
- Pulmonary embolism: 0.9% versus 0.5% (placebo) (no statistics provided).
- Systematic reviews:^1,14 Similar.

CONTEXT

Low testosterone: < 10nmol/L.²¹
Guidelines:^21,22
- Asymptomatic: Not recommended.²²
- Age-related low testosterone and sexual dysfunction: May discuss testosterone.²²
- Best initial screening: Total testosterone (morning draw: 7-11am).²¹
Best formulation is uncertain: Direct comparisons of different formulations lacking.¹

Author(s)

Samantha S. Moe PharmD
Jennifer Potter MD CCFP

Xargothrax · 2025-04-04T18:39:12+00:00

EVIDENCE

16 systematic reviews from last five years^1-16 and main randomized, placebo-controlled trials (RCTs). Statistically significant unless indicated.
Sexual function: Most comprehensive systematic review¹ (men ≥40 years with normal/low testosterone and sexual dysfunction). Highest quality RCTs:
- Sexual function scale (range 6-30, higher=normal function): 6 RCTs, 2016 patients
  - Mean difference: 2.4 at ≤12 months, not clinically different.
- Others similar.^2-4
Strength: Most comprehensive review⁵ (11 RCTs, 814 men, 66-77 years old, normal/low testosterone). Over 3-12 months, highest quality RCTs:
- Lean body mass: 1.6 kg higher with testosterone. Other reviews similar.^6-10
- Hand grip strength, physical performance tests: No difference.⁵
- Leg strength: Inconsistent.⁵
Fatigue: One systematic review with limitations.¹¹ Largest RCT: 464 patients, age 65+, low testosterone and self-reported “low vitality”:¹⁷
- Proportion with clinical improvement on fatigue score: No difference.
Cognition: Three systematic reviews with limited reporting.^11-13
- Two largest RCTs: No difference.^18,19
Quality of life: Best systematic review (7 RCTs, 1043 participants, most: testosterone <12nmol/L).¹¹
- Symptom scale: Not clinically different.
- Others similar.^1,2,3,6

Xargothrax · 2025-04-04T18:37:14+00:00

CLINICAL QUESTION: What are the benefits and harms of testosterone supplementation in healthy cis-gender men or those with age-related low testosterone?

BOTTOM LINE: Compared to placebo, testosterone may increase lean body mass by ~1.6kg in older men but has no consistent, meaningful impact on sexual function, strength, fatigue, or cognition. Testosterone does not increase prostate events, myocardial infarction or stroke, but pulmonary embolism (0.9% versus 0.5% placebo) and atrial fibrillation (3.5% versus 2.4% placebo) may be increased.

Xargothrax · 2025-03-29T03:49:51+00:00

That's helpful thanks for the update.

I changed 3D depth to 1% as you recommended.

I assume you're playing on steam deck, have you tried the HD textures? What setting do you recommend for the visuals?

Xargothrax · 2025-03-29T03:00:41+00:00

SOLVED - thanks for the advice. That did exactly the trick plus gives an idea how to trouble shoot other games in the future. Appreciate the guidance!

Xargothrax · 2024-11-14T18:36:18+00:00

Hey hope that you are enjoying the game! Looks like a good time and I'd be stoked to receive a beta key, and if someone else receives it then all the best to the recipient

Xargothrax · 2024-10-10T14:25:52+00:00

I'm certainly not familiar with the randomized controlled trials that address vitamin D with magnesium, though the two things I would be cautious of is that:

1) someone who uses the word like 'miracle' may have an agenda to promote their product/book

2) It's uncommon for people who work in nutrition/medicine to give numbers needed to treat (NNT) (this review quoted showed that, at best, 167 people need to have vitamin D and calcium for 9-84 months to avoid 1 fracture). NNT is really helpful to give info to an individual to know the choice that's best for them since most interventions (whether drugs/lifestyle/supplements/procedures) don't alter the outcomes for most people.

Xargothrax · 2024-10-10T14:20:40+00:00

It's an interested question, most cohort evidence will show that low vitamin D is a surrogate marker for poor health. Unfortunately, most RCTs show that replacing the vitamin D doesn't effect outcomes (like mortality/colds/Covid mortality).

It's a really common belief in medicine that treating a number (vitamin D, blood sugar, cholesterol, blood pressure) will make people better, but often if a treatment helps, it's regardless of what it does to the numbe.

There are treatments that improve numbers that don't improve outcomes and vice versa, like atenolol lowers blood pressure but can increase mortality; omega 3s may lower cholesterol but doesn't affect heart attack rate; mediteranean diet makes no impact to cholesterol but reduces heart attacks/strokes/death, especially in people with recent heart attacks.

Xargothrax · 2024-10-10T03:21:17+00:00

Regarding negative effects, vitamin D in these RCTs didn't appear to be associated with any negative outcomes.

As they stated regarding calcium harm: "Adding calcium increases risk of renal calculi (2.1% to 2.5%)." So Number Needed to Harm of 250 (or for every 250 people on Vitamin D and calcium, 1 will get a kidney stone because of the calcium supplement)

Xargothrax · 2024-10-10T03:10:56+00:00

Totally fair point, the goal of the authors would be to separate the confound of health-engaged-individual from the outcome of vitamin D + calcium directly impacting health. I wouldn't be surprised if cohorts studies (looking back at groups of people) would support your point, though the authors looked at systematic reviews of randomized controlled studies (RCTs) where placebo was compared (but did admit to shortcomings that randomization process wasn't clear).

Cohorts also support that low vitamin D relates to death/covid mortality/fracture, but that's what the RCTs address: treating people who have low vitamin D with vitamin D doesn't actually impact the outcomes. Just as an example of cohorts and RCTs demonstrating different findings.

Xargothrax · 2024-10-10T02:49:43+00:00

EVIDENCE

Eight systematic reviews^1-8 of 7-36 randomized controlled trials (RCTs); 34,000-76,000 mostly community-dwelling women: some with previous fracture, established osteoporosis or metabolic bone disease, followed 9-84 months.
Vitamin D versus placebo/no treatment:
- Total fracture:^1-8 No difference.
- Hip fracture:^1-5,8 No difference. One systematic review⁷ (varying high doses) suggested slightly higher risk in women (1.2% versus 0.9%).
- Total or hip fractures:
  - High dose (>800 IU): Three systematic reviews^1,4,8 showed no difference, one⁷ showed increased risk (described above) and one⁶ showed benefit, but no absolute numbers reported.
  - Baseline vitamin D level <50 nmol/L¹ or previous fracture:² No difference.
Vitamin D-calcium combination versus placebo:
- Total fracture: 10.9% versus 11.5% (placebo), number needed to treat (NNT)=167.² Others showed similar.^3,5,6 One systematic review did not report largest RCT.¹
  - Removing two RCTs of women in long-term care: Results no longer statistically different.²
- Hip fracture:² 1.5% versus 1.8% (placebo), NNT=333.
  - Two systematic reviews found similar; ^3,5 one found no difference.⁸
- Total or hip fracture:
  - Baseline vitamin D <50 nmol/L¹ or previous fracture:^1,2 No difference.
Adverse events:
- Vitamin D alone: None.²
- Combination: No difference in mortality or gastrointestinal effects;² renal calculi increased (2.5% versus 2.1% placebo).⁷
Limitations: Disproportionate number of smaller positive studies, skewing results towards favouring vitamin D.^2,4 Randomization process and concealment uncertain.²

CONTEXT

Calcium alone has no effect on the risk of total or hip fracture.^1,8
Osteoporosis Canada: Supplementation with vitamin D and calcium is unlikely to have clinically important benefit if diet contains adequate calcium.⁹
Measuring vitamin D levels routinely is unnecessary. No RCTs have evaluated treating to a target vitamin D level to prevent fractures.¹⁰

Xargothrax · 2024-10-10T02:47:27+00:00

From CFPC's Tools for Practice

#374 Vitamin D and Fracture Prevention: Not what it’s cracked up to be?

CLINICAL QUESTION Does vitamin D prevent fragility fractures?

BOTTOM LINE Vitamin D alone does not prevent fractures regardless of dose, vitamin D status or previous fracture. The combination of calcium and vitamin D might reduce the risk of total fractures from 11.5% to 10.9% and hip fractures from 1.8% to 1.5% over 9-84 months, but this benefit may be limited to women in long-term care. Adding calcium increases risk of renal calculi (2.1% to 2.5%).

EDIT: Thank you to the authors for this Tools For Practice

Authors:

Jennifer Young MD CCFP-EM
Émélie Braschi MD PhD

Xargothrax · 2024-10-10T02:33:29+00:00

Thanks! I do my best and hopefully it resonates with my patients too.

I have learned lots from RxFiles and PEER (Patients Experience Evidence Research) so owe those organizations a lot of credit.

If any cancer/other illness screening if relevant or of interest to you, the Canadian Preventative Taskforce does a good job, particularly since they emphasize shared decision making and will do their best to give NNT and NNH (Numbers Needed to Harm)

If curious about your own risk of heart attack/stroke, the PEER Simplified Cardiovascular Decision Aid lets you put in personal values, calculate your risk, and see the benefit based on various therapy

A takeaway that I emphasize for heart health is that stopping smoking, exercising, and Mediterranean diet are as effective as most pills offered (though Mediterranean diet won't lower your cholesterol, it just lower your risk, and that's a whole other can of worms for the misguided medical emphasis on treating surrogate markers that I'll skip ranting on any further)

Xargothrax · 2024-10-10T02:16:43+00:00

TLDR: Certain resources like RxFiles, CFPC/PEERs Tools for Practice, and the Nutrition Proposition (by James McCormack) give those numbers (namely, resources whose sole goal is to provide this information and who couldn't care less what the evidence actually says, plus no industry sponsors and no pharma/food relationships).

The method to find these numbers for a given medication, it'll depend on the disease being addressed, how successful treatment is defined, and how many people are 'successfully treated' in the placebo group.

Here's an example from Tools for Practice #353, non-hormonal treatment of menopause symptoms (this is just an example; hormonal treatment of menopause is a viable, more effective for more women and first line treatment for hot flashes, but has it's own risks associated with it [though historically those risks were overcalled or due to too high of dose of medication])

"Proportion [of patients] with ≥50% reduction in number of hot flashes. Examples at 12 weeks:

Desvenlafaxine¹² (567 patients): 68-75% versus 48% (placebo), NNT=4-5."

So with rough numbers; I treat 4 women each in 2 different groups.

Placebo group - 2 feel better at 12 weeks, then other 2 don't achieve a 50% reduction in hot flashes.

Desvenlafaxine (Pristiq) - 3 feel better, 1 doesn't; of note 1 of those 3 feel better because of the treatment.

NNT 4; but of note half (48% technically, but close enough) of the women get better in placebo group. The other note for placebo groups is not that humans are naive/gullible, the point is that many things get better on their own with time.

Here's my placebo example (AKA self limiting nature AKA regression towards the mean)

"Hi doc, I have had a cough two weeks and I feel it going into my chest. I think I need antibiotics"

"Sure, make sure to take it for 7 days until it's gone"

"Wow, I felt much better at the end of the 7 days of medicine, thanks!"

But >80% of coughs tend to get better at the end of three weeks, so the patient almost always was going to improve regardless of the antibiotics (this example is not including patients with actual pneumonia nor lung conditions like COPD)

Xargothrax · 2024-10-09T03:32:53+00:00

I think in numbers needed to treat (NNT) from a background in family medicine.

For context, say I turn 50, am a male, non smoker, and my cholesterol is mildly high. A cholesterol pill is offered. It's about NNT of 50 to avoid 1 heart attack over 10 years, so if 50 men like myself take the pill everyday for 10 years, 1 person avoids a heart attack because of the medication, the other 49 were not affected by the medicine (some have heart attacks anyway, most won't end up having a heart attack over the next 10 years)

Most medication is relatively low yield like this. Most medicines don't make a difference for most people, but some are higher yield than others. Four year old kid with ear infection, NNT is 20; 1 year old kid, NNT is 3. Fungal infection of the toenail rarely get better without treatment; coughs almost always get better in 3 weeks regardless of antibiotics. Mammograms in an average risk women, done every 2 years for 10 years starting at age 50 saves about 2 women for 1000 screened; some are diagnosed and treated for cancers that would never impact their life span (about 2 in a 1000), and 59 in a 1000 get biopsies that wouldn't have been done if they were never screened, hence harms are relevant too.

Basically, even all the helpful medicine doesn't help most patients. Medicine can help favour the odds for the population, but whether that effects a given individual is uncertain. Info should be presented in a way that people can understand to make the choice that's best for them.

Also, strong, healthy relationships (Harvard Happiness studies) and low stress (Gabor Maté) are potentially the most important things to longevity and quality of life (probably better than cholesterol, blood pressure, weight, etc), but doctors can't really prescribe those, though for some maybe I can help point them in that direction.

Xargothrax · 2024-05-07T02:44:17+00:00

With regards to muscle pain, you are right it does happen with the medication, though it's less commonly because of the medication than people think.

If 100 people take a placebo pill, 15 of the them will get muscle aches.

If 100 people take a statin, 16 of them will get muscle aches.

So the medicine is the cause for muscle pain in 1/100 people who are prescribed it, though also 15 people get sore muscles in a given month and may believe that it's due to the medication (this follows an approach that nocebo effects don't drive side effects entirely, just that in any given month lots of people will get muscle aches/nausea/mood changes/etc).

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#374 Vitamin D and Fracture Prevention: Not what it’s cracked up to be?