Effects of HRT: Alone, in Combination or Sequencing

@dmshope
I’ve been using transdermal estradiol 0.025mg/day patches and oral micronized progesterone 100mg daily at bedtime.

My endocrinologist and a bone specialist originally advised titrating up to the standard 0.05mg/day patch dose (roughly the equivalent of the CEE dose used in the WHI study). However, when they saw my CTX drop to 302 after just 3mo, they had me hold at the lower dose. By 6mo mark, my labs confirmed that the 0.025mg/day was adequate for suppression. Please note that my 1st year BTMs were influenced by coming off Forteo, with a high turnover rate at the time; therefore, part of those initial CTX changes was likely due to that transition.

I’m nearing the end of my second year on HRT, and my CTX has consistently remained below 120 during second year. I won’t have my next DXA results until later this year to see the formal BMD impact.

Have you finished your Evenity course? If so, you may want to keep an eye on your CTX closely as it can take 6-9mos for estrogen to reach its peak anti-resorptive effect, if you choose HRT route.

There is evidence suggesting that low-dose and conventional-dose patches can be equally effective at preventing bone loss across all post-menopausal ages:
https://pubmed.ncbi.nlm.nih.gov/8706298/
I believe @debbie1956 used the same dosing as mine and I’ll tag her here. I’ll also tag @teb who has been on HRT for quite a long time and shared similar experiences in the past, just in case either of them has a moment to chime in with their experiences.

@mayblin - here's my convoluted, less that ideal BTM, Evenity, HRT, BTM journey so far:

July '25 (prior to Evenity) - P1NP: 34 CTX: 444 (fasting, but not informed about avoiding biotin or collagen)
July '25 - begin Evenity (spine -3.5; hips both -2.8)
Apr '26 - begin HRT
June '26 - last Evenity injections
July '26 - DXA: spine 1.0; hips -1.9 (great improvement after Evenity)
Aug '26 - P1NP: 21 CTX: 177 (different lab, fasting, early morning draw, no biotin or collagen)

As we've discussed, BTM have their own unique pathway following Evenity. I don't know if the HRT would have had much impact from late Apr to early Aug. No BTM were taken during or after the Evenity course except for the self-pay ones that I'm reporting right now.

I suspect that Evenity is still being reflected in the BTM results (I saved the chart you sent). At least I'll have my own baseline to work from as I consider another draw 3-mo from now and then again 6-mo until I see a pattern emerge.

I should have tagged this onto another thread...but couldn't find it!

@singingbones, thanks for sharing!

The baseline BTMs are unfortunately not reliable, mainly due to biotin and collagen effects on the CTX, and the differences in assay methods because different labs were used.

I may have asked before but couldn’t recall, what’s the dose and form of estrogen you are using now? You are currently on HRT only without a bisphosphonate right?

The recent CTX of 177 is a nice reading. Does your endo have a CTX target during maintenance phase? I’ve read and was advised by a bone specialist to target the lower half of the healthy premenopausal range with HRT during the antiresorptive phase. That said, you are only about 2mo out from your last Evenity injection and about 4mo into estrogen - so the expected CTX rebound after stopping Evenity has just begun to play out, while estrogen has not yet reached its maximal effect on bone. The true trajectory will only become clear with continued monitoring.

HRT is a recognized antiresorptive. However, the evidence for maintaining bone gains specifically after Evenity is for bisphosphonates and Prolia, not yet for HRT. I’m in a similar boat as you.

@mayblin - Correct--no bisphosphonate. I've used vaginal estriol/estradiol for yrs to avoid recurring UTIs as well as 100 mg prometrium oral capsules. My new dr added the systemic dose of transdermal gel of 0.25 mg in April to begin to address bone health. I will be seeing her at the end of this month to see how she wants to proceed in terms of modification.

My Evenity prescribing dr is actually an orthopedic surgeon (no longer doing surgeries). She has no interest in BTMs, as she says DXA is sufficient. My recent DXA was nicely timed w/the end of the Evenity course, so she was satisfied. That's why I'm self-paying for my own BTMs. I'll ask my PCP for those labs next time, but I still plan to get them done more frequently for my own peace of mind.

Yes, we are trail-blazing a bit for sure. I have read of personal success stories on Inspire.com where others have chosen HRT as their follow-up antiresorptive. I do appreciate that drs need to follow the studies and they are sparse or non-existent for this protocol.

Pls unpack your statement for me: "I’ve read and was advised by a bone specialist to target the lower half of the healthy premenopausal range with HRT during the antiresorptive phase." I want to understand this better. Thanks!

@singingbones
Just to clarify my earlier comment about aiming for the lower half of the healthy premenopausal CTX range: this isn’t a standard recommendation or a validated target. It’s an empirical approach some doctors use to gauge antiresorptive effect. The bone specialist I spoke with happens to be one of them.

Unlike bisphosphonates, estrogen comes in many doses (and formulations), and its dose-response with BTMs is less well studied. That said, a few publications (including an ASBMR Task Force report) describe experts using the premenopausal range as a practical signal, for example, restarting treatment of bisphosphonates after a holiday when markers rise above the lower half. The Endocrine Society, on the other hand, stresses that there’s real uncertainty about what an “optimal” BTM response even is, and that serial measurements need the same assay and must exceed the least significant change (around 56% for CTX in their example).

In my case, my doctors had planned to bump the estradiol patch from 25 to 50mcg. The specialist suggested looking for CTX in the lower half of the premenopausal range, but my response to 25 mcg was already very strong, so I was instructed to keep using the same low dose.

So my point wasn’t that guidelines say estrogen dose should be titrated to a specific CTX level - just that some docs use this range empirically, and that’s what happened in my situation. And of course, always best to follow your own physicians, who know your full clinical picture.

@mayblin - here's my convoluted, less that ideal BTM, Evenity, HRT, BTM journey so far:

July '25 (prior to Evenity) - P1NP: 34 CTX: 444 (fasting, but not informed about avoiding biotin or collagen)
July '25 - begin Evenity (spine -3.5; hips both -2.8)
Apr '26 - begin HRT
June '26 - last Evenity injections
July '26 - DXA: spine 1.0; hips -1.9 (great improvement after Evenity)
Aug '26 - P1NP: 21 CTX: 177 (different lab, fasting, early morning draw, no biotin or collagen)

As we've discussed, BTM have their own unique pathway following Evenity. I don't know if the HRT would have had much impact from late Apr to early Aug. No BTM were taken during or after the Evenity course except for the self-pay ones that I'm reporting right now.

I suspect that Evenity is still being reflected in the BTM results (I saved the chart you sent). At least I'll have my own baseline to work from as I consider another draw 3-mo from now and then again 6-mo until I see a pattern emerge.

I should have tagged this onto another thread...but couldn't find it!

@mayblin - thank you - this is very helpful.

I have read a couple of other posts where the gals are getting BTMs checked every 3 mo to track the impact of HRT. Some had to increase estradiol and some were similar to yours...where their response was already strong at a low or conservative dose. I understand your comment about it being used empirically. But for me, this seems to make more sense than attempting to reach a particular blood serum level of estradiol to impact bone density. That seems to be too general/standardized. It's nice to have both, I guess, so I'm curious as to what direction/preference my new dr will advise.

@singingbones
Congrats on the great BMD improvements! How did I manage to forget this important part last time?!

My thoughts are pretty similar to yours - a blood estradiol level tells us how much of the drug is being delivered and absorbed from the patch - it does not directly tell us how our bone is responding to the estrogen, whereas BTMs reflect the state of bone remodeling in response to HRT around the time of the blood draw.

Also, from what I understand, for fracture prevention, neither a blood E2 level nor BTM is a validated target to adjust HRT dosing. The evidence that HRT reduces fractures comes mainly from the WHI, which used a fixed standard dose - conjugated equine estrogens (Premarin) 0.625 mg, rather than adjusting the dose to hit a particular blood estradiol level or CTX value. A 0.05mg/day estradiol patch is approximately equivalent to Premarin 0.625 mg. (For bone protection specifically, even lower patch doses are FDA-approved.)

So either approach (blood level or BTM) is being used empirically as a surrogate marker. The most established way to confirm that treatment is actually protecting our bones remains serial DXA scans

With all that said, a better-suppressed bone remodeling is associated with a high probability of BMD stabilization in clinical studies:
for transdermal estradiol patch - https://pubmed.ncbi.nlm.nih.gov/10831925/
for oral estrogen +/- progestin - https://onlinelibrary.wiley.com/doi/10.1359/jbmr.1999.14.9.1583

If you’ve been wondering, my 25 mcg patches put my blood E2 at 42pg/ml (trough, just one lab so far), CTX stayed consistently under 120 in year two. Now just waiting on judgment day… the DXA scan.

@mayblin

The estrogen+/- progestin article was published in 1999. While I'm reluctant to use AI, I'll use it to find the most recent data on HRT and women's health.

@singingbones
Congrats on the great BMD improvements! How did I manage to forget this important part last time?!

My thoughts are pretty similar to yours - a blood estradiol level tells us how much of the drug is being delivered and absorbed from the patch - it does not directly tell us how our bone is responding to the estrogen, whereas BTMs reflect the state of bone remodeling in response to HRT around the time of the blood draw.

Also, from what I understand, for fracture prevention, neither a blood E2 level nor BTM is a validated target to adjust HRT dosing. The evidence that HRT reduces fractures comes mainly from the WHI, which used a fixed standard dose - conjugated equine estrogens (Premarin) 0.625 mg, rather than adjusting the dose to hit a particular blood estradiol level or CTX value. A 0.05mg/day estradiol patch is approximately equivalent to Premarin 0.625 mg. (For bone protection specifically, even lower patch doses are FDA-approved.)

So either approach (blood level or BTM) is being used empirically as a surrogate marker. The most established way to confirm that treatment is actually protecting our bones remains serial DXA scans

With all that said, a better-suppressed bone remodeling is associated with a high probability of BMD stabilization in clinical studies:
for transdermal estradiol patch - https://pubmed.ncbi.nlm.nih.gov/10831925/
for oral estrogen +/- progestin - https://onlinelibrary.wiley.com/doi/10.1359/jbmr.1999.14.9.1583

If you’ve been wondering, my 25 mcg patches put my blood E2 at 42pg/ml (trough, just one lab so far), CTX stayed consistently under 120 in year two. Now just waiting on judgment day… the DXA scan.