Estrogen for Osteoporosis Prevention and Treatment

by Jeffrey Dach MD

Sally is a 54 year old post-menopausal patient, one of the few who recovered completely from Graves’ hyperthyroidism after medical treatment. However the bouts of hyperthyroidism took their toll, and Sally’s latest DEXA scan showed a loss of bone density. The T-score at the spine and hip was -2.5 and -2.6.

Starting Estrogen Hormone Replacement

Estrogen is now accepted as first line treatment for prevention and treatment of post-menopausal loss of bone density. (17) (22-27)

We started Sally on our standard office protocol for bioidentical hormone replacement including topical estrogen and progesterone. After 6 months. Sally went to the lab to do a follow up hormone panel showing a serum estradiol level of 32 pg/ml.

Sally has a PhD in biological sciences and does her own research. She pointed out to me that based on a 1992 study by Dr. Jean Reginster the minimal level of estradiol to prevent post-menopausal bone loss is 60 pg/ml, not the 32 pg/ml she has on her lab. Her estradiol level should be higher.(5)

I explained to Sally two things. Firstly, all patients have the liberty of increasing the topical estrogen cream gradually at home. We use the  Topi-click dispenser which makes it easy to adjust dosage at home by increasing the number of clicks used each day. As dosage is increased, eventually one reaches the point of estrogen excess, with obvious symptoms of breast enlargement, breast discomfort, nipple sensitivity, etc. Estrogen stimulates breast tissue. This will be obvious to the patient. A small amount of breast tissue stimulation is expected. Too much becomes annoying and uncomfortable. If this happens, the patient is instructed to take a break from the hormone cream for 5-7 days, and return at half dosage once symptoms have resolved. The second symptom is fluid retention. The clothes fit more tightly and the patient turns into a beach ball. Again this will be obvious. We have found that many women will have symptoms of estrogen excess when estradiol levels exceed 60 pg/ml. Our treatment goal is not to target a serum estradiol level. Our treatment goal is a dosage of estradiol which provides complete relief from menopausal symptoms. Higher dosages of estradiol may be associated with adverse side effects.

Paucity of Evidence to Set Estradiol Target Goals

Secondly, Dr. Jean Reginster’s old 1992 study is outdated. Since then, the science has changed and target goals for serum estradiol levels have been abandoned. In 2002, Dr. Armston reviewed this issue of target goal for estradiol to prevent bone loss, saying there is a paucity of evidence to support the setting of target levels at present, writing.

Evidence in the literature for using a particular cut-off value for plasma estradiol, which is sufficient to prevent osteoporosis, is compromised by:

. Lack of documentation of the estradiol method used.
. Differences in bias between laboratory estradiol assays.
. Lack of reference to the timing of sampling in relation to patch change or gel application.
. The small number of women included in many studies (seeTables 2-5).
. In the case of patch studies, a failure to specify the type of patch studied.
. For gel preparations, lack of standardization of gel application area.

Despite these limitations, the trend to use HRT preparations which deliver lower doses of estradiol means that the clinical need for establishing a bone density response is greater than ever. Early measurement  of estradiol levels within the first few months of treatment has been proposed to fulfill this need. However, there is a paucity of evidence to support the setting of target levels at present. Further studies are clearly required in this area.(8)

In 2000, Dr. Tomas Andersson studied two trans-dermal estradiol delivery systems (Menorest® or Climara®), finding 25 pg/ml sufficient to relieve menopausal symptoms, 40 pcg/ml was the minimal concentration for preventing bone loss, and 60 pg/ml the upper limit because of tolerability.

Dr. Tomas Andersson writes:

The quantitative effects of estradiol are described by relating plasma levels to three proposed therapeutic or safety concentration limits for transdermal estradiol [17] with 25 pg/ml as the minimum concentration for therapeutic effect on menopausal symptoms, 40 pg/ml as the estimated concentration required for osteoporosis prevention and 60 pg/ml as an upper limit because of tolerability.(7)

The above target of 40 mcg/ml does not apply to our type of HRT program because we use a topical cream applied twice a day. We do not use the Menorest® or Climara®  estradiol skin patches studied by Dr. Andersson. Instead, we use compounded hormone creams applied topically to the skin twice a day. The skin patch stays on while the patient has a blood draw for serum estradiol level. Not so for the topical cream. The patient is instructed to hold AM topical application of cream prior to the blood draw. The estradiol level with the compounded topical hormone cream may be lower than the estradiol patch because of timing since last application. The serum level one hour after application may be considerably higher than the patch, and yet it may be lower than the patch 12 hours later.

When it comes to estradiol dosage for preservation of bone density, less is more. Excess estrogen can be uncomfortable and may lead to undesirable side effects. Serum estradiol target levels are not reliable for a variety of reasons as listed by Dr. Armston above, and it is futile to set target levels. Using our program of topical estradiol, estriol, and progesterone we have found bone density either staying the same or increasing in our post-menopausal patients.

Of course we also use a bone building nutritional supplement program and weight bearing exercise program.

Conventional Medicine Now Accepts Estrogen Replacement as First Line Treatment for Prevention of Post Menopausal Bone Loss.

In 2021, Dr Anna Gosset reviewed menopausal hormone therapy for the management of osteoporosis, saying that estrogen hormone replacement is the first line treatment for prevention of bone loss, writing:

Postmenopausal osteoporosis is for a large part the consequence of both quantitative and qualitative bone alterations induced by estrogen deficiency which occurs within the first years of the menopause transition. Bone is a strong estrogen-dependent tissue and estrogens play a major role in the acquisition and maintenance of bone mineral content throughout life. (17) (22-27)

Conclusion: Estrogen replacement is now first line treatment for prevention of post menopausal bone loss. Since 2002, we no longer set targets for serum estradiol levels, as this is inaccurate and misleading. We use the minimum dosage that relieves menopausal symptoms. Our post-menopausal hormone replacement including low dose topical estrogen, bone building nutrients and exercise is very effective for maintaining bone density.

Articles with Related Interest:

The new Osteoporosis Drugs, The Good, Bad and Ugly

FDA Says Osteoporosis Drugs Cause Bone Fractures

Fosamax, Actonel, Osteoporosis and Toulouse Lautrec

Estrogen for Prevention and Treatment of Osteoarthritis

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
www.jeffreydachmd.com

References:
1) Barnes, Randall B., and Seth G. Levrant. “Pharmacology of Estrogens.” Treatment of the Postmenopausal Woman. Academic Press, 2007. 767-777.

Maximum levels of 300 pg/mL for estrone and 65 pg/mL for estradiol are achieved after 2 mg oral micronized estradiol (75,77).
Vaginal micronized estradiol 0.5 mg in saline results in serum estradiol level of 860 pg/mL for 3 hours, which then drops to 250 pg/mL after 6 hours.
Three milligrams of percutaneous estradiol result in an estradiol level of about 100 pg/mL within 4 to 6 hours and reaches a steady state after 3 to 5 days (54,88). Three milligrams and 1.5 mg of estradiol administered by percutaneous gel daily for 14 days result in mean estradiol serum levels of 103 ± 40 pg/mL and 68 ± 27 pg/mL, respectively, compared with 114 ± 65 pg/mL and 41 ± 14 pg/mL after 2 mg oral micronized estradiol and 50 mg/day transdermal estradiol (77)

2) Çetinkaya, Mehmet B., et al. “Comparison of the effects of transdermal estrogen, oral estrogen, and oral estrogen-progestogen therapy on bone mineral density in postmenopausal women.” J Bone Miner Metab 20 (2002): 44-48.

Weiss et al. [14] have reported that transdermal estrogen 0.025 mg/day effectively prevented bone loss in postmenopausal women.

3) Weiss SR, Ellman H, Dolker M (1999) A randomized controlled
trial of four doses of transdermal estradiol for preventing postmenopausal
bone loss. Transdermal Estradiol Investigator
Group. Obstet Gynecol 94:330–336

Objective: To determine the effects of four doses of a 7-day transdermal 17beta-estradiol (E2) delivery system, including 0.025 mg/day, on bone loss in postmenopausal women.
Methods: This was a multicenter, double-masked, randomized, placebo-controlled study of the effects of transdermal E2 at doses of 0.025, 0.05, 0.06, and 0.1 mg/day for the prevention of postmenopausal osteoporosis. Efficacy was evaluated from bone mineral density of lumbar vertebrae L2-L4, radius, proximal femur, and total hip measured with dual-energy x-ray absorptiometry. Serum osteocalcin and urinary pyridinoline and deoxypyridinoline concentrations were measured.
Results: At 24 months, E2 doses of 0.025, 0.05, 0.06, and 0.1 mg/day resulted in mean increases in bone mineral density of the lumbar spine of 2.37%, 4.09%, 3.28%, and 4.70%, respectively, and increased bone mineral density of the total hip by 0.26%, 2.85%, 3.05%, and 2.03%, respectively. All increases were statistically significantly greater than placebo, which decreased bone mineral density by 2.49% at the spine and 2.04% at the hip. Consistent and significant improvements in biochemical markers of bone turnover also were noted at various intervals in all treatment groups. The most frequent adverse events were local reactions from the transdermal drug-delivery system, effects of estrogen, and menopausal symptoms.
Conclusion: Transdermal E2 at doses of 0.025, 0.05, 0.06, and 0.1 mg/day effectively prevented bone loss in postmenopausal women.

4) Delmas, PD, et al. “A dose-ranging trial of a matrix transdermal 17b-estradiol for the prevention of bone loss in early postmenopausal women.” BONE 24.5 (1999): 517-523.
This international, randomized, double-blind, placebo-controlled, parallel group, dose-ranging trial was designed to determine the efficacy of 2 years of therapy with a new matrix transdermal 17beta-estradiol (Menorest) in preventing bone loss in early postmenopausal women, and to identify an appropriate dose. Two hundred ninety-two ambulatory women with natural or surgical menopause for 1-6 years were randomized to receive patches delivering 17beta-estradiol 50, 75, or 100 microg/day twice weekly for 25 days per 28 day cycle (with dydrogesterone 10 mg twice daily from days 11 to 24) or placebo, for 24 months. The primary outcome measure was the percentage change from baseline in lumbar spine bone mineral density (BMD) at 2 years. Secondary endpoints were percentage changes from baseline in three sites of proximal femur BMD and total body BMD, and in biochemical bone turnover markers. At 2 years, the difference from placebo in percentage change from baseline of L1-4 spine BMD was 6.2%, 7.6%, and 7.8% in the 50, 75, and 100 microg/day groups, respectively. Lumbar spine bone increased in 65.5%, 76.8%, and 81.0% of patients in the respective active treatment groups, compared with 4.9% on placebo. BMD increased significantly relative to placebo in the femoral neck, trochanter, total hip, and total body. Serum osteocalcin, bone alkaline phosphatase and urinary type I collagen C-telopeptide decreased significantly and dose dependently in 17beta-estradiol patients vs. placebo. For example, at 2 years, the difference between placebo and the 50 microg/day group, expressed in percentage change from baseline, was 3.25% at the femoral neck, 3.92% at the trochanter, 3.52% for total hip, and 2.40% for the total body. Breast pain and skin reactions were more common in the actively treated groups, but tolerability was generally good. Therefore, after 2 years, 17beta-estradiol was well-tolerated and highly effective at doses of between 50 and 100 microg/day in preventing bone loss and reducing bone turnover in early postmenopausal women. The dose of 50 microg/day, the lowest dose tested, is a suitable dose. There was little clinical benefit of increasing the dosage from 75 to 100 microg/day.

1992 XXXXXXXXXXXXXXXXXXX

We suggest that oral or percutaneous ERT should induce a minimal value of 60 pg/ml to prevent postmenopausal bone loss.

(article from T.T.)

5) Reginster, Jean Yves, et al. “Minimal levels of serum estradiol prevent postmenopausal bone loss.” Calcified tissue international 51 (1992): 340-343.
Biochemical parameters reflecting bone resorption [urinary calcium/creatinine (Ca/Cr) and hydroxyproline/creatinine (OH/Cr)] were related to serum estrogens [estrone (E1) and estradiol (E2)] in 262 healthy women including 158 patients receiving estrogen replacement therapy (ERT) for at least 6 months, 49 eugonadal women, and 55 untreated postmenopausal women. A significant (P < 0.001) correlation exists between serum E2 and Ca/Cr: Ca/Cr (mg/dl) = -0.00044 E2 (pg/ml) + 0.129 (n = 262; r = -0.37), serum E2 and OH/Cr: (OH/Cr (mg/g) = -0.049 E2 (pg/ml) + 18.76 (n = 262; r = -0.36), serum E1 and Ca/Cr: Ca/Cr (mg/dl) = -0.0003 E1 (pg/ml) + 0.127 (n = 261; r = -0.28) but not between serum E1 and OH/Cr.

Women with circulating levels of E2 between 60 and 90 pg/ml have a significant (P < 0.01) reduction of Ca/Cr and OH/Cr when compared with those with lower levels of E2. Higher values of E2 do not provide additional benefit. We conclude that in postmenopausal women receiving an estrogen replacement therapy (ERT), a significant reduction of bone resorption is achieved when circulating levels of estradiol reach a value (60 pg/ml) corresponding to the one measured, in eugonadal women, during the last days of the early follicular phase of the menstrual cycle. We suggest that oral or percutaneous ERT should induce a minimal value of 60 pg/ml to prevent postmenopausal bone loss.

6) Riis, Bente J., et al. “The effect of percutaneous estradiol and natural progesterone on postmenopausal bone loss.” American Journal of Obstetrics and Gynecology 156.1 (1987): 61-65.

The effect of percutaneous estradiol alone and combined with natural progesterone on postmenopausal bone loss was studied. A total of 57 women who had experienced a natural menopause 6 months to 3 years previously entered the study. After an initial examination the women were allocated in a blinded pattern to treatment with 3 mg of percutaneous estradiol or placebo. The code was broken after 1 year of treatment, and the women receiving estradiol continued with a cyclic addition of progesterone, whereas those receiving placebo continued with placebo. The women were examined every 3 months during the 2 years of treatment. Measurement of the bone mineral content in the forearms (single photon absorptiometry) and the spine and total skeleton (dual photon absorptiometry) showed a significant decrease of 5% to 7% in the placebo group during the 2 years of treatment, whereas it remained constant in all bone compartments in the estradiol group. Addition of progesterone did not influence the results. Biochemical estimates of calcium metabolism changed toward a premenopausal level in the estradiol group but remained unchanged in the placebo group. We conclude that percutaneous estradiol is effective as preventive therapy of postmenopausal bone loss and that addition of progesterone does not influence bone or calcium metabolism.

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KEY ARTICLE
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2000

7) Andersson, Tomas LG, et al. “Drug concentration effect relationship of estradiol from two matrix transdermal delivery systems: Menorest® and Climara®.” Maturitas 35.3 (2000): 245-252.

RISKS

The putatively positive effects of estrogen on cardiovascular and bone mineral status are balanced by an increased risk of cancer in estrogen sensitive tissues such as breasts and endometrium [1]. Another risk with ERT is the recently shown small but significant increase in risk of venous thromboembolism [6], [7], [8].

Decisions concerning duration and intensity of treatment therefore has to be taken for each individual. The plasma levels of estrogen decrease from 40 to 60 pg/ml in early follicular phase pre-menopause to below 20 pg/ml post-menopause see [9]. A clinically effective concentration of estradiol has not been defined, and guidelines for ERT uses recommended daily doses [10] not taking into account inter individual differences in bioavailability of estradiol, whether given orally or transdermally, or that responses to a certain estradiol concentration may vary between individuals.

Attempts have been made to define concentration–effect relationships and required therapeutic plasma levels for estradiol [11], [12], [13], [14], [15]. However, the effect of a certain plasma level of estradiol may vary greatly depending on the route of administration. Transdermal estradiol differs from oral estradiol in several ways [16]. Transdermal systems give steady plasma levels of estradiol, and the metabolite pattern of oral estradiol with increases in estrone and effects on hepatic protein synthesis are avoided. Different still are the effects of conjugated equine estrogens, which contain other pharmacologically active estrogens. All this makes concentration for concentration comparisons difficult.

The quantitative effects of estradiol are described by relating plasma levels to three proposed therapeutic or safety concentration limits for transdermal estradiol [17] with 25 pg/ml as the minimum concentration for therapeutic effect on menopausal symptoms, 40 pg/ml as the estimated concentration required for osteoporosis prevention and 60 pg/ml as an upper limit because of tolerability.

 

ARMSTON

8) Armston, Annie, and Peter Wood. “Hormone replacement therapy (oestradiol-only preparations): can the laboratory recommend a concentration of plasma oestradiol to protect against osteoporosis?.” Annals of clinical biochemistry 39.3 (2002): 184-193.

Oestradiol measurements in plasma from women using patch, gel or implant preparations could be useful provided that consideration is given to the time of sampling and to the assay method used, although target levels have not been established. Further studies are required in this area.

10-fold differences in bioavailability have been reported for both oral and transdermal preparations

Standardized doses of oestradiol have been recommended for HRT, e.g. 0.625 mg/day conjugated equine oestrogens by mouth, 2 mg/day oestradiol by mouth or 0.05 mg/day in a patch.3 However, studies
suggest that between 5 and 20% of women absorb exogenous oestrogens poorly,4 and 10-fold differences in bioavailability have been reported for both oral and transdermal preparations.5 Thus, on standardized doses of oestrogens, some women will not reach
adequate plasma oestradiol levels whilst others may achieve levels which are too high, resulting in side effects.This suggests that oestrogen therapy should be customized as proposed by de Lignieres.6

It has become apparent to the authors whilst attending a variety of clinical meetings that some clinicians use a target concentration of
plasma oestradiol of 200-300 pmol/L =(54-81.7 pg/ml) when treating menopausal women with HRT to prevent osteoporosis. The publication of these target concentrations in at least one textbook1 led us to look at the evidence for such a level. (Rapid reference to HRT. In: Whitehead M, ed. The Prescriber’s Guide to HRT. London: Parthenon Publishing Group, 1998: 3)

oestrogenic component of HRT only. A number of different formulations of HRT are available; these include oral preparations
(either pure oestradiol or equine preparations), transdermal
`patches’, percutaneous gels or subcutaneous implants.

ORAL Estradiol: The large variability in the time of the peak oestradiol
level means that a single untimed sample will give an unreliable estimate of the average exposure over the 24-h period and cannot be recommended.

Equine oestrogens
The equine preparations such as Premarin2, Premique2 and Prempak C2 contain equine oestrogens in addition to oestradiol. For example, Premarin2 contains less than 1% of 17b-oestradiol, its main
components being oestrone sulphate (48%), equilin sulphate (26%), 17a-dihydroequilin sulphate (17%) and 17a-oestradiol sulphate (3%).18

Transdermal patches
Percutaneous and subcutaneous methods of oestradiol
administration avoid high hepatic vein concentrations
and the subsequent conversion to oestrone.

Percutaneous gel
Application of a hydro-alcoholic gel of oestradiol to the
human skin results in rapid penetration of the stratum
corneum.

Divigel2 (Orion Pharmaceutica,Espoo, Finland) containing 0.1% oestradiol delivering 1mg/day. serum estradiol level DAY 16

0.5 mg/day 143 pmols/L = 39 pg/ml
1.0 mg/day  247 pmols/L= 67.3 pg/ml
1.5 mg/day 582 pmols/L = 158 pg/ml

in these two studies the time of sampling, in relation to gel application, is important in interpreting oestradiol levels.

Oestradiol implants
When implants are used, plasma levels of oestradiol
reach a peak approximately 2 weeks after insertion of
a 25 mg implant and then gradually decline

The study of Ettinger and co-workers31 included 64 women who were
assigned to one of four groups (placebo, 0.5mg, 1.0 mg or 2.0 mg micronized oral oestradiol).

A continuous skeletal dose-response effect was observed in the range 0.5-2.0 mg oestradiol

Several studies have looked at the effect of oral, transdermal or
subcutaneous oestradiol preparations on bone density and have also included oestradiol measurements, but in no study has the time of sampling in relation to oestradiol administration been considered

The study published by de Lignieres6 looked at 179
postmenopausal women using oestradiol gel.The study
was conducted over an 18-month period

De Lignieres demonstrated that only 5.5% of women
having mean plasma levels greater than 220 pmol/L (60 pg/ml)
were losing more than1% spinal bone mass per year and
only 3.5% were losing more than 2%. Twenty-eight per
cent of women having mean plasma levels of less than
220 pmol/L (60 pg/ml) were losing more than1% spinal bone mass
and 42.9% more than 2%.6 Similar conclusions were
reached when the patch was studied by Devogelaer et
al.,36

The study of Field and co-workers,34 using oestradiol patches (see Table 5), suggested a similar cut-off for plasma oestradiol based on bone density measurements. The lowest dosage of patch (0.025mg/day)
produced a mean oestradiol level of 140 pmol/L= (38 pg/ml) and
was associated with substantial bone loss. With a mid dosage
patch (0.05 mg/day) the mean oestradiol level observed was 227 pmol/L =(61 pg/ml) and bone loss was prevented at this dose. Optimal results were achieved with the patch delivering 0.1mg oestradiol /day. Accretion of bone was observed at this highest dose when mean oestradiol levels of 400 pmol/L (108 pg/ml) were observed.

Methodology Varies

In the studies in which oestradiol levels were reported for women using either a gel or patch preparation, the preservation of bone density was
achieved at a different level of oestradiol. For example, the mean oestradiol levels in the studies of Palacios et al.32 and Devogelaer et al.36 were 145 pmol/L (39 pg/ml) and 316 pmol/L (86 pg/ml), respectively; method bias in oestradiol measurements is a signi¢cant factor.

Evans and Davie39

A number of studies have now reported results suggesting that lower doses of oestrogens may be effective in preventing osteoporosis, although a consensus has not emerged. The study of Evans and
Davie39 suggested that a transdermal patch delivering 0.025mg/day oestradiol was as effective as a 0.05-mg/day oestradiol patch at preserving bone mineral density (BMD) at both lumbar spine and femoral neck. A similar number of non-responders were identified in each dose group (3.9% at the lumbar spine and 10.4% at the femoral neck).

A study by Weiss and co-workers40 using transdermal
oestradiol patches at 0.025, 0.05, 0.06 and 0.1mg/day also concluded that all doses of HRT effectively prevented bone loss. However, the data clearly show that there were patients who continued to lose
BMD at the lumbar spine and hip. The number of such patients was greatest in the 0.025 mg/day treatment group [e.g. at the hip, 5/14 (35.7%) in the 0.025mg/ day group versus 4/18 (22%), 3/20 (15%) and 5/21 (23.8%) in the 0.05, 0.06 and 0.1mg/day groups, respectively].

Studd and co-workers44 were the first to look at the relationship between plasma oestradiol and bone density in women, using 6-monthly implants of 75mg oestradiol and 0.1mg testosterone…  Of the 23 patients studied, 22 showed an increase in bone density after 1year of therapy. All patients had a pre-implantation serum oestradiol concentration greater than 200 pmol/L (54 pg/ml) at 1year and a correlation between oestradiol level and bone accretion was observed. There was no correlation between plasma testosterone level and the increase in bone density.

In a later study, by the same group, the oestradiol levels using three different doses of implant, 25,50 and 75mg, were reported.45 This study also found a significant relation between plasma oestradiol levels
and increases in bone density at the lumbar spine and proximal femur. They concluded that none of the women lost bone density at the clinically important sites of spine and femoral neck if their oestradiol levels
were above 300 pmol/L. (81 pg/ml) Oestradiol was reported to be measured by RIA.

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Evidence in the literature for using a particular cut-off value for plasma oestradiol, which is sufficient to prevent osteoporosis, is compromised by:

. Lack of documentation of the oestradiol method used.
. Differences in bias between laboratory oestradiol assays.
. Lack of reference to the timing of sampling in relation to patch change or gel application.
. The small number of women included in many studies (seeTables 2-5).
. In the case of patch studies, a failure to specify the type of patch studied.
. For gel preparations, lack of standardization of gel application area.

Despite these limitations, the trend to use HRT preparations which deliver lower doses of oestradiol means that the clinical need for establishing a bone density response is greater than ever. Early measurement
of oestradiol levels within the first few months of treatment has been proposed to fulfill this need. However, there is a paucity of evidence to support the setting of target levels at present. Further studies are clearly required in this area.

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9) Middle, Jonathan G., and John W. Kane. “Oestradiol assays: fitness for purpose?.” Annals of Clinical Biochemistry 46.6 (2009): 441-456.

Oral HRT The most commonly used oral oestrogen preparations are mixtures of water-soluble, oestrogen conjugates, which are converted to a variety of compounds with differing biological activity.4 Circulating oestrogen conjugates can cross-react in the direct serum oestradiol assays that most laboratories now use. Therefore, the measured
value may not reflect bioactive oestrogen or correlate with treatment efficacy.

Micronized pure oestradiol is also used orally but there is little published data on the metabolism of these preparations and whether measurement of serum oestradiol concentrations is useful.

Percutaneous oestrogen patches Serum oestradiol concentrations peak approximately 2–8 h post-application  and are said to plateau before beginning to fall after 72 h. They return to baseline values within 24 h after removal of the patch. The best time to sample is just before applying
a new patch (trough level), the purpose being to confirm the adequacy of oestradiol replacement.25

Oestradiol gels and nasal spray The value of monitoring oestradiol concentrations in these patients is still unclear.

Interpretation of serum oestradiol concentrations
To relieve menopausal symptoms, adequate oestrogen replacement is that which achieves the therapeutic goal! On present knowledge, maintenance of serum oestradiol between 200–300 pmol/L (54.5-82 pg/ml)  is believed to be adequate to protect against osteoporosis. Equally, there is concern to avoid prolonged exposure to excessively high oestrogen. implants should not be repeated if serum oestradiol concentrations are >400 pmol/L. If the concentrations are between 250
and 400 pmol/L, the decision to re-implant must be based on clinical grounds in the individual case.26 The data we have presented show that there are large differences in bias between the various methods that could potentially lead to mistreatment of patients if not taken into account
when setting target concentrations.25

Summary of clinical requirements,state-of-the-art and action points
Table 3 summarizes our conclusions for oestradiol. In many cases, the answer to the question ‘Are oestradiol assays fit for purpose?’ is ‘No’, yet we have the apparent paradox that very many laboratories offer this test and many thousands of tests are regularly requested of them annually. All stakeholders should address this issue and consider our recommendations.

At present, the commercially available direct E₂ immunoassays are capable of measuring serum E₂ reliably only in healthy eugonadal premenopausal women. In all other clinical settings, the direct E₂ immunoassays are likely to provide spurious results and misguide management. While MS methods would provide technically superior performance in terms of sensitivity and specificity, there remains a need to standardise MS methods as for all other clinically applicable analytes.

11) Evans, S. F., and M. W. J. Davie. “Low and conventional dose transdermal oestradiol are equally effective at preventing bone loss in spine and femur at all post‐menopausal ages.” Clinical Endocrinology 44.1 (1996): 79-84.
Objectives: We wished to appraise the effectiveness of hormone replacement therapy (HRT) in early (< 67 years) and late (> 67 years) post-menopausal women referred to a metabolic outpatient clinic for assessment of their bone status. Because older women often experience side-effects with conventional HRT, a low dose preparation (Estraderm 25) was also compared with conventional HRT (Estraderm 50).

Design and setting: Since all patients were symptomatic, the investigation was open and not placebo controlled. Patients were offered HRT and told about the two dosages. If they wished to use HRT, allocation of dosage was made randomly unless there were reasons to use a specific dose.

Patients: One hundred and ninety-six women were studied over 1 or 2 years with 80 reaching 3 years of treatment. Patients were divided into those under 67 years and those over 67 years at the start of treatment. Each group was further divided into those taking Estraderm 25 and those taking Estraderm 50 with norethisterone if appropriate.

Measurements: Bone mineral density (BMD) was measured (DXA, Hologic) at the lumbar spine and femoral neck at 0 year (196 patients), at 1 year (169 patients), at 2 years (139 patients) and at 3 years (80 patients). Patients losing bone were expressed as those whose 3 year BMD was lower than initial or as those whose BMD at 3 years had fallen by more than twice the coefficient of variation for that site (non-responders).

Results: In lumbar spine, BMD increased maximally in the first year in all groups and the gain was maintained after 3 years. The change was similar whether patients were divided by age or dosage. For those on Estraderm 25, mean change after 3 years was 8.1 +/- 6.8% and on Estraderm 50, 9.0 +/- 8.3% (combined 8.7 +/- 7.8%). Only 3.9% of patients were non-responders at the lumbar spine after 3 years. At femoral neck, changes were significant at 3 years only in the Estraderm 25 > 67 years and Estraderm 50 < 67 years groups and averaged 2.3 +/- 5.4% for all patients. At the femoral neck, 10.4% of patients were non-responders after 3 years. Percentage change of BMD over 3 years at lumbar spine correlated with that at the femoral neck (r = 0.56). Percentage change of BMD at lumbar spine over 3 years correlated with menopausal age (r = 0.295). No relation was found between dosage of Estraderm/kg body weight and response of BMD at either site.

Conclusions: Transdermal oestrogen is effective at preventing bone loss in the spine at all post-menopausal ages and is capable of doing this in low dosage. Prevention of bone loss at the femoral neck is less certain and the average change in BMD over 3 years was significantly lower (P < 0.001) than in the lumbar spine. Use of Estraderm 50 is not associated with a greater response of bone mass and there was no evidence of an increasing BMD response as oestradiol dosage/kg body weight increased.

12) Ettinger, Bruce, et al. “Effects of Ultralow-Dose Transdermal Estradiol on Bone Mineral Density: A Randomized Clinical Trial.” Presented at the 25th annual meeting of the American Society for Bone and Mineral. Vol. 4. 2004.

Objective: Because small increments in levels of endogenous plasma estradiol are associated with higher postmenopausal bone mineral density, we investigated the safety and effectiveness in preventing bone loss of unopposed, very-low-dose transdermal estradiol for postmenopausal women.
Methods: This was a randomized, placebo-controlled, double-blind trial with 2-year follow-up at 9 United States clinical centers. The study population comprised 417 postmenopausal women, aged 60-80 years, with intact uterus and bone mineral density z scores of -2.0 or higher, who were randomly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d (n = 208) or placebo (n = 209). All participants received calcium and vitamin D supplementation. Lumbar spine and total hip bone mineral density change was measured by dual-energy X-ray absorptiometry; endometrial hyperplasia incidence was assessed by endometrial biopsy.
Results: Median plasma estradiol level in the estradiol group increased from 4.8 pg/mL at baseline to 8.5 pg/mL at 1 year (P <.001 versus baseline) and to 8.6 pg/mL at 2 years (P <.001 versus baseline) and was unchanged in the placebo group. Lumbar spine bone mineral density increased 2.6% in the estradiol group and 0.6% in the placebo group (between-group difference 2.0%, P <.001). Mean total hip bone mineral density increased 0.4% in the estradiol group and decreased 0.8% in the placebo group (between-group difference 1.2%, P <.001). Osteocalcin levels and bone-specific alkaline phosphatase were lower in the estradiol group than the placebo group (P <.001 each). Endometrial hyperplasia developed in 1 woman in the estradiol group but in none of the placebo group (difference in 2-year rates 0.5%, 95% confidence interval 0-7.3%).

Conclusion: Postmenopausal treatment with low-dose, unopposed estradiol increased bone mineral density and decreased markers of bone turnover without causing endometrial hyperplasia.

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!!!!!!!!!!!!!!!!!!           Blood levels at lowest dose      !!!!!!!!!!!!!!!!!

---

13) Bertonazzi, Abigail, et al. “The smallest available estradiol transdermal patch: a new treatment option for the prevention of postmenopausal osteoporosis.” Women’s Health 11.6 (2015): 815-824.

Minivelle therapy for the prevention of osteoporosis should be started with 0.025 mg per day, applied to the skin twice weekly; the dose can be adjusted as necessary [22].
The estradiol peak concentration (Cmax) for
Minivelle 0.1, 0.05 and 0.025 mg/day
was 117, 56.6 and 30.3 pg/ml, respectively.
The 0.025 mg/day Minivelle dose approved for osteoporosis prevention, currently the lowest dose available, aligns with current guideline recommendations for the lowest effective dose at the shortest possible duration  !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

————————————————

2006

14) Richman, Susan, et al. “PERSONAL PERSPECTIVE Low-dose estrogen therapy for prevention of osteoporosis: working our way back to monotherapy.” Menopause: The Journal of The North American Menopause Society 13.1 (2006): 148-155

The benefits of estrogen in prevention of bone loss are
indisputable

Bar chart from Ettinger included Here

FIG. 4. Change in mean lumbar spine BMD with ultra-low-dose transdermal estradiol (0.014 mg/ d) versus placebo. Adapted from Ettinger et al.70

However, a recent study found that as many as 40% of MHT (Menopausal Hormone Therapy) users discontinued treatment because of reported adverse effects with standard doses of combined estrogen/progestogen in the WHI trial.

After the release of the WHI findings, the American College of Obstetricians and Gynecologists (ACOG) advised that women who desire HT should take the lowest effective dose for the shortest possible time

In a case-control analysis, women with undetectable serum estradiol levels (,5 pg/mL) were approximately 2.5 times more likely to experience hip or vertebral fractures than were women with detectable
levels (5 to 25 pg/mL).2

Sharp et al47 found that indicators of bone turnover decreased
markedly, and to a similar degree, after 1 year of treatment with transdermal estradiol, whether administered at half strength (0.025 mg/d) or the conventional dose (0.050 mg/d).

Prestwood et al 46 found that very low-dose oral estradiol (0.25 mg/d)
reduced bone turnover (as reflected in a variety of biochemical markers) by a degree comparable to that observed at a dose of 1.0 mg/d, but with a side-effect profile similar to that of placebo.

Postmenopausalwomen have a significantly elevated risk of osteoporosis, which increases the risk of serious fracture-associated morbidity and mortality.1-3 The benefits of estrogen in prevention of bone loss are
indisputable, and recent concerns regarding such therapy must be placed in perspective

Lower-than-standard doses of estrogen monotherapy can prevent bone loss without increasing risk of endometrial lesions and possibly venous thromboembolism. Ultra-low-dose unopposed estrogen (monotherapy) has been demonstrated to increase BMD and reduce markers of bone turnover without causing endometrial hyperplasia in a group of elderly women with unusually low circulating estradiol.
Additional studies are needed to confirm these observations and to expand our understanding of the potential effects of low-dose estrogen monotherapy on bone loss and other estrogen-sensitive symptoms.

====================== ================== ===

2018 Levin  Ultra Low DOSE – Serum Estradiol Levels are never mentioned in this article !!!!!

15) Levin, V. A., X. Jiang, and R. Kagan. “Estrogen therapy for osteoporosis in the modern era.” Osteoporosis International 29 (2018): 1049-1055.

HT should be individualized and the once “lowest dose for shortest period of time” concept should no longer be used.

studies support that HT improves BMD and reduces fracture risk in women with and without osteoporosis. Furthermore, the studies suggest that low-dose and transdermal HT are less likely associated with the adverse effects of breast cancer, endometrial hyperplasia, coronary artery disease (CAD), and venous thromboembolism (VTE) previously observed in standard-dose oral HT regimens. Given the need for estrogen in menopausal women and evidence supporting the cost effectiveness, safety, and efficacy of HT, we propose that HT should be considered for the primary prevention and treatment of osteoporosis in appropriate candidates. HT should be individualized and the once “lowest dose for shortest period of time” concept should no longer be used. …

HT in the form of either combined estrogen and progesterone or estrogen alone has been shown to be effective in reducing the number of both vertebral and non-vertebral fractures in postmenopausal women [4], with
efficacy equivalent to that of bisphosphonates…

Randomized controlled trials and observational studies show
that standard-dose HT, which was proposed by the manufacturer
and approved by registration authorities to suit the average
patient needs, reduces postmenopausal osteoporotic fractures
of the hip, spine, and all non-spine fractures in women
with and without osteoporosis [5, 6, 13].

Ultra-low dose of transdermal estradiol (14 μg per day) monotherapy for 2 years has shown a significant increase in BMD and prevention of bone loss without increased risk of endometrial hyperplasia and vaginal bleeding compared to placebo [62];

Comparing Oral to Transdermal Estrogen

Compared with oral estrogen therapy (ET), transdermal ET
is associated with greater reduction in sympathetic tone, little
to no increases in C-reactive protein, and an overall reduced
risk for atherosclerotic vascular disease [12, 25]. These differences
can be explained by physiology as transdermal estrogen
avoids first-pass metabolism in the liver, which permits the
administration of lower doses of unmetabolized estradiol directly
to the blood stream, avoiding overproduction of triglycerides.
Multiple studies showed statistically significant reduction
in serum triglyceride levels with the transdermal route
compared to increased triglyceride levels with oral therapy
[20, 26–29]. Decreased triglycerides result in decreased cardiovascular
events in postmenopausal women. Additionally,
because oral estrogens affect hepatic lipid metabolism and
may lead to supersaturation of bile acids by cholesterol and
gallstone formation, postmenopausal women taking oral ET
may have increased risk of gallbladder disease, cholecystectomy,
and biliary tract surgery [9]. As stated above, transdermal
ET may avoid this increased risk due to absence of firstpass
metabolism [9]. Furthermore, previous studies have demonstrated

Ettinger et al. showed that even a lower dose of transdermal
estradiol at 0.014 mg/day, which is adequate for hot
flash relief in some women, has beneficial skeletal benefits
[42].

Ultra-low dose of transdermal estradiol (14 μg per day)
monotherapy for 2 years has shown a significant increase in
BMD and prevention of bone loss without increased risk of
endometrial hyperplasia and vaginal bleeding compared to
placebo [62]; however, the prescription of low-dose estrogens
in monotherapy in women with an intact uterus is not currently
recommended and requires adequate surveillance in highly
selected patients. Perhaps ultra-low-dose transdermal estradiol
(Table 1) can be given to women aged 60 and older for the
modest increases in estrogenic action to preserve skeletal integrity
without significant breast effects and endometrial stimulation
due to the lower progestogen dose required for endometrial
protection [3]. Additionally, the use of transdermal
preparations has been shown to less likely increase the risk
of VTE, stroke, and CAD than oral preparations. Thus, these
low-dose non-oral HT options may be considered for women
with cardiovascular risk factors (e.g., diabetes, hypertension,
and obesity), women of advancing age, and for those who
choose extended duration use of HT for bone protection.

2020

16) Rozenberg, Serge, et al. “Is there a role for menopausal hormone therapy in the management of postmenopausal osteoporosis?.” Osteoporosis International 31 (2020): 2271-2286.

NO Mention of target serum estradiol levels.

17) Gosset, Anna, Jean-Michel Pouillès, and Florence Trémollieres. “Menopausal hormone therapy for the management of osteoporosis.” Best Practice & Research Clinical Endocrinology & Metabolism 35.6 (2021): 101551.

NO Mention of target serum estradiol levels.

Postmenopausal osteoporosis is for a large part the consequence of both quantitative and qualitative bone alterations induced by estrogen deficiency which occurs within the first years of the menopause transition. Bone is a strong estrogen-dependent tissue and estrogens play a major role in the acquisition and maintenance of bone mineral content throughout life.

In 1947, Fuller Albright established the principles that exogenous estrogen given to postmenopausal women was efficient to maintain bone mass and thus reduce fracture risk [25]. Since then, menopausal hormone therapy (MHT) has long been used to prevent the risk of osteoporosis and related fractures in postmenopausal women. Accordingly, in the mid-1990s and early 2000s, it was widely prescribed in most European and North American countries for this specific purpose. The publication in 2002 of the Women’s Health Initiative (WHI) [26], which was the first large scale randomized controlled trial which aimed to evaluate the impact of the association of conjugated equine estrogens (CEE) with medroxyprogesterone acetate (MPA) on a large variety of postmenopausal health outcomes has completely changed the vision of the benefit-risk balance of MHT. While this hormone therapy regimen decreased the risk of fractures, it was associated with increased risks of cardiovascular and cerebrovascular events, as well as with an increased risk of breast cancer. This led to a dramatic drop in MHT prescriptions worldwide thus raising the question as to whether it should continue to be used for fracture prevention.

Estrogens are strong inhibitors of the increased osteoclastic recruitment and activity which occur at the beginning of menopause. The result is a rapid decrease in bone resorption within 3–6 months after the beginning of treatment, followed by a further decrease in bone formation due to the coupling between these two cellular activities. A new steady state in bone turnover is achieved approximately around 6–12 months after initiation of therapy which lasts as estrogen treatment is maintained. This effect can be illustrated by changes in biochemical markers of bone resorption (C- and N- telopeptides of type 1 collagen) with a rapid decrease and then a plateau effect beyond the 6th month of treatment. As a result, bone mineral density (BMD) usually increases during the first year of treatment, with a smaller additional gain in the second year and stabilization thereafter as long as MHT is maintained (Table 1). This effect is mainly observed at the lumbar spine, which is a bone site rich in trabecular bone, more metabolically active than cortical bone (femoral neck). Similarly, all parameters of bone microarchitecture are preserved [13,29].

There is a dose dependent effect of estrogens on bone turnover and BMD changes. Accordingly, the percentage of non-responders is higher with low dose estrogen therapy compared to “standard” daily doses (i.e. 0.625 mg of CEE, 2 mg of 17β-estradiol (E2) [oral] or 50 μg of transdermal E2). However, most studies have reported that a large majority of women who initiate low dose estrogen therapy will benefit protection against early postmenopausal bone loss [[30], [31], [32], [33], [34], [35]]. This is especially reassuring because the current trend is to use lower estrogen doses than those recommended several years ago as they have since been shown to provide effective vasomotor symptom relief and prevent vaginal atrophy with a better bleeding profile than with higher estrogen dosages.

The only caveat is the lack of certainty regarding the anti-fracture efficacy of low-dose estrogens, as definitive fracture outcome data are scarce [44]

The risk of breast cancer remains the other concern and very often the main limitation to the use and acceptance of MHT by women. Almost all cohort studies as well as the WHI have shown an increased risk of breast cancer associated with the use of MHT [60,61,26]. There are consistent data which indicate that the risk of breast cancer is greater with combination of estrogen + progestogen than with estrogen alone [62,63]. Moreover, the risk appears to depend on the type of progestogen used. In the large cohort study E3N, there was no increase in the risk of breast cancer in women who were given a combination of E2 plus natural progesterone or dydrogesterone for an average 5-year period of treatment whereas a significant increase was found when a synthetic progestogen was combined to E2 [64,65]. Three other European cohort studies also reported a significantly lower risk of breast cancer when E2 was combined with progesterone or dydrogesterone than with other synthetic progestogens [[66], [67], [68]].

2021

18) Rosen, Harold N., Marc K. Drezner, and William F. Crowley Jr. “Menopausal hormone therapy in the prevention and treatment of osteoporosis.” UpToDate. Retrieved March 2 (2021).

Women who seek MHT for menopausal symptoms in their late 40s or early 50s will have the additional benefit of a reduced risk of bone loss and fracture [3,4]. In such women, a separate first-line drug for prevention or treatment of osteoporosis is usually not required with estrogen (estradiol) doses equivalent to or higher than 25 mcg/day of transdermal or 0.5 mg/day oral.

Lower doses of transdermal estradiol (14 mcg) have also been shown to have skeletal benefits. With this ultra-low dose of transdermal estrogen, bone density should be monitored in women at high risk for osteoporosis and fracture as another agent (eg, a bisphosphonate) may be needed.

=========================

2000

Female Sprague-Dawley rats were subjected to bilateral ovariectomy (OVX) or sham surgery (control). Groups of ovariectomized (OVX) and control rats were injected daily with low, medium, or high doses of 17 beta-estradiol (10, 25, or 50 micrograms/kg BW, respectively). An additional group of OVX and control rats was injected daily with vehicle alone. All rats were killed 35 days after OVX, and their proximal tibiae were processed undecalcified for quantitative bone histomorphometry. Trabecular bone volume was markedly reduced in vehicle-treated OVX rats relative to that in control rats (12.1% vs. 26.7%). This bone loss was associated with a 2-fold increase in osteoclast surface and a 4-fold increase in osteoblast surface. The bone formation rate, studied with fluorochrome labeling, was also significantly elevated in vehicle-treated OVX rats (0.111 vs. 0.026 micron3/micron2.day). In contrast, treatment of OVX rats with the three doses of estradiol resulted in normalization of tibial trabecular bone volume and a decline in histomorphometric indices of bone resorption and formation. Our results indicate that estrogen treatment provides complete protection against osteopenia in OVX rats. The protective mechanism involves estrogenic suppression of bone turnover. These findings are consistent with the skeletal effects of estrogen therapy in postmenopausal women.

———————————— —

22) Tella, Sri Harsha, and J. Christopher Gallagher. “Prevention and Treatment of Post-Menopausal Osteoporosis.” The Journal of Steroid Biochemistry and Molecular Biology 142 (2014): 155-170.

23) Nilas, L., and C. Christiansen. “The Pathophysiology of Peri‐ and Post-Menopausal Bone Loss.” BJOG: An International Journal of Obstetrics & Gynaecology 96.5 (1989): 580-587.

24) Capozzi, Anna, et al. “Calcium, Vitamin D, Vitamin K2, and Magnesium Supplementation and Skeletal Health.” Maturitas 140 (2020): 55-63.

25) Gosset, Anna, et al. “Menopausal Hormone Therapy for the Management of Osteoporosis.” Best Practice & Research. Clinical Endocrinology & Metabolism 35.6 (2021): 101551.

26) Stuenkel, Cynthia A. “Menopausal Hormone Therapy and the Role of Estrogen.” Clinical Obstetrics and Gynecology 64.4 (2021): 757-771.

27) Rozenberg, Serge, et al. “Is There a Role for Menopausal Hormone Therapy in the Management of Postmenopausal Osteoporosis?” Osteoporosis International 31 (2020): 2271-2286.

28) Yang, JinXiao, et al. “Association between serum total testosterone level and bone mineral density in middle-aged postmenopausal women.” International Journal of Endocrinology 2022 (2022).

van Geel, Tineke ACM, et al. “Measures of bioavailable serum testosterone and estradiol and their relationships with muscle mass, muscle strength and bone mineral density in postmenopausal women: a cross-sectional study.” European Journal of Endocrinology 160.4 (2009): 681-687

Tok, Ekrem C., et al. “The effect of circulating androgens on bone mineral density in postmenopausal women.” Maturitas 48.3 (2004): 235-242.

Jassal, Simerjot K., Elizabeth Barrett‐Connor, and Sharon L. Edelstein. “Low bioavailable testosterone levels predict future height loss in postmenopausal women.” Journal of Bone and Mineral Research 10.4 (1995): 650-654.

Rariy, Chevon M., et al. “Higher serum free testosterone concentration in older women is associated with greater bone mineral density, lean body mass, and total fat mass: the cardiovascular health study.” The Journal of Clinical Endocrinology & Metabolism 96.4 (2011): 989-996.

Zhang, Han, et al. “Association between testosterone levels and bone mineral density in females aged 40–60 years from NHANES 2011–2016.” Scientific Reports 12.1 (2022): 16426.

Arpaci, Dilek, et al. “Serum testosterone does not affect bone mineral density in postmenopausal women.” Archives of Endocrinology and Metabolism 59 (2015): 292-296.

Haider, Ahmad, et al. “Progressive improvement of T-scores in men with osteoporosis and subnormal serum testosterone levels upon treatment with testosterone over six years.” International journal of endocrinology 2014 (2014).

Wang, Nan, Lixiang Wang, and Chengcheng Huang. “Association of total testosterone status with bone mineral density in adults aged 40–60 years.” Journal of Orthopaedic Surgery and Research 16 (2021): 1-7.

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Above image from: Cosman, Felicia, et al. “Clinician’s guide to prevention and treatment of osteoporosis.” Osteoporosis international 25 (2014): 2359-2381.

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above image: https://commons.wikimedia.org/wiki/File:Bone_Comparison_of_Healthy_and_Osteoporotic_Vertibrae.png

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