Endogenous Estrogen Levels and the Effects of Ultra-Low-Dose
Transdermal Estradiol Therapy on Bone Turnover and BMD in
Alison J Huang,1,2Bruce Ettinger,3Eric Vittinghoff,2Kristine E Ensrud,4Karen C Johnson,5and Steven R Cummings2,6
ABSTRACT: In a randomized controlled trial of a 0.014 mg/d transdermal estradiol patch, serum bone
turnover markers decreased to a greater degree in postmenopausal women with lower versus higher endog-
enous estradiol levels. This suggests that the protective effects of ultra-low-dose estrogen therapy on the
postmenopausal skeletal health may depend critically on women’s endogenous estrogen levels before treat-
Introduction: Postmenopausal women with very low or undetectable estradiol levels have lower BMD, in-
creased bone turnover, and increased risk of hip and vertebral fracture. We assessed whether the effects of
ultra-low-dose 0.014 mg/d transdermal estradiol (Menostar; Berlex, Montvale, NJ, USA) on bone turnover
and BMD are influenced by endogenous estradiol levels.
Materials and Methods: We analyzed data from postmenopausal women (mean age, 66 yr) randomized to an
0.014-mg/d transdermal estradiol patch or placebo in the ultra-low-dose transdermal estrogen (ULTRA) trial.
The free estradiol index (FEI), calculated as the ratio of total estradiol (by mass spectometry) to sex hormone–
binding globulin (SHBG; by immunoradiometric assay) × 100, was used to estimate bioavailable estradiol at
baseline. Among the 382 women who adhered to ?80% of study medication, we examined change in serum
osteocalcin and bone-specific alkaline phosphatase levels at 12 mo and total hip and lumbar spine BMD at 24
mo in each quintile of FEI.
Results: Compared with women in the highest quintile of FEI, those in the lowest quintile of FEI had a 26%
greater reduction in bone-specific alkaline phosphatase and 15% greater reduction in osteocalcin in response
to ultra-low estradiol treatment (p for trend across quintiles < 0.05). There was a trend toward greater
improvement in total hip BMD (p ? 0.06) but not spine BMD (p ? 0.90) in those with lower versus higher
Conclusions: The beneficial effects of ultra-low-dose 0.014-mg/d transdermal estrogen therapy on skeletal
health may depend critically on women’s endogenous estrogen levels before treatment.
J Bone Miner Res 2007;22:1791–1797. Published online on July 9, 2007; doi: 10.1359/JBMR.070707
Key words: endogenous estradiol, estrone, bone turnover, BMD, osteoporosis
to a 2.0–2.5% annual rate of spinal bone loss in the first 5 yr
after menopause, followed by a slower rate of bone loss in
the later postmenopausal years.(1–3)Whereas all women
experience a dramatic decrease in serum estrogen during
STROGEN DEFICIENCY IS a major determinant of bone
loss in older women, with prospective studies pointing
menopause, there remains considerable variation in endog-
enous estrogen levels in older women. Studies using sensi-
tive assays to measure very low levels of endogenous estra-
diol have shown that variations in the range of 0–30 pg/ml
are associated with clinically significant differences in
BMD,(4–12)bone turnover,(5,13–16)bone loss,(5,6,10,17,18)and
fracture risk.(19–22)As a result, there has been growing in-
terest in using very low doses of estrogen to preserve bone
mass, decrease bone turnover, and prevent fractures, while
minimizing the risk of adverse events.
The ultra-low-dose transdermal estradiol assessment
(ULTRA) trial recently showed that systemic administra-
tion of approximately one quarter the usual daily dose of
estrogen protects against bone loss despite producing only
Grant support for the Ultra-Low-Dose Transdermal Estrogen
Assessment (ULTRA) trial was provided by Berlex Laboratories,
Inc., for research purposes only. Berlex also donated the transder-
mal estradiol patches used in this study. (Menostar). Dr Cummings
holds the patent for Menostar. All other authors state that they
have no conflicts of interest.
1Veterans Affairs Medical Center, San Francisco, California, USA;2University of California, San Francisco, California, USA;3Kaiser
Permanente Division of Research, Oakland, California, USA;4Veterans Affairs Medical Center and University of Minnesota, Minne-
apolis, Minnesota, USA;5University of Tennessee Health Science Center, Memphis, Tennessee, USA;6San Francisco Coordinating
Center, California Pacific Medical Center Research Institute, San Francisco, California, USA.
JOURNAL OF BONE AND MINERAL RESEARCH
Volume 22, Number 11, 2007
Published online on July 9, 2007; doi: 10.1359/JBMR.070707
© 2007 American Society for Bone and Mineral Research
24. Hui SL, Perkins AJ, Zhou L, Longcope C, Econs MJ, Peacock
M, McClintock C, Johnston CC Jr 2002 Bone loss at the femo-
ral neck in premenopausal white women: Effects of weight
change and sex-hormone levels. J Clin Endocrinol Metab
25. Garnero P, Hausherr E, Chapuy MC, Marcelli C, Grandjean
H, Muller C, Cormier C, Breart G, Meunier PJ, Delmas PD
1996 Markers of bone resorption predict hip fracture in elderly
women: The EPIDOS Prospective Study. J Bone Miner Res
26. Akesson K, Ljunghall S, Jonsson B, Sernbo I, Johnell O, Gard-
sell P, Obrant KJ 1995 Assessment of biochemical markers of
bone metabolism in relation to the occurrence of fracture: A
retrospective and prospective population-based study of
women. J Bone Miner Res 10:1823–1829.
27. Wasnich RD, Miller PD 2000 Antifracture efficacy of antire-
sorptive agents are related to changes in bone density. J Clin
Endocrinol Metab 85:231–236.
28. Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K,
LaCroix AZ, Black DM 2002 Improvement in spine bone den-
sity and reduction in risk of vertebral fractures during treat-
ment with antiresorptive drugs. Am J Med 112:281–289.
29. Bjarnason NH, Sarkar S, Duong T, Mitlak B, Delmas PD,
Christiansen C 2001 Six and twelve month changes in bone
turnover are related to reduction in vertebral fracture risk dur-
ing 3 years of raloxifene treatment in postmenopausal osteo-
porosis. Osteoporos Int 12:922–930.
30. Bauer DC, Black DM, Garnero P, Hochberg M, Ott S, Orloff
J, Thompson DE, Ewing SK, Delmas PD 2004 Change in bone
turnover and hip, non-spine, and vertebral fracture in alendro-
nate-treated women: The fracture intervention trial. J Bone
Miner Res 19:1250–1258.
31. Cummings SR, Duong T, Kenyon E, Cauley JA, Whitehead M,
Krueger KA 2002 Serum estradiol level and risk of breast can-
cer during treatment with raloxifene. JAMA 287:216–220.
32. Garnero P, Tsouderos Y, Marton I, Pelissier C, Varin C, Del-
mas PD 1999 Effects of intranasal 17beta-estradiol on bone
turnover and serum insulin-like growth factor I in postmeno-
pausal women. J Clin Endocrinol Metab 84:2390–2397.
33. Heaney RP, Draper MW 1997 Raloxifene and estrogen: Com-
parative bone-remodeling kinetics. J Clin Endocrinol Metab
Address reprint requests to:
Alison J Huang, MD, MPhil
1635 Divisadero Street, Suite 600
San Francisco, CA 94115, USA
Received in original form March 17, 2007; revised form June 14,
2007; accepted July 5, 2007.
ENDOGENOUS ESTROGEN AND TREATMENT EFFECTS 1797