Nancy A. Melville

October 17, 2012

MINNEAPOLIS, Minnesota — The initiation of estrogen replacement therapy soon after the onset of menopause is effective in preventing cortical bone loss but does not affect trabecular bone volume fraction or thickness, researchers reported here at the American Society for Bone and Mineral Research 2012 Annual Meeting.

Decreases in cortical bone mass have been linked to postmenopausal declines in estrogen, whereas trabecular bone loss is believed to begin early and continue throughout life, with some acceleration after menopause.

Most previous studies of this have used dual-energy x-ray absorptiometry, which cannot separate trabecular from cortical bone or assess bone microstructure, according to lead author Joshua N. Farr, PhD, from the Mayo Clinic in Rochester, Minnesota.

In their study, Dr. Farr and colleagues used high-resolution peripheral quantitative computerized tomography (HRpQCT), which can assess cortical and trabecular microstructures.

The investigators used HRpQCT to evaluate a subset of women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). In that study, women (mean age, 53 years) were randomized to placebo, oral estrogen (conjugated equine estrogen 0.45 mg/day), or transdermal estrogen (17β-estradiol 50 µg/day). Women receiving estrogen also received progesterone 200 mg/day for 12 days each month.

The women underwent HRpQCT at baseline and after 4 years of therapy to assess cortical and trabecular microstructure at the distal radius.

Because bone changes in the oral and transdermal estrogen groups were similar, the 2 groups were evaluated together.

After 4 years of treatment, there were smaller decreases in volumetric bone mineral density (BMD) in the estrogen group (n = 45) than in the placebo group (n = 31). There were also increases in cortical porosity in the estrogen group.

However, the investigators found no significant differences in trabecular bone volume fraction or trabecular thickness between the estrogen and placebo groups.

After 4 years, there was a significant loss of thoracic spine volumetric BMD at the trabecular and central zones of the T8 and T9 vertebrae in the placebo group. In contrast, thoracic spine volumetric BMD increased slightly in the estrogen group," which was consistent at all skeletal sites, Dr. Farr explained.

Although the findings are consistent with current theories linking cortical bone loss to estrogen deficiency and trabecular bone loss to intrinsic age-related processes, this study showed inconsistent patterns in bone loss not previously observed.

"An unexpected finding was a differential response of estrogen therapy on trabecular volumetric BMD at the distal radius, compared with the thoracic spine," Dr. Farr said. "One explanation may simply be that single CT measures of vertebral volume BMD are affected by changes in the ratio of red to yellow marrow," he noted.

Estrogen therapy has been shown to prevent increases in bone marrow adipocytes in postmenopausal osteoporotic women, which might confound the effect of estrogen treatment on changes in vertebral trabecular volumetric BMD, Dr. Farr explained. "This might be why we saw the slight increase in thoracic spine trabecular volume BMD in the estrogen-treated group over 4 years," he said.

The effect is not an issue at the distal radius because bone marrow is completely yellow at the site from young adulthood onward.

"The findings suggest that 4 years of either transdermal or oral estrogen plus progesterone treatment leads to the preservation of cortical bone at the distal radius in recently menopausal women," Dr. Farr concluded.

"These treatments do not prevent trabecular bone at the distal radius after the onset of menopause but, at least according to single-energy CT, estrogen treatment was able to prevent loss of trabecular bone at the thoracic spine," he explained.

Ego Seeman, MD, from Austin Health, University of Melbourne, in Australia, offered another possible explanation for the findings.

"I do not believe there is inconsistency in the treatment of estrogen on the axial skeleton," he said. "I think that in regions containing both cortical and trabecular bone, intracortical remodeling is creating cortical fragments that look like trabeculi, which are incorrectly included in the calculation of trabecular density in controls," he noted.

"The reduction in trabecular density is therefore underestimated in controls. These should be excluded so the true greater reduction in controls will be seen, and therefore the protective effect of estrogen will be apparent in the treated group," he explained.

"At the spine, there is less cortical bone, so this fragmentation is not occurring as much to falsely elevate spine trabecular density in untreated controls," Dr. Seeman said.

The study authors and Dr. Seeman have disclosed no relevant financial relationships.

American Society for Bone and Mineral Research (ASBMR) 2012 Annual Meeting: Abstract 1138. Presented October 13, 2012.