Pulsed estrogen therapy in prevention of postmenopausal osteoporosis. A 2-year randomized, double blind, placebo-controlled study

The aim of this study was to evaluate the efficacy of pulsed estrogen therapy (intranasal 17β-estradiol) in the prevention of postmenopausal bone loss. A total of 386 women (40–65 years old), less than 5 years past menopause, were randomized to intranasal placebo, 17β-estradiol 150 µg, or 300 µg daily for 2 years. Women with an intact uterus received micronised progesterone 200 mg per day, 14 days of each 28-day cycle. Women randomised to placebo-treatment received placebo progesterone. The primary endpoints were changes in BMD at the spine (L2–L4) and femoral neck. Secondary endpoints were changes in bone turnover markers: serum osteocalcin (sOC) as a marker of bone formation and urinary C-terminal telopeptides (uCTX) as a marker of bone resorption. BMD increased at all measured sites in women receiving active treatment in a dose-related manner, the difference compared to placebo being 5.2% and 6.7% at the spine, and 3.2% and 4.7 % at the hip, respectively, with 150 μg and 300 μg (P<0.001). On the other hand, a decrease versus baseline of −3.2% and −3.3% at the spine and hip, respectively, was observed in women receiving placebo (P<0.001). In the patients with at least one risk factor for osteoporotic fracture, the difference between placebo and 150 μg or 300 µg was even higher at the spine (5.4% and 7.4%, respectively), and at the femoral neck (4.0% and 5.2%, respectively). Correspondingly, uCTX decreased from baseline by 39% and 46 %, and sOC by 22% and 27%, in the 150 µg group and 300 µg group (all P<0.001 versus placebo). A strong correlation was found between variations of bone turnover markers after 1 year and BMD after 2 years, emphasizing that bone markers can predict BMD response during hormonal treatment. Acceptability and general tolerance were good. This study demonstrates that pulsed estrogen therapy at the dose of 150 μg and 300-μg per day prevents bone loss in a dose-dependant manner at each site studied, and normalizes bone turnover markers to premenopausal levels.