Eighty-nine postmenopausal women with osteoporosis or at least 3 risk factors for osteoporosis were randomly assigned to receive, in double-blind fashion, 1 of 4 treatments for 2 years: 1) 500 ml/day of soymilk containing 76 mg/day of isoflavones; 2) transdermal progesterone; 3) the combination of soy and progesterone; or 4) placebo (isoflavone-poor soymilk, containing 1 mg/day of isoflavones). In the progesterone group, 30 g of progesterone cream, containing a total of 540 mg of progesterone, was applied topically over a 3-week period, with a 1-week break before repeating the cycle. All patients received supplemental calcium, magnesium, vitamin D, and other nutrients known to play a role in bone health. The mean change in lumbar-spine bone mineral density (BMD) was +1.1% in the soy group (p < 0.01 vs. placebo), -1.1% in the progesterone group (not significant vs. placebo), -2.8% in the combined treatment group (not significant vs. placebo), and -4.2% in the placebo group. The respective changes in bone mineral content were +2.0% for soy (p = 0.006 vs. placebo), +0.4% for progesterone (p = 0.03 vs. placebo), and -2.4% for combined treatment (not significant vs. placebo), and -4.3% for placebo. No significant changes occurred in femoral-neck BMD.
Comment: The results of this study indicate that daily ingestion of soymilk prevented lumbar-spine bone loss in postmenopausal women. Transdermal progesterone had a modest bone-sparing effect but, when combined with soymilk, a negative interaction occurred, resulting in greater bone loss than with either treatment alone. The apparent negative interaction between soymilk and progesterone may have been due in part to the higher proportion of smokers in the combined-treatment group than in the other groups.
The results seen with progesterone are somewhat disappointing, as they fail to confirm Dr. John Lee's report that transdermal progesterone increased BMD by an average of about 15% over a 3-year period in postmenopausal women (Med Hypotheses 1991;35:316-318). A study by Leonetti et al (Obstet Gynecol 1999;94:225-228) also failed to confirm Lee's work, and found no bone-sparing effect at all from topical progesterone cream. After Leonetti's study was published, Lee argued that progesterone works only in older postmenopausal women who are past the period of rapid postmenopausal bone loss. The mean age of Lee's patients was 65.2 years, compared with 52.5 years for Dr. Leonetti's patients. The patients in the current study had an average age of 58.2 years, and the results were better than those seen by Leonetti, but far worse than those reported by Lee.
A controlled study enrolling older women is needed to determine whether Lee's original uncontrolled trial can be replicated. Dr. Leonetti is planning such a trial, and is attempting to enroll women in the Philadelphia, PA, area. Those interested in participating should contact her at 610-882-3100, ext. 224.
Lydeking-Olsen E, et al. Soymilk or progesterone for prevention of bone loss: a 2 year randomized, placebo-controlled trial. Eur J Nutr 2004;43:246-257.
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