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Effects of Intranasal 17ß-Estradiol on Bone Turnover and Serum Insulin-Like Growth Factor I in Postmenopausal Women

INSERM U-403, Hôpital E. Herriot (P.G., P.D.D.), and Synarc (F.G.), 69437 Lyon, France; Institut de Recherches Internationales Servier (Y.T., C.V.), Courbevoie, France; MAV Hospital (I.M.), Budapest, Hungary; and Hotel Dieu Hospital (C.P.), Paris, France

Address all correspondence and requests for reprints to: Dr. Patrick Garnero, INSERM U-403, Hôpital E. Herriot, Pavillon F, 69437 Lyon Cedex 03, France. E-mail: patrick.garnero{at}synarc.com

Estrogen therapy, using either oral or transdermal routes, decreases bone turnover and prevents postmenopausal bone loss. It has been suggested that oral and transdermal 17ß-estradiol (E₂) may have different effects on serum insulin-like growth factor I (IGF-I), a potent bone-forming growth factor. In this study we investigated the effects of a new route of administration, the intranasal E₂ spray (S21400), on bone turnover and circulating IGF-I and IGF-binding protein-3 (IGFBP-3). Four hundred and twenty early postmenopausal women (<5 yr since menopause; mean age, 52 yr) were enrolled in a 3-month, double blind, placebo-controlled study of four doses of intranasal E₂ (100, 200, 300, and 400 µg/day), two doses of oral E₂ valerate (1 or 2 mg/day), and placebo. One hundred and twelve women were further treated for 12 months with intranasal E₂ (300 µg/day, i.e. the dose that has been shown to be adequate for the majority of postmenopausal women). Markers of bone resorption (urinary type I collagen C telopeptides) and formation [serum osteocalcin, serum type I collagen N-terminal extension propeptide (PINP), and serum bone alkaline phosphatase (BAP)] were measured at baseline, 1 month, 3 months, and 15 months. Serum IGF-I and IGFBP-3 were measured at baseline, 1 month, and 3 months. Urinary type I collagen C telopeptides decreased significantly in all active treatment groups as soon as 1 month (P < 0.001 vs. placebo) and continued to decrease at 3 months with a dose effect for intranasal E₂. Serum osteocalcin and PINP did not change at 1 month for oral E₂ (1 and 2 mg), but decreased significantly at 3 months. In contrast, formation markers increased significantly at 1 month for the two highest doses of intranasal E₂ (P < 0.01 vs. placebo for osteocalcin and BAP) and did not decrease at 3 months. Oral E₂ induced a marked decrease in circulating IGF-I as early as 1 month, which was amplified at 3 months (-29% and -32% for 1 and 2 mg, respectively), whereas no significant change from placebo was observed for intranasal E₂ during the 3-month period. Changes in circulating IGF-I correlated significantly (P < 0.01) with changes in osteocalcin, PINP, and BAP at 3 months. Oral and intranasal E₂ did not induce any significant change from placebo in serum IGFBP-3 at both 1 and 3 months. After 1 yr of treatment with intranasal E₂ (300 µg/day), both resorption and formation markers decreased, reaching the levels in premenopausal women, regardless of the type of treatment during the first 3 months.

We conclude that E₂ administered by this new nasal route normalizes bone turnover to premenopausal levels. The delayed decrease in bone formation observed with intranasal E₂ compared to oral E₂ may be related to different effects on serum IGF-I levels.

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