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Effects of a Triphasic Combination Oral Contraceptive Containing Norgestimate/Ethinyl Estradiol on Biochemical Markers of Bone Metabolism in Young Women with Osteopenia Secondary to Hypothalamic Amenorrhea

Neuroendocrine Unit, Massachusetts General Hospital (S.K.G., K.K.M.), Boston, Massachusetts 02114-2696; Ortho-McNeil Pharmaceutical, Inc. (A.J.F., W.H.O.), Raritan, New Jersey 08869-0602; Ethicon (J.L.), Somerville, New Jersey 08876; and Center for Menopause, Hormonal Disorders and Women’s Health (M.P.W.), New York, New York 10022

Address all correspondence and requests for reprints to: Steven Grinspoon, M.D., Massachusetts General Hospital, Neuroendocrine Unit, Bul 457b, 55 Fruit Street, Boston, Massachusetts 02114-2696. E-mail: Sgrinspoon{at}partners.org.

This multicenter, double-blind, placebo-controlled, randomized study of 45 patients evaluated the short-term effects of an oral contraceptive [Ortho Tri-Cyclen, 180–250 µg of norgestimate (NGM) and 35 µg of ethinyl estradiol (EE)] on biochemical markers of bone resorption, formation, and osteoprotegerin in young women (mean age ± SD, 26.5 ± 6.3 yr) with hypothalamic amenorrhea and osteopenia. Body fat, endocrine, and cognitive function were evaluated as secondary endpoints. Biomarkers of bone metabolism were measured at baseline and after three cycles of NGM/EE or placebo. There were significant decreases in mean values of N-telopeptide [mean (SD), -13.4 (13.4) vs. 1.2 (23.8) nmol bone collagen equivalents (BCE)/mmol creatinine (Cr); P = 0.001] and deoxypyridinoline [-1.2 (2.9) vs. -0.5 (1.5) nmol deoxypyridinoline/mmol Cr; P = 0.021] as well as significant decreases in bone specific alkaline phosphatase [-5.1 (3.5) vs. 0.4 (3.1) ng/ml; P < 0.001], osteocalcin [-5.9 (3.6) vs. -2.9 (3.7); P = 0.016], and procollagen of type I propeptide [-35.2 (44.6) vs. -0.2 (30.0) ng/ml; P = 0.025], but not osteoprotegerin [0.39 (1.46) vs. -0.2 (0.49) pmol/liter; P = 0.397] in the NGM/EE vs. placebo group. There were no significant differences between groups with respect to changes in cognitive function, mood, body weight, body mass index, body fat, percentage of body fat, and all endocrine levels except FSH, [-3.7 (3.8) vs. -0.6 (2.1) IU/liter; P < 0.001, NGM/EE vs. placebo]. No serious adverse events were reported in either group. These results suggest that NGM/EE decreases bone turnover in osteopenic premenopausal women with hypothalamic amenorrhea. Further studies are needed to determine whether estrogen will increase bone density in this population.

Abbreviations: AE, Adverse event; BCE, bone collagen equivalents; BMD, bone mineral density; BMI, body mass index; BSAP, bone specific alkaline phosphatase; Cr, creatinine; DHEAS, dehydroepiandrosterone sulfate; DPYR, deoxypyridinoline; DXA, dual-energy x-ray absorptiometry; EE, ethinyl estradiol; HA, hypothalamic amenorrhea; ITT, intent-to-treat; NGM, norgestimate; NTX, N-telopeptide; OC, oral contraceptive(s); OPG, osteoprotegerin; PICP, procollagen of type I propeptide; POMS, Profile of Mood States; QOL, quality of life.

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