The cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6 induce osteoclast formation and may contribute to the development of postmenopausal osteoporosis. Cross-sectional studies have suggested that both IL-1 and IL-1ra secretion increase on estrogen withdrawal, and that postmenopausal osteoporosis is associated with an inadequate increase in monocyte IL-1ra secretion with age. We measured cytokine mRNA (IL-1β, IL-1ra, IL-6, and TNF-α) directly in bone biopsies from early postmenopausal women to determine if a lower compensatory increase in IL-1ra mRNA could be demonstrated in women with rapid bone loss after the menopause. Biopsies were obtained from 23 early postmenopausal women (mean age 53.9 years) who participated in a randomized study of hormone replacement therapy (HRT) and risk factors for osteoporosis. Bone mineral density was assessed by duel energy X-ray absorptiometry at 0, 1, 2, and 5 years. Women in the control group were recruited to the biopsy study based on their observed rate of bone loss (upper or lower tertile). Consent was also obtained from 11 participants receiving HRT. Biopsies were taken at 2 years, frozen in nitrogen, and homogenized. Cytokine mRNA was measured by competitive reverse transcriptase polymerase chain reaction. The IL-1ra/IL-1β mRNA slope for the slow-loss group was steeper (ΔF = 23.3, p < 0.01) than that observed in the fast-loss group, indicating that slower bone loss was associated with higher IL-1ra mRNA levels relative to IL-1β. During HRT, the IL-1β mRNA level was inversely correlated with serum estradiol (log r2 = 0.77, p < 0.01), and women with a serum estradiol below 200 pmol/L during HRT had IL-1β mRNA levels identical to the control group. In contrast, IL-1ra mRNA was independent of serum estradiol. Histomorphometric analysis revealed weak correlations between IL-1β mRNA and activation frequency (r2 = 0.26, p = 0.06) and between IL-1ra and volume referent bone resorption rate (r2 = 0.19, p = 0.11). TNF-α was not associated with the bone loss rates or with serum estradiol, and only three samples were positive for IL-6 mRNA. The findings support the hypothesis that IL-1β production within bone increases with declining estrogen levels, and that an increase in IL-1ra protects against accelerated bone loss. Copyright (C) 2000 Elsevier Science Inc.