The role of interleukin-6 in the bone microenvironment is controversial. We studied the effect of recombinant human interleukin-6 (rhIL-6) administration on bone metabolism in 10 adult female rhesus monkeys (age 12-27 years). Monkeys received rhIL-6 (15 micrograms/kg/day) daily by subcutaneous injection for 28 days. Serum alkaline phosphatase, osteocalcin, and 24 h urinary calcium excretion were determined before, during (at weeks 2 and 4), and after (at week 6) treatment. Transilial biopsies (right and left) were obtained before treatment was initiated and just after the final (28th) dose at week 4. The serum alkaline phosphatase significantly increased at 2 and 4 weeks of rhIL-6 administration. Osteocalcin and urinary calcium excretion significantly decreased at week 2. Upon treatment with rhIL-6 significant reductions in OS/BS and Ob.S/BS were observed without changes in other static histomorphometry parameters. The reductions in urinary calcium excretion, serum osteocalcin, and the static bone parameters are consistent with an IL-6 induced reduction in bone formation or turnover. Whether this pharmacologic effect is relevant at the physiologic level remains to be determined.