Depo-Provera®; Depot-Medroxyprogesterone Acetate (DMPA) is one of the most used contraceptives and it is currently used by more than 30 million women in most of developed and developing countries. The study was designed to investigate the relationship between serum cortisol and the risk of osteoporosis in Nigerians using Depo-Provera®. We investigated 50 women using Depo-Provera® and 50 age-matched control, not on DPMA. Serum cortisol, progesterone, estrogen, estradiol, serum calcium, cathepsin K and urinary excretion rate of calcium were determined in subjects and controls. Serum cortisol and cathepsin K were significantly higher in women using DPMA Vs controls (P<0.01), we also found a significantly lower estradiol, serum calcium and an increased urinary excretion rate of calcium in subjects using DPMA as compared to controls (P<0.05). We found a positive correlation between serum cortisol and serum calcium (r=0.553) (P<0.01), serum cortisol and cathepsin K (r=0.568, P<0.05). Our study shows that hypercortisolaemia may be responsible for calcium loss, further investigation is needed to determine if cortisol induced calcium loss is responsible for bone demineralization associated with the use of DPMA.