The number of osteoporosis patients is increasing not only in women but in men. Male osteoporosis occurs due to aging or androgen depletion therapies, leading to fractures. However, molecular mechanisms underlying male osteoporosis remain unidentified. Here, we show that hypoxia inducible factor 1 alpha (Hif1 alpha) is required for development of testosterone deficiency-induced male osteoporosis. We found that in mice Hif1 alpha protein accumulates in osteoclasts following orchidectomy (ORX) in vivo. In vitro, Hif1 alpha protein accumulated in osteoclasts cultured in hypoxic conditions, but Hif1 alpha protein rather than mRNA levels were suppressed by testosterone treatment, even in hypoxia. Administration of a Hif1 alpha inhibitor to ORX mice abrogated testosterone deficiency-induced osteoclast activation and bone loss but did not alter osteoclast activities or bone phenotypes in sham-operated, testosterone-sufficient animals. We conclude that Hif1 alpha protein accumulation due to testosterone-deficiency promotes development of male osteoporosis. Thus Hif1 alpha protein could be targeted to inhibit pathologically-activated osteoclasts under testosterone-deficient conditions to treat male osteoporosis patients. (C) 2016 Elsevier Inc. All rights reserved.