This paper reviews the interventions to stabilize calcium balance and bone metabolism and prevent bone loss in astronauts during space flight. Weightlessness during space flight results in calcium, vitamin D, and vitamin K deficiency, increases urinary calcium excretion, decreases intestinal calcium absorption, and increases serum calcium level, with decreased levels of serum parathyroid hormone and calcitriol. Bone resorption is increased, whereas bone formation is decreased. The loss of bone mineral density (BMD) in the spine, femoral neck and trochanter, and pelvis is 1.0-1.6% per month. High calcium intake and vitamin D supplementation during space flight does not affect bone metabolism, but prevents an elevation of serum calcium level through increased calcitriol level, while vitamin K counteracts the reduction in bone formation. However, there are no data to show the efficacy of pharmaceutical agents for prevention of development of osteoporosis in astronauts during flight, although the preventative effect of bisphosphonates, testosterone, and vitamin K2 on cancellous bone loss in the tibia or BMD loss in the hindlimb was reported in tail-suspended mature rats. It still remains uncertain whether these agents can prevent cortical bone loss caused by weightlessness in tail-suspended rats. Therefore, in addition to calcium, vitamin D, and vitamin K supplementation, agents that have both potent anti-resorptive and anabolic effects on cancellous and cortical bone may be needed to stabilize calcium balance and bone metabolism and prevent bone loss in astronauts during space flight.