Skylab and Russian Space data shows us that astronauts lose approximately 8% bone mineral density after 84 days in space. This increases to 19% by 140 days. Theoretically, an astronaut could lose up to 50% or more of their bone mineral density over a 3-year space mission.
Significant atrophy of skeletal muscle starts after only 5 days in space, and there is no idea if and when a plateau of atrophy would be reached. Most of these changes appear to be due to deconditioning and not any particular microgravity pathology. However, cycling and treadmill activity do not appear to affect muscle density loss but do prevent biophysical changes (gait changes, foot drop) that worsen density loss and recovery.
There are some changes in the cardiovascular system (decreased fluid volume, decrease in stroke volume and cardiac output by about 15%) with prolonged space travel. However, there are no noted changes in heart rate or function so these changes do not appear to be a health risk at this time.
NASA has extensively worked to identify therapeutic and preventive measures to combat these issues.