A total of 25 plasma protein indicators may have a significant causal relationship with osteoporosis (P < 0.05), and 10 of them, such as ANKED46, KLRF1, and LPO, CA9 may have a protective effect on osteoporosis (OR: 0.996–0.999), while the other 15 such as ATP1B1, zinc finger protein 175, could increase the risk of osteoporosis (OR: 1.001–1.004). This evidence concerns the gene KLRF1 and osteoporosis.