Osteoporosis is a chronic skeletal disease characterized by low bone mass and increased risk of fracture. Obvious symptoms are not present until fracture occurs. It has become a life-threatening problem worldwide1. When the T value is less than or equal to -2.5, or the T value is greater than -2.5 combined with low traumatic fracture (including distal forearm, hip, and vertebral compression fracture), it can be diagnosed as osteoporosis2. Risk factors for osteoporosis include low body mass index, previous fractures, a family history of fractures, the use of glucocorticoids, active cigarette smoking, and alcohol consumption3. In Taiwan, the prevalence of osteoporosis for men and women was 23.9% and 38.3%, respectively4. Taiwan will become an aging society by 2026, when more than 20% of the population will be elderly5. Approximately one-third of women and one-fifth of men will have at least one osteoporosis-related fracture in their lifetime2. Hip fractures not only cause disability but also increase mortality. Thirty percent of patients die within one year after their first hip fracture6. Currently, there are two main types of drugs for the treatment of osteoporosis. Anabolic drugs stimulate bone formation, and antiresorptive drugs slow bone resorption. According to Taiwanese osteoporosis practice guidelines (Chinese version revised 2020), the effects of anti-osteoporosis drugs can not only improve bone mineral density (BMD) but also lower the incidence of fracture. However, the cost of current medicine therapy is expensive, and some adverse effects, such as fever, arthralgia, myalgia, hypocalcemia, etc., are noted7.

Chinese herbal medicines (CHMs) are mainstream therapies in Asian countries and important alternative treatments for osteoporosis7,8. CHMs are associated with higher cost efficiency and fewer side effects for the treatment of osteoporosis 8, 9, 10. For the treatment of osteoporosis, preventing bone loss and promoting bone formation is similar to the balance of yin and yang in the theory of traditional Chinese medicine (TCM)11. When this balance is destroyed, osteoporosis will occur. Wang et al.12 found that osteoporosis patients in Taiwan using CHMs had a lower incidence rate of fractures. In Taiwan, more than 70% of patients with osteoporosis use CHMs. Among the commonly used TCM formulas, Guilu Erxian Jiao (GEJ) ranks among the top five formulas12,13. GEJ, a well-documented TCM formula, originated from the ancient book of TCM called “The Golden Mirror of Medicine”. No adverse gastrointestinal effects or impacts on cardiopulmonary, hepatic, or renal function have been associated with GEJ, except for mild dry mouth14,15. In an animal study, it was found that GEJ enhances ALP activity and increases bone morphogenetic protein-2 (BMP-2) production through the PI3K/Akt/NF-κB signaling pathway16. Li et al.17 found that GEJ could increase the BMD of the lumbar spine and femoral neck in postmenopausal women. Unfortunately, this study did not track and document subsequent fractures in the long term. The doses of GEJ in other retrospective studies were lower and often included other traditional Chinese medicines. Although TCM can lower the incidence of fractures12, it is difficult to know which part of the fracture is most improved and how much it can improve BMD. The Chang Gung Research Database (CGRD)18 was used to evaluate the probable influence of the GEJ on the change in the T-score and the cumulative rates of fracture in osteoporosis patients. This is the first long-term case-control study of the effects of GEJ on the rates of fracture in patients with osteoporosis.