Biosimilar Denosumab Matches Reference Drug for Bone Density in Chinese Women

For postmenopausal women managing osteoporosis, the high cost of biologic therapies like denosumab has long stood between patients and consistent access to fracture prevention. A new phase 3 trial suggests a lower-cost alternative may close that gap without compromising results.1

Trial Compares Biosimilar to Reference Denosumab

Researchers evaluated KN012, a proposed biosimilar to denosumab, against the US reference product (Prolia) in a 12-month, double-blind, randomized, active-controlled phase 3 study conducted across 25 centers in China (CTR20201555). Denosumab, a fully human monoclonal antibody targeting RANKL, inhibits RANK–RANKL signaling, reduces osteoclast activity and bone resorption, and thereby increases bone mass and strength. While the reference drug has demonstrated years of proven efficacy and safety, treatment costs have remained a barrier to access.

That access gap has persisted despite the drug's long track record. A recent review noted that osteoporosis remains marked by delayed diagnosis, undertreatment, and poor adherence even though effective therapies exist, and pointed to denosumab biosimilars as a means of narrowing that gap.2 Since 2024, several denosumab biosimilars have secured approval from regulators, including the FDA and European Medicines Agency, reflecting a broader international push to widen access to antiresorptive therapy for patients at risk of fracture. The Chinese trial adds to that growing body of comparative evidence supporting biosimilar adoption in osteoporosis care.1

Investigators enrolled 280 postmenopausal women between the ages of 50 and 80 years who were at high risk of fracture, randomizing them 1:1 to receive 60 mg of either KN012 or the reference drug subcutaneously at baseline and month 6. All patients also received daily calcium and vitamin D supplementation throughout the study. Of those randomized, 279 patients received treatment, and 262 (93.6%) completed the study period.

Bone Density Gains Were Comparable Between Groups

The primary endpoint, mean percent change in lumbar spine bone mineral density (BMD) from baseline at month 12, showed a least squares mean difference of 0.22% between the biosimilar and reference groups in the full analysis set, and 0.11% in the per-protocol set. Both confidence intervals fell entirely within the prespecified equivalence margin of plus or minus 1.75%, meeting the trial's equivalence criteria. Lumbar spine BMD increased by roughly 5.8% in the biosimilar group and 5.5% in the reference group by month 12, figures the authors noted were consistent with earlier pivotal trial data for the reference drug. Similar gains were observed at the total hip, femoral neck, and trochanter, with no statistically significant differences between treatment arms. Bone turnover markers, including serum CTX and PINP, declined by at least 60% from baseline across both groups, reflecting expected suppression of bone resorption and formation activity.

Safety and Immune Response Profiles Aligned Closely

Treatment-emergent adverse events occurred in similar proportions between groups, affecting 85.7% of patients receiving the biosimilar and 86.3% of those receiving the reference drug. Adverse drug reactions occurring in more than 5% of patients in either group included hypocalcemia, hypophosphatemia, and urinary tract infection, with comparable rates across arms. Serious adverse events were reported in 8.6% of the biosimilar group and 13.7% of the reference group. Immunogenicity testing showed low rates of antidrug antibodies in both groups, and no patients in either arm tested positive for neutralizing antibodies at any point during the study.

Population pharmacokinetic modeling, conducted using data from 277 patients, further supported the comparison. Geometric mean ratios for key pharmacokinetic parameters and their 90% confidence intervals fell entirely within the standard bioequivalence range of 80% to 125%.

Findings Build on Limited Head-to-Head Comparisons

The authors noted that this trial represented the first active-controlled, head-to-head phase 3 comparison between a denosumab biosimilar and the reference product in a Chinese population, distinguishing it from prior placebo-controlled biosimilar studies conducted in the same country. As they explained, this design "addresses the inferential limitations of placebo controls for equivalence testing and provides more direct, robust evidence of clinical equivalence."

Still, the trial carried limitations common to biosimilar development programs. The 12-month observation window was considerably shorter than the multiyear safety data available for the reference product, limiting insight into rarer, longer-term risks such as atypical femoral fractures or osteonecrosis of the jaw, none of which were observed during this study. The population studied was also limited to Chinese postmenopausal women, and additional research may be needed to confirm generalizability across broader patient populations.

Overall, the authors concluded that the biosimilar demonstrated comparable efficacy, safety, and pharmacokinetic behavior to the reference drug, supporting its potential as an accessible treatment option for postmenopausal women at high risk of fracture.

References

1. Zhu X, Liu J, Mao Y, Li J, Shao F, Lin H. Comparison of KN012, a denosumab biosimilar, versus reference denosumab in Chinese postmenopausal women with osteoporosis: efficacy, safety, and population pharmacokinetics in a 12-month phase III study. Bone Rep. 2026;29:101916. doi:10.1016/j.bonr.2026.101916
2. Aapro M, Hadji P, Santini D, Schmidmaier R, Eastell R. Biosimilars in osteoporosis treatment: focus on denosumab. Expert Opin Biol Ther. 2025;25(8):887-898. doi:10.1080/14712598.2025.2540471