Efficacy and safety of denosumab biosimilars in the treatment of postmenopausal osteoporosis: A systematic review of randomized clinical trials

Abstract

Denosumab biosimilars were developed to provide cost-effective alternatives to the reference monoclonal antibody for postmenopausal osteoporosis (PMO). This review assessed their efficacy, safety, and immunogenicity in the treatment of PMO. A systematic search of PubMed/Medline, Ovid-Embase, and Web of Science (to April 2025) identified randomized controlled trials comparing denosumab biosimilars with either the originator (Prolia^®) or placebo. Data on bone mineral density (BMD), bone turnover markers, adverse events, and immunogenicity were synthesized descriptively. In addition, the National Institutes of Health (NIH) Quality Assessment Tool was employed to evaluate the risk of bias across all eligible studies. Eleven RCTs met the inclusion criteria. Biosimilars showed therapeutic equivalence to the reference product, with comparable BMD gains at the lumbar spine, total hip, and femoral neck, and similar reductions in CTX and P1NP. In placebo-controlled trials, biosimilars significantly increased BMD and reduced bone turnover by more than 70%. Safety and immunogenicity profiles were comparable to the originator, with no new safety signals or neutralizing antibodies. Denosumab biosimilars demonstrate efficacy and safety equivalent to Prolia^®, offering an accessible, cost-efficient option for PMO management. Long-term data are needed to confirm sustained antifracture benefits.

Supplementary Information

The online version contains supplementary material available at 10.1007/s10238-026-02070-1.

Introduction

Osteoporosis is a systemic skeletal condition characterized by a reduction of bone mineral density and structural deterioration of bone tissue, affecting nearly 20% of the adult population globally [1]. Osteoporosis represents a significant clinical and public health concern due to its strong association with age-related fracture risk, mostly in the hip, wrist, and spine [2]. In addition to pain, fractures cause limited mobility and hospitalizations, which negatively affect the quality of life and impose medical, social, and economic burdens [3]. The prevalence of the disease is higher in women than in men, with postmenopausal women being particularly affected due to the reduction in endogenous estrogen levels following menopause [4]. Notably, in the United States, postmenopausal women account for more than two-thirds of all diagnosed osteoporosis cases [5]. Moreover, over 50% of postmenopausal White women are expected to experience an osteoporosis-related fracture during their lifetime, imposing a substantial burden on both affected women and healthcare systems [6].

Approximately 10% of bone tissue undergoes remodeling each year, a process essential for maintaining bone density and structural integrity [7]. Bone remodeling is mediated by osteoclasts, which are responsible for bone resorption, and osteoblasts, which are involved in bone formation. Estrogen is one of the key hormones regulating this dynamic balance. In postmenopausal women, estrogen deficiency disrupts the bone remodeling cycle by increasing osteoclastic activity and reducing osteoblastic function, ultimately leading to decreased bone mass. Estrogen deficiency primarily accelerates trabecular bone loss due to enhanced resorption; however, with aging, both trabecular and cortical bone loss occur gradually in both sexes as a result of diminished bone formation [8]. Environmental and lifestyle factors can further influence bone health. Smoking, excessive alcohol consumption, and prolonged use of glucocorticoids exacerbate bone loss, whereas regular physical activity, adequate Vitamin D levels, and calcium supplementation have been shown to support bone density [9]. It is imperative to note that up to 50% of osteoporotic women who sustain hip fractures fail to regain their pre-fracture functional capacity. This decline contributes to reduced mobility, chronic pain, and psychological distress, underscoring the significant personal and societal impact of osteoporosis.

Several pharmacological therapies have been approved for the treatment of postmenopausal osteoporosis (PMO) and the prevention of associated fractures [10]. The main aims of PMO therapy include decreasing bone resorption (antiresorptive therapies), stimulating bone formation (anabolic therapies), or combining both mechanisms. Bisphosphonates, approved by the U.S. Food and Drug Administration (FDA), act by accelerating osteoclast apoptosis and subsequent inhibition of bone resorption [11]. While all biphosphonates are effective in reducing vertebral fracture risk, long-term use has been associated with rare but serious complications such as osteonecrosis of the jaw and atypical femur fractures. Moreover, given that estrogen deficiency following menopause accelerates bone loss, menopausal hormone therapy is effective in preserving bone mass in postmenopausal women [12]. However, prolonged use of combined hormone replacement therapy has been linked to an increased risk of breast cancer, which limits its long-term application. Denosumab, a human monoclonal antibody, selectively targets the receptor activator of nuclear factor kappa-B ligand (RANKL) [13]. By binding to RANKL, denosumab suppresses its interaction with the RANK receptor on osteoclasts, thereby inhibiting osteoclast formation, function, and survival. This results in a significant reduction in bone resorption. Nonetheless, the considerable expense of manufacturing and obtaining denosumab has limited its widespread clinical use, particularly in low- and middle-income countries [14]. To address this challenge, several biosimilar versions have been developed to enhance therapeutic accessibility and reduce overall treatment costs [15]. To date, several denosumab biosimilars have shown favorable efficacy and safety outcomes in patients with PMO; nonetheless, despite multiple clinical investigations, no comprehensive systematic review has synthesized the overall evidence comparing these agents with the originator [15–17]. A thorough understanding of their mechanisms of action and clinical effectiveness is essential to inform evidence-based and personalized treatment strategies. Herein, we aim to systematically evaluate the efficacy and safety of denosumab biosimilars in the management of PMO.

Materials and methods

This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [18]. The corresponding PRISMA checklists are provided in Tables S1 and S2.

Search strategy

The search strategy was performed in three different databases, including PubMed/MedLine, Ovid-Embase, and Web of Science, covering the period up to April 19^th, 2025. A full list of search terms (MeSH terms and keywords) is mentioned in Table S3.

Eligibility criteria and study selection

This systematic review included randomized controlled trials (RCTs) and phase II-III clinical studies that evaluated the efficacy, safety, pharmacodynamics, or immunogenicity of denosumab biosimilars in postmenopausal women diagnosed with osteoporosis. Eligible studies were required to meet the following inclusion criteria in accordance with the PICOS framework:

Population (P)

Postmenopausal women diagnosed with primary or secondary osteoporosis based on established diagnostic criteria (e.g., WHO or local BMD-based definitions).

Intervention (I)

Administration of any denosumab biosimilar formulation at a dosage equivalent to the reference product (Prolia^®), either as monotherapy or in combination with calcium and vitamin D supplementation.

Comparator (C)

Reference denosumab (Prolia^®), placebo, or an alternative active comparator.

Outcomes (O)

Quantitative assessment of efficacy and/or safety, including at least one of the following endpoints.

• BMD at lumbar spine, total hip, or femoral neck;

• Bone turnover markers [serum C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (P1NP)];

• Incidence of vertebral or non-vertebral fractures;

• Adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs);

• Immunogenicity profiles (anti-drug antibodies, neutralizing antibodies).

Study design (S)

Only double-blind, randomized, active- or placebo-controlled trials published as full-text, peer-reviewed articles were included.

In addition, the exclusion criteria were as follows: Non-randomized studies, observational designs, case reports, case series, conference abstracts, editorials, letters, or reviews; preclinical (animal or in vitro) studies; studies including mixed populations (e.g., men, premenopausal women, or other disease conditions) without separate data for postmenopausal osteoporosis; and articles not available in English or lacking sufficient outcome data for extraction.

Two independent reviewers (F.S. and S.M.) screened all retrieved records in a two-step process. First, titles and abstracts were screened to identify potentially relevant studies. Subsequently, full texts of the shortlisted articles were evaluated against the eligibility criteria. Any discrepancies between reviewers were resolved through discussion or consultation with a third investigator (N.H.) or the corresponding author (A.H.).

Data extraction

The data extraction process for the eligible study was independently conducted by two reviewers (F.S. and S.M.). The process was as follows: (I) Extraction of study and patient characteristics, including study ID (author, year), study design, sample size, age mean, past medical history and comorbidities, disease conditions and duration, previous treatments, and type of current treatment. (II) Extraction of results, including outcome measurements, efficacy, safety, adverse effects, and follow-ups. Moreover, Microsoft Excel software, version 16.64, was used for data extraction.

Risk of bias assessment

The methodological quality and risk of bias of all included studies were independently appraised by two reviewers (F.S. and S.M.) using the National Institutes of Health (NIH) Quality Assessment Tool for Clinical Trials [14]. A detailed summary of the bias assessment findings is provided in Table S4.

Results

Search results

A systematic search conducted up to April 19th, 2025, yielded 182 relevant studies, comprising 43 from PubMed/Medline,81 from Ovid-Embase, and 58 from Web of Science. After removing duplicates, 98 underwent title and abstract screening. Subsequently, two independent investigators (F.S. and S.M.) conducted a full review of 16 selected articles. Following the final eligibility assessment, 11 studies met the inclusion criteria for data extraction. Figure 1 illustrates the PRISMA flowchart of this systematic review. According to the evaluations conducted using the NIH Quality Assessment Tool for Clinical Trials, all included studies demonstrated a “good” level of methodological quality.

Fig. 1.

PRISMA 2020 flow diagram for new systematic reviews, which included searches of databases and registers only

Characteristics of eligible studies

A total of eleven RCTs were included in this study, recruiting a total of 4,227 patients, of whom 213 cases had prior treatment with bisphosphonate (Table 1). The investigated biosimilars and their patient population were as follows: SB16 (n = 864), FKS518 (n = 553), CT-P41 (n = 479), MW031 (n = 440), GP2411 (n = 527), QL1206 (n = 455), LY06006 (n = 448), Arylia (n = 190), Intas (n = 114), and one other biosimilar (n = 177). In eight studies, the denosumab biosimilar was compared to the original product [16, 19–25], whereas in three investigations, the denosumab biosimilar was compared to a placebo [17, 26, 27]. The studies compared the denosumab biosimilar with the original product, carried out two treatment periods (TPs): in TP1, patients were randomized with a 1:1 ratio to receive the biosimilar or reference denosumab at a dosage of 60 (up to weeks 20–32), and in TP2, cases who were prescribed reference denosumab were rerandomized to receive biosimilar or reference denosumab. In studies that compared denosumab biosimilar with placebo, the ratio of randomization was 3:1 for receiving denosumab biosimilar or placebo. The following measurements, scores, indexes, or values were evaluated throughout the investigations: BMD at the lumbar spine, total hip, and femoral neck; rate of vertebral fracture; and bone turnover markers, such as CTX and P1NP.

Table 1.

Characteristics of eligible studies utilizing denosumab biosimilars for postmenopausal osteoporosis patients

Study ID (Author, year)	Study design	Sample Size	Age	Past Medical History and Comorbidities	Disease condition and patients characteristics	Previous Treatments	Treatment[s] of Study	Outcome Measurement and Efficacy	Safety, Adverse Effects, and immunogenicity
Paul,2025 (19)	Prospective, Active-controlled, Randomized, Double-blind, Multicenter, Phase III	Total: 177 Biosimilar denosumab:116 Reference denosumab:61	Biosimilar denosumab: mean age of 63.28 Reference denosumab: mean age of 63.69	NA	Biosimilar denosumab: mean weight of 55.20, mean baseline BMD of lumbar spine of 0.7375, mean baseline BMD of femoral neck of 0.662 Reference denosumab: mean weight of 55.18, mean baseline BMD of lumbar spine of 0.7461, mean baseline BMD of femoral neck of 0.663	NA	Biosimilar denosumab or reference denosumab at a dosage of 60 mg SC in baseline and day 180	Primary efficacy endpoint: the LS mesn percent change difference between groups in lumbar spine BMD in month 6 of 0.61 in the mITT population and 0.84 in the PP population, and in month 12 of − 0.05 in the mITT population and 0.10 in the PP population: no statistically significant difference in LSM percentage change across the treatment groups The LSM percent change difference between groups in femoral neck BMD in month 6 was 0.51 in the mITT population and − 0.70 in the PP population, and in month 12, it was − 0.14 in the mITT and − 0.84 in the PP. No statistically significant difference in LSM percentage change across the two treatment groups	TEAs: A total of 86 in 55 patients SAEs: Biosimilar denosumab: compression fracture in 1 participant, vocal cord paralysis and pulmonary tuberculosis in 1 participant; all three unlikely related to the study drug Reference denosumab: d Parkinson’s disease in 1 participant, unlikely related to the study drug No positive test for the antidenosumab antibody at the end of the study
Chung, 2025 (20)	Randomized, clinical trial, phase III	Total: 407 SB16 + SB16: 206 DEN+SB16 : 100 DEN + DEN: 101	SB16 + SB16: mean age of 66.1 DEN+SB16: mean age of 65.8 DEN + DEN: mean age of 66.4	NA	SB16 + SB16: mean BMI of 25.00, mean years since menopause of 16, vertebral fracture at baseline: (n = 92), T-score of lumbar spine − 3.05, T-score of total hip − 1.82, T-score of femoral neck − 2.17 DEN+SB16: mean BMI of 24.55, mean years since menopause of 15, Prevalence of vertebral fracture at baseline: (n = 57), T-score of lumbar spine − 3.06, T-score of total hip − 1.88, T-score of femoral neck − 2.20 DEN + DEN: mean BMI of 24.95, mean years since menopause of 17, Prevalence of vertebral fracture at baseline: (n = 49), T-score of lumbar spine − 3.07, T-score of total hip − 1.85, T-score of femoral neck − 2.17	SB16 + SB16: Prior use of oral bisphosphonates (n = 40) DEN+SB16: Prior use of oral bisphosphonates (n = 16) DEN + DEN: Prior use of oral bisphosphonates (n = 14)	TP1: month 0 to month 12, SB16 or denosumab at a dosage of 60 mg, SC, at month 0, 6,12 TP2: month 12 to month 18, re-randomization (1:1) in denosumab to continue 60 mg denosumab (DEN + DEN group) (n = 101)or switch to 60 mg of SB16 (DEN+SB16 group)(n = 100) or 60 mg of SB16 (SB16 + SB16 group)(n = 206)	Primary efficacy endpoint: the LS mean difference between treatment groups for the percent change from baseline in lumbar spine BMD of 0.33% in the full analysis set(FAS) and 0.39% in the per-protocol set(PPS): fully contained within the pre-defined equivalence margin in both the FAS and PPS Comparable mean percent changes from baseline in BMD for the lumbar spine, total hip, and femoral neck across treatment groups at Month 18	TEAEs during TPII (at switching period): SB16 + SB16 group 35.4%, DEN+SB16 group 29.0%, DEN + DEN group 34.7% Common TEAEs during TPII: Hypocalcemia Frequently reported (2%) TEAEs: Arthralgia, Bronchitis, COVID-19, Headache, Hypercholesterolemia, Nasopharyngitis, Upper respiratory tract infection, Vitamin D deficiency SAEs during TPII: SB16 + SB16 group 0.9%, DEN+SB16 group 0.0%, DEN + DEN: group.0% None of the SAEs related to the study drug Similar positive ADA results between groups
Sadek, 2024 (21)	Randomized, double-blind	Total: 553 FKS518: 276 Denosumab originator: 277	NA	NA	lumbar spine BMD T-score ≤−2.5 and ≥−4.0,	NA	Three 60 mg administrations of FKS518 or the denosumab originator Randomization of patients receiving the denosumab originator to continue their treatment or switch to FKS518 for the third dose at week 52	Clinically relevant increases in LS-BMD were evident at week 52 in both the FKS518 and originator product groups: therapeutic equivalence A similar percent change from baseline in BMD at the femoral neck and total hip between the two groups at week 52	TEAEs: FKS518: 185 (66.8%) patients Originator product: 189 (68.5%) patients No notable differences between FKS518 and the originator product groups in safety evaluation
Reginster, 2024 (16)	Double-blind, randomized, active-controlled, Phase 3 trial	Total: 479 CT-P41: 240 US-denosumab: 239	CT-P41: median age of 66.00 US-denosumab: median age of 66.00	CT-P41: current smoker (n = 46), former smoker (n = 30), never smoker (n = 164) US-denosumab: current smoker (n = 40), former smoker (n = 36), never smoker (n = 163)	CT-P41: median BMI of 24.35, ≥ 1 vertebral fracture at baseline (n = 59), ≥ 1 nonvertebral fracture (n = 75), median years since menopusal of 16.0 US-denosumab: median BMI of 24.80, ≥ one vertebral fracture at baseline (n = 50), ≥ 1 nonvertebral fracture (n = 93), median years since menopause of 16.0	CT-P41: bisphosphonate therapy (n = 32) US-denosumab: bisphosphonate therapy (n = 28)	TP1: Week 0 to Week 52, CT-P41 or US-denosumab at a dosage of 60 mg, SC, at Weeks 0 (Day 1), 26, and 52 TP2: Week 52 to Week 78,re-randomization (1:1) in US-denosumab to continue US-denosumab or switch to CT-P41 (n = 101)	Primary efficacy endpoint: the LS mean difference between treatment groups for the percent change from baseline in lumbar spine BMD at Week 52 of − 0.139 in the full analysis set and − 0.280 in the per-protocol set: fully contained within the pre-defined equivalence margin Increased and comparable mean ± SD percent changes in BMD at lumbar spine, total hip, and femoral neck during TPI across groups at Weeks 26 and 52 Comparable BMD outcomes at lumbar spine, total hip, and femoral neck across groups during TPII Small and similar mean ± SD changes from baseline in OPAQ-SV, EQ-5D-5 L index, and EQ VAS scores during TPI and TPII, including post-switch from US-denosumab to CT-P41.	TEAEs during TPI: CT-P41 group 75.7%, US-denosumab group 70.2% Common TEAEs during TPI: COVID-19 TESAEs during TPI: CT-P41 2.9%, US-denosumab 4.2% One death during TPI, unrelated to the treatment Similar positive ADA results between groups in both TPs
Langdah, 2024 (22)	Randomized, double-blind, multicenter phase 3 clinical trial study	Total: 457 SB16 (n = 225), DEN (n = 232)	SB16: mean age of 66.5 DEN: mean age of 66.3	NA	SB16: mean BMI of 25.2, mean years since menopause of 16, vertebral fracture at baseline (n = 104), mean T-score of lumbar spine of −3.04, mean T-score of total hip of −1.81, mean T-score of femoral neck − 2.16 DEN: mean BMI of 24.9, mean years since menopause of 16, vertebral fracture at baseline (n = 117), mean T-score of lumbar spine of −3.05, mean T-score of total hip of −1.82, mean T-score of femoral neck − 2.16	SB16:Prior use of oral bisphosphonates (n = 42) DEN: Prior use of oral bisphosphonates (n = 33)	TP1: month 0 to month 6, SB16 or DEN (randomized in a 1:1 ratio), 60 mg SC, at month 0 and month 6 TP2: month 12 to month 18, re-randomization in DEN to continue with DEN or switch to SB16 up to month 18 (n = 205)	Primary efficacy endpoint: the LS mean difference between treatment groups for the percent change from baseline in lumbar spine BMD of 0.33% in the full analysis set(FAS) and 0.39% in the per-protocol set(PPS): fully contained within the pre-defined equivalence margin in both the FAS and PPS Increased and comparable mean percent changes from baseline in lumbar spine BMD, total hip BMD, and femoral neck BMD between SB16 and DEN at month 6 and month 12 Comparable mean serum concentrations between SB16 and DEN up to month 12	TEAEs during TP1 (up to month 12): SB16 group 70.7%, DEN group 71.0% Any TEAEs occurring in > 5% of patients up to month 12: hypocalcemia, arthralgia, COVID-19, headache, urinary tract infection, upper respiratory tract infection, nasopharyngitis Study drug-related TEAEs: SB16 group 11.6%, DEN group 14.3% SAEs up to month 12: SB16 group 3.6%, DEN 3.5% Common SAEs: Injection site reactions, Permanent discontinuation of the study None of the TEAEs and SAEs with fatal outcomes up to month 12 similar positive ADA results between groups
Jiang, 2024 (26)	Randomized, double-blind, placebo-controlled, multicenter clinical trial study	Total: 440 MW031: 329 Placebo :111	MW031 : 66.05 ± 5.79 Placebo: 64.93 ± 6.23	NA	MW031: years since menoupausal of 17, T-score of lumbar spine BMD(n = − 2.82 ± 0.64), T-score of total hip BMD(n = − 1.94 ± 0.67), T-score of femoral neck BMD (n = − 2.33 ± 0.67), vertebral fracture (n = 128), hip fracture (n = 3) Placebo: BMI (n= 23.43 ± 2.67), years since menopause of 15, T-score of lumbar spine BMD (n = − 2.83 ± 0.77), T-score of total hip BMD (n= −2.01 ± 0.68), T-score of femoral neck BMD (n = − 2.42 ± 0.71), vertebral fracture (n = 37), hip fracture (n = 1)	NA	MW031 or placebo with a 3:1 ratio every 6 months for 12 months MW031 with an initial loading dose of 60 mg subcutaneously placebo with the same sequence	Significant increase in the lumbar spine BMD in the MW031 group compared with the placebo group after 12 months Significant difference in BMD change rate at the lumbar spine and total hip in month 6 An increase in BMD at the total hip and femoral neck by 3.65% and 2.93%, respectively, in the MW031 group, compared with 1.31% and 1.88% in the placebo group in month 12; a significant difference for total hip	AEs: MW031 71.3%, placebo 74.3% SAEs: MW031 9.3%,placebo 14.2% TRAEs: MW031 group 12.5%, placebo group 4.4%, common TRAEs: arthralgia, abnormal hepatic function, pain in extremity, muscle spasms, limb discomfort, hypocalcaemia, hypercalcaemia, periodontal disease, headache, dizziness, rash 6 patients were positive in the MW031 group for ADA
Jeka, 2024 (23)	Randomized, multicenter, double-blind, integrated phase I/phase III clinical trial study	Total: 527 GP2411: 263 REF-DEN: 264	GP2411: median age of 64.0 REF-DMAb: median age of 64.0	NA	GP2411: mean weight of 62.3, ≥ 1 vertebral fractures (n = 123), mean LS-BMD T-score of − 3.1 REF-DMAb: mean weight of 63.4, ≥ 1 vertebral fractures (n = 116), mean LS-BMD T-score of − 3.1	NA	TP1: Week 0 to Week 52, GP2411 or REF-DMAb at a dosage of 60 mg, SC, at Weeks 0 (Day 1), 26, and 52 TP2: Week 52 to Week 78, re-randomization (1:1) in REF-DMAb to continue REF-DMAb or switch to GP2411 (n = 124)	Primary efficacy endpoint: the mean difference in LS-BMD and Mean %CfB between REF-DMAb and GP2411 in the TP1 at week 52 of- 0.177 in the full analysis set(FAS) and − 0.145 in the per-protocol set(PPS): fully contained within the pre-defined equivalence margin Similar and comparable efficacy between GP2411 and REF-DMAb, with CIs for all endpoints contained within the prespecified equivalence margins	TEAEs during TP1: GP2411 59.7%,REF-DMAb 68.6% most frequent TEAE during TP1 : hypocalcemia, nasopharyngitis, COVID19 serious TEAEs in TP1:GP2411 4.6%, REF-DMAb 3.0% One death during TPI, unrelated to the treatment serious TEAEs in TP2 :GP2411/GP2411 1.6%, REF-DMAb/REF-DMAb 1.6%,REF-DMAb/GP2411 0% TESAEs during TP2 :GP2411/GP2411 26.9%, REF-DMAb/REF-DMAb37.6%, REF-DMAb/GP2411 38.7% Similar positive ADA results between groups
Zhang, 2023	A phase III randomized, double-blind, placebo-controlled trial	Total: 455 QL1206:337 Placebo:118	QL1206: mean age of 66.0 Placebo: mean age of 67.5	QL1206: concomitant diseases (n = 314), hypertension (n = 113), hyperlipidemia (n = 106), spinal osteoarthritis (n = 59), diabetes (n = 36), chronic gastritis (n = 47), vitamin D deficiency (n = 34), osteoarthritis (n = 28), herniated disc (n = 31), parent history of hip fracture (n = 93) Placebo: concomitant diseases (n = 117), hypertension (n = 48), hyperlipidemia (n = 47), spinal osteoarthritis (n = 17), diabetes (n = 23), chronic gastritis (n = 16), vitamin D deficiency (n = 18), osteoarthritis (n = 21), herniated disc (n = 13), parent history of hip fracture (n = 27)	QL1206: mean BMI of 23.02, mean years since menopause of 17.2, mean Spine BMD of 0.730, mean Femoral neck BMD of 0.613, mean Total hip BMD of 0.706, vertebral fracture (n = 58), hip fracture (n = 8) Placebo: mean BMI of 23.48, mean years since menopause of 18.8, mean Spine BMD of 0.733, mean Femoral neck BMD of 0.612, mean Total hip BMD of 0.701, vertebral fracture (n = 20), hip fracture (n = 5)	NA	QL1206 and placebo with 3:1 ratio every 6 months QL1206 with an initial loading dose of 60 mg subcutaneously placebo with the same sequence	Primary endpoint: significant difference of 4.780% between QL1206 in BMD at the lumbar spine and the placebo group Increased BMD levels at all sites measured at months 6 and 12 and reduced CTX and P1NP at months 1, 6, and 12 with QL1206 treatment Significant treatment-related difference with QL1206 compared with placebo for the mean percent change in BMD for the lumbar spine, total hip, femoral neck, and trochanter at month 6 Significant treatment-related difference with QL1206 compared with placebo for the mean percent change in BMD for the total hip, femoral neck, and trochanter at month 12 Significant treatment-related difference with QL1206 compared with placebo for the median percent change in CTX at months 1, 6, and 12	TEAEs: QL1206 group 81.3%, placebo group 80.9% Treatment related TEAEs: QL1206 group34.5%, placebo group 29.6% Common treatment-related TEAEs: Dyslipidemia, hypocalcemia, blood alkaline phosphatase is reduced, Hypophosphatemia, urinary tract infection, Arthralgia, Backache, Elevated blood glucose SAEs: QL1206 group 8.6%, placebo group 14.8% no relation to the study drug in severe TEAEs treatment-emergent SAEs: one posterior circulation ischemia, age-related cataract, fracture of the left lateral malleolus Negative ADAs for all participane except for 3subjects who were positive before the first drug administration
Gu, 2023 (27)	Randomized, double-blind, placebo-controlled, multicenter phase III	Total: 448 LY06006: 337 placebo: 111	LY06006: mean age of 65.3 placebo: mean age of 65.1	LY06006: Previous fracture (n = 118) placebo: Previous fracture (n = 50)	LY06006: mean BMI of 23.37, BMD T-score in lumbar spine of −3.14 placebo: mean BMI of 22.842,BMD T-score in lumbar spine of −3.09	NA	LY06006 or placebo at a dosage of 60 mg SC at baseline and month 6	Primary efficacy endpoint: a 4.71% treatment difference (significant) in the percent change in lumbar spine BMD from baseline to month 12 in the LY06006 group compared with the placebo group based on the FAS population Significant treatment difference with LY06006 compared with the placebo for the mean percent change in BMD for the lumbar spine, femoral neck, total hip, and trochanter	TEAEs: LY06006: 261 (77.7%) subjects placebo: 82 (75.5%) subjects The most common TEAEs: urinary tract infections and upper respiratory tract infections Study drug-related TEAEs: LY06006: 105 (31.3%) subjects placebo: 24 (21.8%) subjects Related to the study drug with a high incidence TEAEs: urinary tract infections, arthralgia, back pain, decreased blood alkaline phosphatase levels, hypocalcemia, and hypercalcemia in the two groups No ADA-positive subjects in the control group, 4(1.2%) subjects with positive ADA at least once after administration in the test group
Jamshidi, 2022 (24)	Phase III, randomized, two-armed, double-blind, parallel, active-controlled, and noninferiority clinical trial	Total: 190 Arylia: 95 Prolia: 95	Arylia: mean age of 61.59 Prolia: mean age of 60.60	NA	Arylia: mean BMI of 28.35 T score, SD of spine(L1-L4): − 3.09 (0.54) Prolia: mean BMI of 27.10 T score, SD of spine(L1-L4): − 3.10 (0.54)	Arylia: bisphosphonate therapy(n = 6) Prolia: bisphosphonate therapy(n = 2)	Either biosimilar (Arylia) or reference denosumab (Prolia) at a dosage of 60 mg SC every 6 months, including at baseline, month 6, and month 12	Primary efficacy endpoint: not statistically significant difference between treatment groups in terms of SE percentage change in BMD at lumbar spine, total hip, and femoral neck at month18, constrained within pre-defined equivalence margins	SAEs: 13 unrelated to treatment in 12 patients Most common AEs: Hypocalcemia and hypertension, with no significant differences between the groups negative for anti-denosumab antibodies at all time points except one sample
Singh, 2021 (25)	Randomized, assessor-blind, active-controlled clinical trial	Total: 114 Intas: 58 Denosumab-reference: 56	Denosumab-biosimilar: mean age of 62.6 Denosumab-reference: mean age of 59.7	NA	Denosumab-biosimilar: mean weight of 57.8, mean BMD of 0.78 at lumbar spine, mean T-score of −3.15 for lumbar spine Denosumab-reference: mean weight of 58, mean BMD of 0.79 at lumbar spine, mean T-score of −3.06 for lumbar spine	NA	Either denosumab-biosimilar (Intas, India) or denosumab-reference (Prolia, USA) at a dosage of 60 mg SC every 6 months	Primary efficacy endpoint: mean difference between treatment groups for the percent change from baseline in lumbar spine BMD to the 12th month of −0.40 in the PP population and −0.34 in the ITT population: matching between the denosumab-biosimilar and denosumab-reference Similar percent change in BMD at the left and right hip to 12 months between the denosumab-biosimilar and denosumab-reference groups for the PP population and ITT population, Similar change to 6 months between the denosumab-biosimilar and denosumab-reference groups for the PP population and ITT population	64 AEs in 45 patients with similar adverse event incidence in both denosumab-biosimilar and denosumab-reference groups Common AEs: Asthenia, pyrexia, and arthralgia No positive patient for anti-denosumab antibodies. no death report

Abbreviations: ADA: Anti-drug antibody; AEs: Adverse events; BMD: Bone mineral density; BMI: Body mass index; CI: confidence intervals; DEN: reference denosumab; FAS: full analysis set; ITT: intent-to-treat; LS: Least square; LSM: least square mean; mITT: modified intent-to-treat; NA: not applicable; PP: per-protocol; PPS: The Per-Protocol Set; SAEs: severe adverse events; SC: Subcutaneous; TEAE: treatment-emergent adverse event; TP: Treatment period; TRAEs: Treatment-related adverse events

Biosimilar versus reference product

Primary efficacy endpoint

While one study focused on secondary endpoints [20], other articles defined the primary efficacy endpoint as the mean difference between treatment groups for the percent change from baseline in lumbar spine and femoral neck BMD at months 6 and 12 [16, 19, 21–25]. With respect to the primary efficacy endpoint, six articles indicated statistically significant improvement in the mean percentage change from baseline in both lumbar spine and femoral neck BMD in months 6 and 12 of the study. The point estimate of the mean difference in percentage change of lumbar spine and femoral neck BMD from baseline was matched between the two groups and was fully contained within the pre-defined similarity margin, suggesting therapeutic equivalence between the denosumab biosimilar and reference.

Secondary efficacy endpoints

Six studies defined BMD as a secondary efficacy endpoint between biosimilar recipients and reference product recipients. In the RCT conducted by Chung et al. [20], the mean percent changes from baseline in BMD for the lumbar spine, total hip, and femoral neck were comparable between all treatment groups at month 18 of the investigation. Moreover, switching from reference denosumab to SB16 did not affect the secondary efficacy endpoints.

Moreover, in the study by Sadek et al. [21], a similar percentage change from baseline in BMD at the femoral neck and total hip was reported across FKS518 and reference denosumab groups at week 52 of the study, demonstrating the secondary endpoints.

In another RCT carried out by Reginster et al. [16], CT-P41 was compared with reference denosumab. As a result, secondary efficacy outcomes, including percent change in BMD at the lumbar spine, total hip, and femoral neck at Weeks 26, 52, and 78, demonstrated similar increases across treatment arms. Fracture incidences remained low and balanced between groups. Notably, new vertebral fractures occurred in ≤ 0.5% of patients per group, non-vertebral fractures were rare, and no hip fractures were reported. Health-related quality of life (HRQoL), assessed using OPAQ-SV, EQ-5D-5 L, and EQ VAS, showed only minor, comparable changes across all groups.

The results of another RCT by Langdahl et al. [22] illustrated that secondary efficacy outcomes, including percent changes from baseline in BMD at various skeletal sites, were comparable between the SB16 and denosumab groups. At Month 6, lumbar spine BMD increased by 3.69% and 3.81% in the SB16 and denosumab groups, respectively. Total hip BMD improved by 2.78% and 2.24% at Month 6, and by 3.50% and 3.25% at Month 12. Femoral neck BMD increased by 2.11% (SB16) vs. 1.77% (denosumab) at Month 6, and 2.79% vs. 2.30% at Month 12. These consistent trends across skeletal sites support the equivalent efficacy of SB16.

Jeka et al. [23], in another investigation, compared the efficacy of GP2411 and reference denosumab in PMO subjects. Consequently, percentage changes from baseline BMD were similar between groups at lumbar spine, femoral neck, and total hip sites. At Week 78 of the investigation, the cumulative percentage changes from baseline in lumbar spine-BMD were 6.82% for GP2411/GP2411 and 6.91% for reference denosumab/reference denosumab group. Similarly, femoral neck-BMD increased by 3.22% and 3.13%, and total hip-BMD by 3.83% and 3.92%, respectively. These results were consistent across the switch group (reference denosumab/GP2411), confirming maintained efficacy after transition.

Similarly, in the RCT designed by Jamshidi et al. [24], no new vertebral fractures were observed in either treatment group over the 18-month period, indicating comparable fracture prevention efficacy between Arylia and Prolia^®.

Safety outcomes and immunogenicity

Across all included trials, denosumab biosimilars exhibited a favorable safety profile, with TEAEs generally mild to moderate in severity and largely unrelated to the study drugs. No clinically significant safety concerns or immunogenicity issues were identified. In the study by Paul et al. [19], 55 patients experienced a total of 86 TEAEs; SAEs occurred in 5.2% of biosimilar-treated and 6.6% of reference-treated patients. Chung et al. [20] reported that TEAEs during the switching period (TP II) were similar between the SB16 and reference denosumab arms, with no increase in adverse events post-switch. At the 18-month assessment, immunogenicity analyses indicated that a single patient in the reference denosumab+SB16 treatment group developed ADAs; however, neutralizing antibodies (NAbs) were not detected in this individual. Sadek et al. [21] reported TEAEs in 66.8% of FKS518 recipients and 67.5% of originator-treated patients. In Reginster et al. [16] investigation, the incidence of TEAEs during TP1 was 75.7% in the CT-P41 group and 77.4% in the US-denosumab group, with no safety signal following crossover. Moreover, the proportions of patients testing positive for ADAs at each study visit were comparable across treatment groups in both treatment periods. Similarly, Langdahl et al. [22] reported TEAE rates of 61.8% and 63.4% in the SB16 and reference arms, respectively, with hypocalcemia being the most frequently reported event, usually asymptomatic and self-resolving. Notably, one patient (0.4%) in the SB16 group and two patients (0.9%) in the reference denosumab group tested positive for ADAs by Month 12. None of these patients demonstrated neutralizing antibody positivity. Moreover, Jeka et al. [23] confirmed a comparable safety profile for GP2411 and reference denosumab, reporting new vertebral fracture rates of 9.9% (GP2411/GP2411), 13.6% (reference denosumab/reference denosumab), and 13.7% (reference denosumab) across treatment arms. The incidence and type of adverse events, including nasopharyngitis and musculoskeletal complaints, were consistent between groups. No treatment-related SAEs or immunogenic responses were observed. In the Jamshidi et al. study [24], the overall TEAE rate was similar across groups. Notably, no cases of osteonecrosis of the jaw, atypical femoral fractures, or treatment-related discontinuations were reported. Only one patient tested transiently positive for anti-denosumab antibodies, with no neutralizing activity or clinical relevance. Finally, the Singh et al. study [25] reported TEAEs in 39.5% of biosimilar-treated and 33.9% of reference-treated patients, most commonly arthralgia, pyrexia, and asthenia. No SAEs were considered related to the study drug, and no anti-denosumab antibodies were detected. Moreover, none of the patients were positive for ADAs.

Overall, the safety and immunogenicity findings consistently support the tolerability of denosumab biosimilars, with no evidence of increased risk compared to the reference product in postmenopausal women with osteoporosis.

Pharmacokinetics and pharmacodynamics

Regarding bone turnover biomarkers, serum type I CTX, P1NP, and NTX were evaluated and compared between biosimilar agents and their respective reference products. Across the included studies, serum CTX levels exhibited a consistent decline over the pre-defined follow-up periods, with no statistically significant differences in mean change from baseline observed between biosimilar-treated and reference-product–treated cohorts [16, 19, 20, 23, 28, 29]. Similarly, P1NP concentrations were not differentially affected by treatment allocation, demonstrating comparable temporal reductions in both groups throughout the study duration [20, 23, 28, 29]. In addition, serum NTX levels decreased over an 18-month follow-up, without significant between-group differences between biosimilar and reference product recipients [29]. Pharmacokinetic profiles, including Cmax, AUC0–120d, AUC0–∞ as well as serum denosumab concentrations, were also comparable between treatment groups with insignificant differences in both treatment period I and II [16, 19, 20, 25].

Biosimilar versus placebo

To date, three investigations have evaluated the efficacy and safety of denosumab biosimilars compared with placebo. In a double-blind, RCT performed by Jiang et al. [26], a total of 448 Chinese women with PMO were randomized in a 3:1 ratio to receive either MW031, a denosumab biosimilar (n = 335), or placebo (n = 113) at a dosage of 60 mg subcutaneously every 6 months for 12 months. The primary efficacy outcome was the percentage change in lumbar spine BMD from baseline to 12 months, while secondary endpoints included BMD changes at the total hip and femoral neck, alterations in bone turnover markers (serum CTX and P1NP), and safety outcomes. The results demonstrated that MW031 significantly increased lumbar spine BMD compared to placebo (5.80% vs. 1.94%, respectively). Similarly, significant improvements were observed at the total hip (3.65% vs. 1.31%), whereas the increase at the femoral neck was not statistically significant (2.93% vs. 1.88%). Moreover, MW031 induced a rapid and sustained reduction in serum CTX levels, reaching a 71.7% decrease at month 1, and a maximum 49.1% reduction in P1NP at month 9 of the study. Furthermore, while not a primary outcome, the incidence of clinical vertebral fractures was significantly lower in the MW031 group compared to placebo (0% vs. 2.7), suggesting a potential benefit in fracture risk reduction. In terms of safety, the overall incidence of AEs was similar between the MW031 and placebo groups (71.3% vs. 74.3%). However, TEAEs were more frequently reported in the MW031 group (12.5% vs. 4.4%), though none were severe or led to discontinuation. Notably, no cases of osteonecrosis of the jaw or atypical femoral fractures were reported. Immunogenicity was low, with only 1.8% of MW031 recipients testing positive for ADA, and a single case (0.3%) of NAb positivity.

In another double-blind RCT conducted by Zhang et al. [17], 455 postmenopausal Chinese women with osteoporosis and high fracture risk were randomized in a 3:1 ratio to receive either QL1206, a denosumab biosimilar (n = 337), or placebo (n = 118), administered subcutaneously every 6 months for 12 months. All participants received daily calcium (500 mg) and vitamin D (400 IU) supplementation. The primary endpoint was the percentage change in lumbar spine BMD at 12 months, with secondary endpoints including BMD changes at other skeletal sites and serum levels of bone turnover markers (CTX and P1NP). The findings indicated that QL1206 treatment resulted in a significantly greater increase in lumbar spine BMD compared to placebo (mean change: 5.30% vs. 0.52%). Significant improvements were also reported in total hip, femoral neck, and trochanter BMD, with differences of 3.93%, 2.73%, and 4.06%, respectively, at 12 months. Additionally, QL1206 significantly suppressed bone turnover markers: CTX decreased by 77.35% and P1NP by 50.87% at 12 months compared to placebo, indicating effective inhibition of bone resorption. Regarding safety, TEAEs occurred in 81.3% of QL1206-treated patients and 80.9% of placebo-treated patients, with no significant between-group difference. No deaths, atypical femoral fractures, or osteonecrosis of the jaw were reported. Mild hypocalcemia and hypophosphatemia were more frequent in the QL1206 group (4.5% and 3.3%, respectively) but were transient and manageable. Immunogenicity testing revealed that 10.7% of QL1206 recipients developed ADA, with only 0.6% testing positive for NAb; none of these led to treatment discontinuation or serious complications.

In another randomized, double-blind, placebo-controlled phase III trial carried out by Gu et al. [27], a total of 448 individuals with PMO and high fracture risk were recruited in a 3:1 ratio to receive either LY06006, a denosumab biosimilar (n = 337), or placebo (n = 111), subcutaneously at baseline and 6 months. All participants also received daily oral calcium (500 mg) and vitamin D (600 IU) throughout the 12-month investigation. The primary outcome was the percentage change in lumbar spine BMD at 12 months, while secondary endpoints included BMD changes at other skeletal sites and bone turnover markers (CTX and P1NP). The trial results illustrated a statistically significant increase in lumbar spine BMD in the LY06006 group compared to placebo at 12 months (mean difference: 4.71%; 95%). Additionally, significant improvements were observed at the total hip (3.11%), femoral neck (2.82%), and trochanter (3.77%) compared to placebo. LY06006 also significantly suppressed serum CTX and P1NP at all measured time points, with a maximal reduction of 78.42% and 55.31% at month 1 and month 12, respectively. Considering the safety profile, AEs occurred in 78.6% of LY06006-treated patients and 75.5% of placebo-treated subjects, with most events being mild to moderate and unrelated to the study drug. No deaths, osteonecrosis of the jaw, or atypical femoral fractures were reported. The incidence of treatment-related AEs was slightly higher in the LY06006 group (31.3% vs. 21.8%), with urinary tract infections, arthralgia, back pain, and mild hypocalcemia being the most common. Immunogenicity analysis showed that only 1.2% of LY06006 recipients developed ADA after administration, with one case of NAb positivity, none of which were associated with clinical adverse outcomes.

Discussion

This systematic review comprehensively evaluated the current evidence on the efficacy, safety, and immunogenicity of denosumab biosimilars in postmenopausal women with osteoporosis. Across the included randomized controlled trials, denosumab biosimilars demonstrated therapeutic equivalence to the reference product in improving BMD at key skeletal sites, including the lumbar spine, total hip, and femoral neck. The observed percentage changes in BMD were consistently contained within pre-defined equivalence margins, confirming comparable antiresorptive effects. Furthermore, all biosimilars exhibited similar reductions in bone turnover markers, such as CTX and P1NP, supporting equivalent suppression of bone resorption. Importantly, safety profiles were favorable across all studies, with TEAEs being mild to moderate in severity and comparable between biosimilar and reference groups. These findings collectively suggest that denosumab biosimilars can provide a clinically effective and well-tolerated alternative to the originator product for the management of postmenopausal osteoporosis.

Osteoporosis develops as a consequence of disrupted bone remodeling, in which the rate of bone resorption exceeds that of bone formation [11]. The remodeling process begins with osteoclastic resorption, followed by osteoblastic bone formation to maintain skeletal integrity. Although the precise molecular events triggering this dysregulation remain incompletely elucidated, the signaling cascades modulating bone turnover have been extensively characterized in previous studies [30, 31]. Osteoclasts serve as the principal effector cells responsible for bone resorption [32]. These multinucleated cells originate from the granulocyte–macrophage lineage within the mononuclear phagocyte system and arise through the fusion of monocyte precursors under the influence of regulatory factors secreted by bone marrow stromal cells. A wide range of biological mediators, including hormones, cytokines, and noncoding RNAs, modulate osteoclast activity by targeting specific molecular pathways that stimulate their differentiation and function. Among these, the RANKL/RANK/OPG axis and the interleukin-1 (IL-1)/tumor necrosis factor-α (TNF-α) signaling cascade play pivotal roles in the regulation of osteoclastogenesis and bone resorption.

Considering management, various treatments have been utilized, including bone nutritional supplements, bisphosphonates, estrogen-related therapy, calcitonin, cathepsin K inhibitors, PTH analogues, and anti-sclerotin antibody [11]. Denosumab, a fully human monoclonal antibody targeting RANKL developed by Amgen (USA), inhibits the interaction between RANKL and its receptor RANK on osteoclasts and their precursors, thereby suppressing osteoclast formation and activity [33]. This inhibition effectively reduces bone resorption and promotes an increase in bone mass. In comparison with bisphosphonates, denosumab induces more rapid and pronounced improvements in BMD across both cortical and trabecular bone and is associated with a greater reduction in fracture risk [7]. Moreover, long-term clinical investigations have illustrated that continuous denosumab therapy maintains progressive BMD gains for up to ten years, which is superior to bisphosphonate regimens. Nevertheless, abrupt discontinuation of denosumab has been shown to result in a rapid decline in BMD due to rebound osteoclastic activation, consequently elevating the risk of multiple vertebral fractures [34]. In addition to its established role in treating postmenopausal and glucocorticoid-induced osteoporosis in individuals with elevated fracture risk, denosumab also has clinical utility in subjects who underwent hormone-deprivation therapy for breast or prostate malignancies [35]. The drug is administered via subcutaneous injection at a dose of 60 mg every six months. Despite its favorable efficacy profile, denosumab may be associated with several adverse effects, including hypocalcemia and alterations in mineral metabolism, as well as an increased susceptibility to infections and certain dermatologic complications.

Biosimilars are biologic medicinal products that are highly similar to an already approved reference biologic, exhibiting no clinically meaningful differences in terms of quality, efficacy, or safety, although minor variations in clinically inactive components may exist [36]. The active substance of a biosimilar is highly comparable to that of its reference biologic and is generally administered at the same dosage, following identical indications and therapeutic regimens for the treatment of the same disease. The introduction of biosimilars into osteoporosis management offers a cost-effective alternative to reference biologics, enhancing treatment accessibility and affordability for patients. Their broader availability has the potential to improve the economic burden associated with long-term osteoporosis therapy and to meet the rising global demand for effective pharmacologic interventions [15].

In head-to-head trials comparing denosumab biosimilars to the reference drug (Prolia^®), the percent changes in lumbar spine, femoral neck, and total hip BMD from baseline were consistently contained within pre-defined equivalence margins, confirming comparable antiresorptive efficacy [16, 19–25]. Improvements were observed as early as six months and sustained through 12 to 18 months of therapy. Parallel reductions in bone turnover markers, such as serum CTX and P1NP, further validated similar biological activity between biosimilar and originator formulations. Safety outcomes were likewise comparable: TEAEs were predominantly mild to moderate, and SAEs were rare and not treatment-related. Importantly, switching from the reference product to a biosimilar did not increase AEs or diminish efficacy, indicating that transitioning between formulations is clinically acceptable and safe. Immunogenicity assessments revealed low ADA rates with no neutralizing antibodies detected, underscoring the high molecular similarity and biocompatibility of biosimilar formulations.

In addition to active-controlled studies, three randomized, placebo-controlled phase III trials provided pivotal evidence supporting the intrinsic efficacy and safety of denosumab biosimilars. Across these investigations, biosimilars such as MW031 [26], QL1206 [17], and LY06006 [27] produced substantial and statistically significant increases in lumbar spine BMD compared with placebo after 12 months of treatment. Similarly, total hip and femoral neck BMD also improved significantly in biosimilar recipients, reflecting consistent efficacy across multiple skeletal sites. Moreover, serum bone turnover markers showed marked and sustained suppression: CTX levels declined by approximately 70%–78% within the first month of therapy, and P1NP levels decreased by 45%–55% over 12 months, demonstrating potent inhibition of bone resorption comparable to that observed with the reference denosumab. Some trials also noted a numerical reduction in new vertebral fractures among biosimilar users, suggesting potential anti-fracture benefits, although these studies were not powered to detect significant differences in fracture outcomes. The safety profiles of biosimilars in placebo-controlled settings were favorable and consistent with the known effects of denosumab. The overall incidence of TEAEs was similar between biosimilar and placebo groups (approximately 70%–80%), with most events being mild or moderate in intensity.

Interchangeability refers to a regulatory product attribute indicating that a medicinal product may be substituted for another while maintaining equivalent clinical efficacy and therapeutic outcomes [37]. Of these investigated biosimilars, Sandoz (GP2411) [23], Samsung (SB16) [28], and Celltrion (CT-P41) [16] have been approved by the FDA and European Medicines Agency (EMA) as interchangeable biosimilars to reference denosumab for the treatment of certain types of osteoporosis. In comparison with reference denosumab, these biosimilar formulations demonstrated comparable reductions in bone turnover biomarkers, similar incidences of hypocalcemia and ADA formation, and no clinically meaningful differences in BMD changes following transition from the reference product to the biosimilar.

Our findings align with real-world data suggesting that patients treated with denosumab biosimilars experience BMD gains and maintain favorable tolerability, comparable to those receiving the originator, with no SAEsnoted in small observational cohorts [38]. Additionally, recent meta-analytic syntheses of six RCTs comprising 1,784 cases report no statistically significant differences between biosimilars and reference denosumab for BMD changes at the lumbar spine, femoral neck, or total hip, and near-identical risks of overall and SAEs, confirming the efficacy equivalence [39].

Nevertheless, current trials are primarily designed for equivalence on surrogate outcomes such as BMD and biochemical markers, with limited duration and power to detect differences in fracture incidence or long-term adverse events. Therefore, future research should include long-term real-world studies and post-marketing surveillance to evaluate fracture prevention, durability of BMD gains, and rare but serious safety outcomes such as osteonecrosis of the jaw or atypical femoral fractures.

Conclusions

This systematic review demonstrates that denosumab biosimilars exhibit therapeutic equivalence to the reference product in enhancing BMD, reducing bone turnover markers, and maintaining a favorable safety and immunogenicity profile among postmenopausal women with osteoporosis. Evidence from both active- and placebo-controlled RCTs indicates consistent and clinically meaningful gains in BMD at the lumbar spine, femoral neck, and total hip, with efficacy and tolerability comparable to the originator. Collectively, these findings support denosumab biosimilars as reliable, cost-effective, and accessible therapeutic alternatives for the management of PMO. Nevertheless, the currently available studies are limited by relatively short durations and a focus on surrogate endpoints rather than direct fracture outcomes. Future long-term and real-world investigations are warranted to confirm sustained antifracture benefits, evaluate rare adverse events, and establish clinical availability across broader patient populations.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

ADA

Anti-drug antibody

AE

Adverse event

BMD

Bone mineral density

BP

Bisphosphonate

CTX

C-terminal telopeptide of type I collagen

EMA

European Medicines Agency

FDA

U.S. Food and Drug Administration

HRQoL

Health-related quality of life

IL-1

Interleukin-1

Nab

Neutralizing antibody

NIH

National Institutes of Health

NTX

N-terminal telopeptide

OPG

Osteoprotegerin

P1NP

Procollagen type I N-terminal propeptide

PMO

Postmenopausal osteoporosis

PK/PD

Pharmacokinetic/pharmacodynamic

RCT

Randomized controlled trial

RANK

Receptor activator of nuclear factor κB

RANKL

Receptor activator of nuclear factor κB ligand

SAE

Serious adverse event

TEAE

Treatment-emergent adverse event

TNF-α

Tumor necrosis factor-alpha

Author contributions

Equal contributions to the current study are F.S. and S.M. in the design, database search, screening publications, literature review, and drafting of the manuscript. N.H. in the literature review and drafting of the manuscript. A.H. in conceptualization, project administration, drafting, and revising the manuscript critically for the importance of intellectual content. All authors read and approved the final manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data availability

All data presented in this review are available in the text and supplementary materials.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.