Efficacy and Safety of the Biosimilar Denosumab Candidate (Arylia) Compared to the Reference Product (Prolia®) in Postmenopausal Osteoporosis

A Phase III, Randomized, Two-Armed, Double-Blind, Parallel, Active-Controlled, and Noninferiority Clinical Trial

Ahmadreza Jamshidi; Mahdi Vojdanian; Mohsen Soroush; Mahmoud Akbarian; Mehrdad Aghaei; Asghar Hajiabbasi; Zahra Mirfeizi; Alireza Khabbazi; Gholamhosein Alishiri; Anousheh Haghighi; Ahmad Salimzadeh; Hadi Karimzadeh; Fatemeh Shirani; Mohammad Reza Hatef Fard; MohammadAli Nazarinia; Soosan Soroosh; Nassim Anjidani; Farhad Gharibdoost


Arthritis Res Ther. 2022;24(161) 

In This Article

Abstract and Introduction


Background/Objective: Osteoporosis is a global health concern with an increasing prevalence worldwide. Denosumab is an antiresoptive agent that has been demonstrated to be effective and safe in osteoporotic patients. This study aimed to compare the efficacy and safety of the biosimilar denosumab candidate (Arylia) to the originator product (Prolia®) in postmenopausal osteoporotic patients.

Methods: In this randomized, double-blind, active-controlled, noninferiority trial, postmenopausal osteoporotic patients received 60 mg of subcutaneous Arylia or Prolia® at months 0, 6, and 12 and were followed up for 18 months. The primary endpoint was the noninferiority of the biosimilar product to the reference product in the percentage change of bone mineral density (BMD) in 18 months at the lumbar spine (L1-L4), total hip, and femoral neck. The secondary endpoints were safety assessment, the incidence of new vertebral fractures, and the trend of bone turnover markers (BTMs).

Results: A total of 190 patients were randomized to receive either biosimilar (n = 95) or reference (n = 95) denosumab. In the per-protocol (PP) analysis, the lower limits of the 95% two-sided confidence intervals of the difference between Arylia and Prolia® in increasing BMD were greater than the predetermined noninferiority margin of − 1.78 at the lumbar spine, total hip, and femoral neck sites (mean differences [95% CIs] of 0.39 [− 1.34 to 2.11], 0.04 [− 1.61 to 1.69], and 0.41 [− 1.58 to 2.40], respectively). The two products were also comparable in terms of safety, new vertebral fractures, and trend of BTMs.

Conclusion: The efficacy of the biosimilar denosumab was shown to be noninferior to that of the reference denosumab, with a comparable safety profile at 18 months.

Trial Registration: ClinicalTrials.gov, NCT03293108; Registration date: 2017-09-19.


Osteoporosis is a common metabolic bone disease,[1] affecting an estimated more than 200 million people worldwide,[2] and is highly prevalent in the elderly population in Iran.[3] It is characterized by diminished bone mineral density (BMD) and deterioration of bone quality (microarchitectural changes), leading to compromised bone strength and an augmented risk of fractures.[4,5] According to the International Osteoporosis Foundation (IOF), it is estimated that worldwide, approximately 30% of women and 20% of men over the age of 50 develop osteoporosis-induced fractures in their lifetime.[6]

Postmenopausal osteoporosis guidelines highly recommend pharmacologic treatment in patients with osteoporosis and patients with osteopenia at high risk for fractures.[7,8] The initial pharmacologic treatment for most osteoporotic patients at high fracture risk includes denosumab, zoledronate, and teriparatide.[7,9] Denosumab is a fully human monoclonal antibody that blocks the interaction between receptor activator of nuclear factor kappa-B ligand (RANKL) and its receptor (RANK) on osteoclasts, leading to inhibition of osteoclast formation as well as osteoclast-mediated bone resorption.[10,11] Denosumab was the first drug to be approved by the US Food and Drug Administration (FDA) with this mechanism and has been used for osteoporosis since 2010.[12] In the main study of denosumab (FREEDOM study), the drug effectively reduced the risk of new vertebral and nonvertebral fractures and improved the BMD at the lumbar spine and total hip.[13]

Considering the global aging population and the expected increase in osteoporosis incidence, developing drugs and preventive approaches are of great importance in managing osteoporosis and its consequences. Biosimilar products are comparable in safety, efficacy, and quality to licensed biological reference products. They are often provided at a lower cost and provide better accessibility in lower-income countries. The preclinical studies of the biosimilar denosumab (Arylia, AryoGen Pharmed, Iran) showed no meaningful difference from the reference product (Prolia®, Amgen Inc., USA). In the present study, we assessed the noninferiority of Arylia to Prolia® and compared their efficacy and safety profiles in postmenopausal osteoporotic patients within 18 months.