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


In this study, the noninferiority of the biosimilar denosumab compared with the reference denosumab in improving BMD at the lumbar spine (L1–L4), total hip, and femoral neck among osteoporotic postmenopausal women was established. As in other studies,[15,16] the primary outcome can be determined by considering only the lumbar spine BMD since this site shows the highest incidence of osteoporosis, and the best results will be observed in short-term treatment compared to the total hip or femoral neck. Additionally, the primary outcome of a denosumab biosimilar candidate produced by Sandoz company is the assessment of BMD changes at the lumbar spine.[17] This ongoing phase 3 trial, which began after our study, shows that measuring BMD at the lumbar spine is sufficient for demonstrating bio-similarity.

In this study, in the PP set and after 18 months of treatment, the mean percentage change in BMD increased significantly in both treatment groups at the lumbar spine, total hip, and femoral neck. In the FREEDOM study,[13] lumbar spine and total hip BMD increased in postmenopausal women with osteoporosis at 36 months of treatment with denosumab. In the study by Tomonori Kobayakawa and colleagues[18] comparing denosumab versus romosozumab in postmenopausal women with osteoporosis, the BMD at the lumbar spine, total hip, and femoral neck increased during 12 months of treatment in both groups. The increase in lumbar BMD was approximately two times that of the total hip and more than 2.5 times that of the femoral neck in the denosumab group. In another study, the percentage change in lumbar spine BMD with the biosimilar denosumab (Intas Pharmaceutical Ltd, India) was comparable to Prolia® and increased at 12 months of treatment in postmenopausal osteoporotic women.[19] In a study evaluating the efficacy of denosumab vs. teriparatide in glucocorticoid-induced osteoporotic patients, the BMD showed an increase at the lumbar spine and femoral neck; however, the percent change in the total hip BMD was not significant.[20] Overall, the results of our study on the percentage of BMD change in the three study sites are in line with the findings of the above studies, indicating an increase in BMD between 12 and 36 months of treatment.

Regarding the incidence of new vertebral fractures, both drugs were the same without any new vertebral fractures in patients. The role of denosumab in long-term fracture prevention is reviewed in an article published in 2020.[21] Evaluation of fracture reduction with denosumab in postmenopausal osteoporosis in the FREEDOM study[13] showed that denosumab reduced the risk of new vertebral fractures, which is in line with the results of this study.

In addition, changes in biomarkers were not significantly different between the two groups, and the final values decreased relative to baseline. In a study conducted in postmenopausal patients in Argentina, changes in total alkaline phosphatase, OC, and serum CTX were downward during 12 months of treatment with denosumab regardless of previous bisphosphonate treatment.[22] In another study on postmenopausal women with osteoporosis in Japan,[18] serum P1NP decreased at 6 and 12 months of treatment with denosumab. In the FREEDOM study,[13] serum P1NP and CTX levels decreased during 36 months of treatment with denosumab. According to the above studies, a decreasing trend in BTMs has been observed since the early months of treatment with denosumab, indicating that such markers can be used for the early evaluation of effectiveness, and this trend has continued for up to 36 months, which is in accordance with the results of the present study.

Since osteoporosis is a chronic condition, safety concerns are a prerequisite for any treatment. Based on the trial findings, Arylia and Prolia® are generally comparable in terms of safety parameters. The overall incidence of AEs (77.89% and 64.21%, respectively, p = 0.26) and SAEs (6.32% and 6.32%, respectively, p = 1) were comparable between the two arms.

In this study, the most common adverse event was hypocalcemia (16.84% in the Arylia arm and 11.58% in the Prolia® arm) which was similar to another study that compared denosumab with zoledronic acid.[23] Additionally, the FREEDOM trial reported no difference in hypocalcemia incidence between the treated and placebo groups.[24] According to the FREEDOM study, denosumab can be associated with an increased risk of serious infections in women with postmenopausal osteoporosis. In the present study, reports by infections and infestations SOC were comparable between the Arylia and Prolia® arms (5.26% and 4.21%, respectively). In randomized, placebo-controlled trials comparing denosumab with placebo, more cases of neoplasm have been reported in the denosumab group compared with the placebo group by McClung et al. (1.9% versus 0%), Bone et al. (2.4% versus 0.6%), and in the FREEDOM trial (4.8% versus 4.2%).[25] In this study, no cases of neoplasms occurred in the Arylia arm, compared to three cases in the Prolia® arm (p = 0.08). According to the investigators' opinion, all the cases were unrelated to the treatment. There were no cases of ONJ and AFF in this study. There have been no reports of ONJ and AFF in osteoporosis clinical trials. Only in the fourth and fifth years of the FREEDOM extension trial were two cases of ONJ reported.[24,26]

A possible limitation of this study was the assessment duration. To evaluate rare and long-term AEs such as ONJ and new fractures, further studies with more prolonged periods and larger sample sizes are needed. In addition, a larger sample size can potentially detect more specific clinical differences between the two products.