(1) While a number of medications have been shown to induce bone loss, the actual incidence and prevalence of medication-induced osteoporosis has not been well quantified. (2) Oral corticosteroids contribute to an increased prevalence of osteoporosis and an increased incidence of fracture in a number of different populations. The increased incidence of fracture in patients receiving inhaled corticosteroids for respiratory disease may be attributed to disease pathogenesis rather than the effects of medication. (3) Other therapies that increase the incidence and/or prevalence of medication-induced osteoporosis and fracture include androgen-deprivation therapy, aromatase inhibitors, protease inhibitors, selective serotonin reuptake inhibitors and prolactin-raising antiepileptic agents. (4) It is difficult to make definitive conclusions on the actual increase in the prevalence and/or incidence of osteoporosis in patients receiving certain medications, as values are often reported differently and studies are mainly retrospective and are therefore open to inherent selection biases and other confounders. Furthermore, there is little available information as to whether specific medications within a class are associated with a higher rate of bone disease than others.

Three biosimilar products are now licensed for the treatment of rheumatic diseases in Europe. The European Medicines Agency (EMA) requires that similarity between a biosimilar and its reference product is demonstrated using a rigorous, stepwise process that includes extensive physicochemical and biological analytical testing, non-clinical pharmacology, clinical evaluations, and pharmacovigilance plans. Each step is highly sensitive to any differences between products and progressively reduces any uncertainty over similarity; all steps must be satisfied to demonstrate biosimilarity. The US Food and Drug Administration (FDA) requires a similar stringent biosimilar development process. The etanercept biosimilar SB4 (Benepali®), recently approved for the treatment of rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis (ankylosing spondylitis, non-radiographic axial spondyloarthritis), and plaque psoriasis, is herein used to demonstrate the detailed analytical characterisation and clinical testing that are required by the EMA before biosimilars are approved for use. A comprehensive characterisation study involving >55 physiochemical and >25 biological assays demonstrated that SB4 has highly similar structural, physicochemical, and biological quality attributes to reference etanercept. A Phase I study demonstrated pharmacokinetic equivalence between SB4 and reference etanercept in healthy male subjects. Furthermore, a Phase III, randomised, controlled trial performed in patients with moderate-to-severe rheumatoid arthritis despite treatment with methotrexate (MTX) showed that SB4 was equivalent to etanercept in terms of efficacy, safety, and immunogenicity. In conclusion, the biosimilar development process performed according to EMA or FDA guidelines is highly rigorous and comprehensive. Biosimilars such as SB4 are now available in clinical practice and are likely to improve access, reduce costs, and ultimately, improve health outcomes.

Biosimilars follow a rigorous regulatory approval pathway designed to collect and review the totality of evidence from non-clinical analytical comparability exercises as well as clinical Phase I and III studies between the biosimilar and the reference biological. Once the European Medicines Agency (EMA) has given a positive opinion on the generated totality of evidence, the agency may extrapolate the biosimilar’s clinical data from the indication in which the biosimilar was studied to other indications for which the reference biological was approved. A prerequisite for this step is a convincing demonstration of biosimilarity within a studied clinical Phase III population that is suitably sensitive to detect potential clinically relevant differences in efficacy, safety, or immunogenicity. This regulatory pathway was used for all currently available biosimilars including SB2 (Flixabi®), a recently approved biosimilar that is licensed for use across all indications approved for its reference biologic infliximab (Remicade®), including inflammatory bowel disease (IBD). Further to robust non-clinical evaluations of SB2 in 46 physicochemical and 23 biological assays, a Phase I study demonstrated pharmacokinetic equivalence between SB2 and reference infliximab. Furthermore, a Phase III study performed in patients with moderate-to-severe rheumatoid arthritis (RA) — a scientifically appropriate, sensitive patient population — showed that SB2 was equivalent to infliximab in terms of its primary endpoint, American College of Rheumatology 20% improvement (ACR20) response rate at Week 30, and comparable with regard to safety and immunogenicity up to Week 54. Additional analyses of treatment-emergent adverse events (TEAEs) by anti-drug antibody (ADA) status up to Week 54 demonstrated a comparable incidence of TEAEs in both treatment arms. The ACR response rates, safety, and incidence of ADAs remained comparable also in the transition extension period up to Week 78 between patients who continued to receive either SB2 or reference infliximab, and patients who transitioned from reference infliximab to SB2. Biosimilars have an important place in the treatment of IBD. Increased use of biosimilars in patients with Crohn’s disease (CD) or ulcerative colitis is likely to reduce costs, expand access of eligible patients to biologic therapy, and improve overall health outcomes.