Clinical trials of bone-targeted therapy for new indications

This thesis evaluates the effect of bone-targeted therapies on new indications in two areas of major clinical and public health significance, namely osteoarthritis and vascular calcification. The first of these indications is osteoarthritis (OA). OA is the most common joint disease characterised by articular cartilage loss, joint pain and disability. There are currently no approved disease-modifying OA drugs (DMOADs), and conservative treatments only have small to moderate effects on joint symptoms. Subchondral bone abnormalities predict both structural and symptomatic progression of OA and have increasingly been recognised as a potential treatment target. Bone-targeted therapies (e.g. bisphosphonates and denosumab) are anti-resorptive agents that have been widely used for the prevention and treatment of osteoporosis. Previous evidence has indicated that these bone-targeted therapies may be promising DMOADs especially in patients with a marker of high bone turnover (e.g. subchondral bone marrow lesions [BMLs], Modic type vertebral endplate changes). The second indication, vascular calcification, is important as it is an independent predictor of cardiovascular disease. Animal studies and small trials suggest that bisphosphonates may be protective against the progression of vascular calcification, but data from large trials are lacking. A further issue in the clinical use of bone-targeted therapies is that intravenous (IV) bisphosphonates frequently lead to a high incidence of acute phase responses (APRs). This thesis aims to investigate whether zoledronic acid (an IV bisphosphonate) and/or denosumab are effective for the treatment of knee and spine OA and abdominal aortic calcification (AAC), and whether co-administration of methylprednisolone reduces the high incidence of APRs caused by zoledronic acid. Data from four multi- or single-centre, double-blinded, randomised, placebo-controlled trials were analysed. Cartilage volume, BMLs, Modic changes and disc degeneration were evaluated using magnetic resonance imaging (MRI). Radiographic joint space narrowing (JSN) and AAC were measured on knee and spine x-rays, respectively. Bone mineral density (BMD) was assessed using dual energy x-ray absorptiometry (DXA). Multiple questionnaires were used to assess pain and functional disability of the knee and the low back. APRs and other adverse events were recorded throughout the trials. Chapter 4 evaluates the effect of zoledronic acid on tibiofemoral cartilage volume loss and change in BML size and knee pain over 2 years in 223 patients with symptomatic knee OA and BMLs. Annual infusion of 5 mg zoledronic acid did not significantly slow the progression of cartilage volume loss, reduce the size of BMLs, or alleviate knee pain compared to placebo, but may be beneficial for knee pain in patients without radiographic JSN. Adverse events, particularly APRs, were more frequent with zoledronic acid than placebo as expected. Chapter 5 assesses the effect of zoledronic acid plus methylprednisolone versus zoledronic acid alone and placebo on the incidence of APRs and changes in knee pain, disability and BML size over 6 months in 117 patients with symptomatic knee OA and BMLs. Adding 10 mg methylprednisolone to zoledronic acid showed no effect on APRs compared to zoledronic acid alone but may have symptomatic benefits compared to placebo. Chapter 6 evaluates the effect of zoledronic acid and denosumab on low back pain (LBP) and Modic changes over 6 months in 103 patients with chronic LBP and type I, II or mixed Modic change. Both zoledronic acid and denosumab improved LBP and the effect was stronger in patients with type I Modic change, non-neuropathic pain or mild disc degeneration. While neither treatment reduced the size of Modic change overall, denosumab decreased the size of type I Modic change. Chapter 7 investigates the effect of annual infusion of zoledronic acid on the progression of AAC over 3 years in 502 postmenopausal women with osteoporosis, and the correlation between change in BMD and AAC progression. Zoledronic acid showed no beneficial effect on AAC progression, and there were no correlations between change in femoral neck or total hip BMD and change in AAC scores. In conclusion, these randomised controlled trials (RCTs) indicate that bone-targeted therapies have at best a small to moderate effect on clinical symptoms in early OA with BML/Modic change, and that zoledronic acid does not affect structural progression of knee OA or the progression of vascular calcification. APRs caused by zoledronic acid cannot be reduced by co-administration of 10 mg methylprednisolone. These findings imply a limited role of bonetargeted therapies in the treatment of OA and vascular calcification. Future work should confirm the symptomatic benefit of bone-targeted therapies in early OA and evaluate the effect of bone-targeted therapies on Modic change over a longer time interval (e.g. 1 year).