Denosumab - Therapy for Prevention and Treatment of Osteoporosis

Amgen's denosumab (formerly AMG 162) is an investigational biological therapy in development for the prevention and treatment of osteoporosis and other disorders characterised by bone loss. These include postmenopausal osteoporosis, rheumatoid arthritis, and cancer treatment-induced bone loss.

Denosumab is currently in phase III development, where studies have shown that it can significantly increase bone mineral density in women experiencing post-menopausal bone loss.

OSTEOPOROSIS AND OTHER BONE LOSS CONDITIONS

Osteoporosis is a serious health problem that affects millions of post-menopausal women. The progressive loss of bone density that follows the menopause predisposes women to greatly increased risk of bone fractures.

As the proportion of elderly people in the population of industrialised nations continues to grow, so the problem will grow and place an increasingly heavy burden on healthcare budgets.

Data from the US show that currently over 10 million people have osteoporosis with a further 34 million estimated to have low bone mass, a risk factor for osteoporosis.

Bone loss is associated with a number of other disorders including multiple myeloma, bone metastases and rheumatoid arthritis. It can also occur as a consequence of hormone-ablative therapy for breast or prostate cancer.

DENOSUMAB TARGETS RANK LIGAND

By targeting RANK ligand, denosumab represents an entirely new approach to the prevention and treatment of bone loss. RANK ligand is a protein that plays a pivotal role in the process during which bone is formed and resorbed. RANK ligand is the primary mediator of osteoclast formation, cells responsible for bone removal.

In diseases associated with bone loss there is an imbalance between RANK ligand and osteoprotegerin, a protein that counteracts the action of RANK ligand. By blocking the effects of RANK ligand, denosumab effectively mimics the bone-protecting effects of osteoprotegerin.

In preclinical models of bone loss, inhibition of RANK ligand proved an effective approach to improving cortical and trabecular bone density, volume, and strength.

CLINICAL TRIALS DEMONSTRATE EFFICACY

The clinical effectiveness of denosumab is being investigated in a series of clinical trials including four phase III and two phase II trials in post-menopausal osteoporosis.

In a double-blind, head-to-head study with alendronate in post-menopausal women with low bone mineral density (BMD), denosumab achieved significantly greater BMD gains at the total hip, hip trochanter, and distal radius. BMD improvement at the total hip was approximately 40% greater in the denosumab treatment arm compared with those receiving alendronate (primary endpoint).

Twice-yearly injections of denosumab also achieved significant increases in BMD in a pivotal 332-patient study, in which it was compared with placebo.

At the end of the two-year study period, denosumab-treated patients had a significantly greater increase in lumbar spine BMD compared with placebo recipients (6.5 vs -0.6%; p<0.001).

Similar significant differences were observed between active treatment and placebo with respect to BMD at the total hip (3.4 vs -1.1%; p <0.0001), wrist (1.4 vs -2.1%; p<0.0001) and total body (2.4 vs -1.4%; p<0.0001).

Treatment with denosumab appeared well tolerated by patients enrolled in clinical trials performed to date.

MARKETING COMMENTARY

The market for treatments to address bone loss in osteoporosis and other conditions is large and growing. Until recently, hormone replacement therapy (HRT) was considered the mainstay of prevention and treatment of osteoporosis.

However, concerns about the safety of HRT in long-term use suggest that increasingly it will be restricted to short-term treatment of climacteric symptoms. This change in treatment practice will see greater use of alternative therapies such as bisphosphonates and selective estrogen receptor modulators (SERMS) among others.

Although the range of treatments for osteoporosis is increasing, the need for safe and effective long-term medications for prevention and treatment of bone loss remains. RANK ligand inhibitors represent an entirely new class of agents for osteoporosis and other bone loss conditions. At present, denosumab is the only RANK ligand inhibitor in advanced-stage development.