RANK Ligand Inhibition

Highly specific inhibition of the excessive bone loss with RANK ligand inhibitors offers a novel treatment option for osteoporosis.

Osteoporosis is a disorder of normal bone turnover with resultant excessive bone loss and loss of bone mineral density (BMD), which increases the risk of a bone fracture.

Bone mass accumulates to a maximum in the first two decades of life and then with age the bone quantity begins to deteriorate. Peak bone mass depends on a combination of genetics and body size. After peak bone mass is achieved the bone is preserved through a process of bone remodeling, which involves bone resorption and formation.

Certain diseases, metabolic abnormalities or deficiencies, and drug therapies may blunt the acquisition of bone mass during growth. This can make certain individuals more prone to the development of osteoporosis at a younger age.
So in adults, after full skeletal growth has been achieved, a healthy balance is struck through bone turnover whereby damaged bone is replaced with new bone.

Osteoporosis is generally a disease of the elderly. In older women, due to a post-menopausal oestrogen deficiency, and in older men, due to androgen deficiency, bone turnover is disturbed in favour of excess resorption.

Vitamin D deficiency is more common in the elderly. Typically it impairs calcium absorption leading to secondary hyperparathyroidism, which also increases bone loss. Supplementation of the diet with calcium and vitamin D is recommended in general for people who are considered to be at risk of osteoporosis.

Preserving normal bone structure and reducing fracture risk are the key treatment options. The aim is to normalize the balance between bone loss and bone formation.

There are a number of mechanisms and therapeutic approaches to preserving bone function and density.
There are good drugs for treating osteoporosis. Drugs that strengthen bone include the anti-resorptive agents, such as hormone replacement agents (oestrogen and raloxifene) and the bisphosphonates, effectively prevent bone loss in postmenopausal women and men with osteoporosis. Anabolic agents, such as teriparatide and strontium ranelate, increase bone formation in these patients. These therapies work well but the effectiveness of treatment of osteoporosis is limited by patient adherence. Compliance with therapies is low in osteoporosis indicating that although there are many non-drug related reasons for non-compliance that there may be a medical need for more tolerable agents. Some patients may find individual agents more tolerable than others for a variety of reasons.
A novel approach to modulating bone resorption is through prevention of osteoclast activation. The activation of osteoclast cells triggering bone resorption is a central process in osteoporosis pathogenesis. This leads to an increased risk of bone fragility and fractures.
The receptor activator of nuclear factor-kappa B ligand (RANKL) on osteoclast precursors through binding to RANK is a pivotal regulator of osteoclast activity.
Osteoprotegrin (OPG) is a natural inhibitor of RANKL and helps regulate bone loss in the healthy state through the osteoclast activation pathway. However, when OPG is deficient the balance in bone turnover is awry, osteoclasts are activated and there is rapid bone loss. OPG is depleted in oestrogen deficiency, hyperparathyroidism and other conditions that promote bone resorption.

The RANKL Inhibitors are a new class of drugs that were developed to mimic OPG action, but target osteoclast activation more selectively than OPG. The first RANKL inhibitor, Denosumab, is a highly specific monoclonal antibody, biologic medicine, which binds to RANKL. It is administered as a 6-monthly subcutaneous injection as it is slowly metabolized.


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