Pharmacotherapy of osteoporosis 2

Published on August 31, 2015   41 min
0:04
Let's just turn and discuss denosumab. This is one of the newer treatments for osteoporosis, and its availability grew out of new understanding of the molecular control and modulation of bone remodeling. As you're aware, RANK Ligand is a protein secreted by osteoblasts and osteoclasts. The action to RANK LIGAND is necessary for the activation and proliferation of osteoclasts. Denosumab is a fully human monoclonal antibody that binds to and then activates RANK Ligand. And as a result, denosumab therapy inhibits the differentiation proliferation and activity of osteoclasts and substantially reduces bone resorption. As with bisphosphonates because of a decrease number in activity of osteoclasts, the feedback to osteoblast is reduced, and there is a secondary inhibition bone formation as well. The pharmacokinetics of denosumab, which is given subcutaneously, is complex. One dose of 60 milligrams or greater reduces bone turnover for at least six months. In the studies that have been performed, denosumab therapy results in a progressive increase in bone mineral density over at least the first eight years of therapy, different and greater in magnitude than we observe with bisphosphonate therapy. Because of the pharmacokinetics, once therapy is discontinued, there's a very rapid and complete reversal of the effects on bone remodeling within just a few weeks of missing the every six-month dose.
1:52
These are data looking at the bone density response to denosumab in the extension of the pivotal FREEDOM trial over an interval of eight years, showing progressive increases in bone density in both the lumbar spine and in the total hip region, with changes from baseline being more than 18% in the spine at eight years, and more than 8% in the total hip region at that time point. Again, different patterns and greater magnitude of change than we're seeing with long-term bisphosphonate therapy.
2:30
In the pivotal FREEDOM study, denosumab was shown to be very effective in protecting patients with osteoporosis from fractures. Vertebral fracture risk was reduced by 68%, hip fracture by 40%, non-spine fracture by 20%. Again, as with bisphosphonates, the effect on fracture protection is evident within months of starting therapy and continues as long as treatment is administered. Importantly, as we'll show in the extension of the FREEDOM trial, it appears that non-vertebral fracture risk may actually decrease with long-term therapy. That would be an important observation. The administration of the drug by subcutaneous injection every six months insures adequate adherence to therapy, at least between those doses.
3:22
The data from the pivotal FREEDOM trial are shown here. Again, simply quantifying the 68% reduction in vertebral fracture risk, 20% reduction in non-verterbral fracture risk, and the 40% decrease in hip fracture risk in response to denosumab over the first three years of the study.
3:44
A more detailed look at the effect on vertebral fracture is shown here with the year-by-year effective therapy, although the primary endpoint in the study, for regulatory reasons, was the three-year data with a 68% reduction in vertebral fracture risk. Similar relative risk reductions were observed as early as one year after beginning treatment.
4:08
The cumulative incidence of hip fracture in the placebo group, as shown on top, and the treated group, as shown in white, is demonstrated here, with overall a 40% reduction in risk over the three years of the study. But again, the two curves appear to diverge roughly a year in to the treatment with denosumab.
4:31
These are data from the extension trial of the FREEDOM study, where patients who had completed the first three years of the study were given the opportunity of remaining on denosumab therapy, and will be followed for a total of 10 years. These are the data from the six-year analysis. Shown is the incidence of non-vertebral fracture during years four to six of the study. A lower incidence and was observed during the first three years of the study. This is the first time there's been a suggestion that fracture risk reduction actually improves with longer-term therapy with any of our osteoporosis drugs. The longer-term follow-up in this extension study will help clarify whether that's a real finding or not.
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Pharmacotherapy of osteoporosis 2

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