New and emerging treatments for osteoporosis

Published on March 31, 2016   44 min

Other Talks in the Series: Bone in Health and Disease

Other Talks in the Series: Small Molecule Drug Discovery

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E. MICHAEL LEWIECKI: Hello, this is Mike Lewiecki. I'm talking to you today about new and emerging treatments for osteoporosis. I'm director of New Mexico Clinical Research and Osteoporosis Center in Albuquerque, New Mexico, and on the faculty of the University of New Mexico School of Medicine.
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This is my disclosure. I'll be talking about limitations of current therapy
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for osteoporosis, new data on available medications for osteoporosis, recently approved treatments, novel treatments for intervention, investigational agents, new delivery systems, and strategies to address unmet needs in the care of osteoporosis. These are approved medications for osteoporosis
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treatment and prevention. We can classify drugs at the present time into those that reduce bone remodeling, typically called antiresorptives, and those that increase bone remodeling, called anabolics, or osteoanabolics. As you can see, most drugs fall into the antiresorptive category. The biggest group within that category is the bisphosphonates, alendronate, risedronate, ibandronate, and zoledronic acid. We have a selective estrogen receptor modulator, raloxifene, a rank ligand inhibitor, denosumab, estrogen, nasal calcitonin, and a combination of estrogen and a SERM, with conjugated estrogens and bazedoxifene. This is called a tissue selective estrogen complex. On the anabolic side, we have one drug, parathyroid hormone in the form of teriparatide, which is PTH 1 to 34. Strontium ranelate is a drug that works by unclear mechanisms and has sometimes been said to have both antiresorptive and anabolic properties. The current treatments that we have are pretty good.
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The best fracture risk reduction we have in randomized controlled clinical trials are a vertebral fracture relative risk reduction of 70% with zoledronic acid, nonvertebral fracture relative risk reduction of 53% with teriparatide, and hip fracture relative risk reduction of 51% with alendronate. These are pretty good, but we could do better. There is coupling of bone resorption and bone formation so that the antiresorptive drugs that we currently have also reduce bone information, which seems to limit their effects on bone mineral density. And anabolic drugs, despite increasing bone formation, also increase bone resorption, which limits their activity as well. We have complex and inconvenient methods of administration. This is a particular concern for the oral bisphosphonates, which must be taken fasting with plain water. Patients must abstain from eating or drinking or taking other medications for 30 to 60 minutes and must be upright during that time. A big problem with many patients are side effects, and more importantly, fear of side effects. There are uncertainties on how long to treat with the bisphosphonates. And it confuses patients and physicians. There are issues with cost and insurance coverage. And despite having pretty good medications, osteoporosis remains a disease that's underdiagnosed and undertreated. On the left, you see an image of normal trabecular bone.
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It has a robust structure with thick trabecular struts and optimal spacing between these. On the right, you see a bone that represents osteoporotic trabecular bone, as you might see in the spine. The question arises whether it's possible, at least in theory, to convert an osteoporotic product back to a normal trabecular microarchitecture, which would be the holy grail of osteoporosis therapy. Thus far, we're not able to do this, but with new and emerging drugs, perhaps we can come closer to doing this. It's important to understand the bone remodeling process,
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because post-menopausal osteoporosis is a disorder of bone remodeling. And all the current therapeutic agents that we have modulate bone remodeling in one fashion or another. At the center of this graphic, you see a cell which represents the osteocyte, which is considered to be a mechanostat and master regulator of the bone remodeling process. If we begin on the left hand side of the graphic with bone in the resting phase, you see bone lining cells, coating the bone. In response to an activating process which might, for example, be a microfracture, these lining cells split apart. Multi-nucleated large cells called osteoclasts attach to this bone and resorb the bone. Following this, there's a reversal phase where cells come in and clean up the debris left over by the bone resorption process, followed by osteoblasts-producing osteoid, which subsequently becomes mineralized. If this process is in a complete state of balance, just as much bone is replaced as is taken away, and bone mineral density remains stable. With post-menopausal osteoporosis, resorption is an excess of formation. There's a net loss of bone with each remodeling cycle. And ultimately this may lead to osteoporosis. There are multiple signaling molecules and enzymes, including rank ligand, OPG or osteoprotegerin, sclerostin, DKK1, estrogen, parathyroid hormone, serotonin, nitric oxide, cathepsin K, and many more. Each one of these signaling molecules and enzymes represents a potential target for therapeutic intervention. There are some very interesting, new, and emerging
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New and emerging treatments for osteoporosis

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