Combination and sequential therapy for the treatment of Osteoporosis

Published on January 19, 2015   22 min
0:00
Hello, my name is Felicia Cosman. I'm an endocrinologist and medical director of the Clinical Research Center at Helen Hayes Hospital, and professor of medicine at Columbia University College of Physicians and Surgeons. Today, I'll be talking about the role of combination anabolic and antiresorptive therapy for the treatment of severe osteoporosis Here are my disclosures.
0:28
The majority of pharmacologic agents for osteoporosis are antiresorptive medications, which act primarily by inhibiting osteoclast number, lifespan, and/or activity, and thereby reducing the rate of bone resorption. Antiresorptive medications include all of these listed here. But the most commonly used for the treatment of osteoporosis, at least in adults above age 65, are the bisphosphonates, including oral alendronate, risedronate, and ibandronate, the intravenous bisphosphonate zoledronic acid, and the RANK ligand inhibitor denosumab. There is only one class of anabolic therapy with two agents that are both parathyroid hormone analogues, the intact PTH 1-84 molecule and the amino terminal PTH peptide teriparatide. With anabolic agents, the mechanism of action is a direct stimulation of osteoblast number, activation, and/or function leading to a rapid increase in bone formation and a subsequent stimulation of osteoclast activity and overall bone remodeling with a persistent net increment in bone formation.
1:43
At the current time, we do not have any guidelines, or really even any consensus of opinion, about which patients should receive anabolic medication as first line treatment instead of antiresorptive medication. Certainly I would argue that for the highest risk patients, such as those with recent fractures within the preceding year, or those with a history of multiple prior fractures, these patients would be appropriate candidates in whom to use anabolic medication, and perhaps, as I hope to illustrate in this talk today, maybe even combination therapy for these very high risk individuals. Unfortunately, many doctors are not choosing to use anabolic therapy until patients have already had a sub-optimal response to their first osteoporosis medication and antiresorptive treatment. This is sometimes mandated by payer limitations, but also is often a lack of understanding, that we do see a different response than to anabolic therapy in patients who have already been treated with potent antiresorptive medication. And then in fact, in this group of patients, we really have no fracture efficacy data at all.
2:52
Although a combination therapy approach utilizing concomitant anabolic and antiresorptive medication could theoretically result in an additive or perhaps even synergistic improvement in bone density and bone strength. Combination therapy is almost never utilized. In part, this is related to additional cost and potential for adverse effects with these two agents. And very importantly, we have no fracture endpoint data with any combination therapy studies. But it is also related to the mistaken belief that combination therapy provides no benefit to BMD, and might even be inferior to teriparatide or PTH monotherapy. This misinterpretation of the data is based on results of the so-called PaTH trial, where 238 women were randomized to receive PTH alone, alendronate alone, or a combination treatment.
3:48
The DXA BMD results from this study showed that the PTH alendronate combination group showed no greater improvement in spine BMD compared to PTH monotherapy. That was a disappointment. Because a superior gain was expected. However, the combination treatment did produce a superior effect on hip and radius BMD.
4:13
So clearly, the potential benefits of combination therapy should not be discounted by results of this one study. Furthermore, there are a number of caveats that need to be considered when interpreting data from this trial. The daily alendronate dose administered in the PaTH study could have a small potential inhibitory effect on osteoblast function. Data from PTH alendronate combination should not be assumed to reflect the effects of other PTH antiresorptive combinations. Furthermore, the PTH treatment used in this combination trial, the full 1-84 PTH molecule, may not produce an identical effect to the inner terminal paratide peptide. And finally, this study was performed in treatment naive women. And these results may not apply to patients who have already been established on prior potent antiresorptive medications.
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Combination and sequential therapy for the treatment of Osteoporosis

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