83 In open label studies alendronate blunted the ability of teriparatide to

83 in open label studies alendronate blunted the

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83 In open-label studies, alendronate blunted the ability of teriparatide to increase BMD when the therapies were combined, 79 whereas in another study patients that had been previously treated with risedronate showed better improvement in BMD in response to teriparatide than patients that had previously been on alendronate therapy. 84 Randomized trials that examined the effect of combining PTH (1–84) itself with alendronate showed no synergistic effects on BMD at multiple sites. 84 However, if patients that had taken PTH (1–84) for 1 year were randomized to alendronate, they showed significant improvement in BMD. 84 Recently, a pilot randomized study examining the effect of concurrent or sequential administration of ibandronate with just 6 months PTH (1–84) demonstrated overall improvements in BMD but with a blunting of the anabolic effect of PTH. 85 Taken together, these data demonstrate that more studies are needed to clarify the most appropriate combination therapies to best exploit the anabolic potential of intermittent PTH-based therapies. The exact mechanism leading to the anabolic effect of teriparatide is not fully understood, but it has been shown to enhance osteoblast formation from its circulating precursors and prevent osteoblast apoptosis. 85,86 Despite its anabolic effect on bone, the use of teriparatide in osteoporosis remains guarded due to the associated high incidence of osteosarcoma in animal models; however, a long-term clinical study has so far found no association between osteosarcoma and teriparatide in humans. 87,88 Teriparatide is approved by the FDA as an anabolic treatment for osteoporosis in individuals at high risk of fracture. The potential to reduce the frequency of administration (and hence increase compliance) is a possibility given that a single 20 µ g dose of teriparatide is effective for up to 1 week. 89 In addition, alternative delivery systems (such as intranasal and transdermal) are currently being tested, and an implantable wirelessly controlled drug delivery device for teriparatide is in clinical trial for postmenopausal osteoporosis. 90,91 Strontium ranelate Divalent strontium ions have the capacity to substitute for calcium within bone without adversely affecting mineralization. 92 Strontium ranelate (Protelos ® ) increases BMD and reduces the risk of vertebral and nonvertebral fractures. 93–95 The protective effect of strontium ranelate results from an uncoupling of bone formation from resorption, thereby increasing functional osteoblasts whilst simultaneously decreasing osteoclasts. 96 The mechanism by which strontium has these concomitant effects is thought to involve, at least in part, the calcium sensing receptor (CaSR) (Figure 3), the receptor responsible for mediating cellular responses to extracellular calcium ions.
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