Bisphosphonate treatment of osteoporosis
Section snippets
Mechanism of action
As mentioned above, bisphosphonates are considered “antiresorptive” drugs because they reduce bone resorption. Non-nitrogen-containing bisphosphonates (such as etidronate and clodronate; see Table 1) produce toxic analogs of adenosine triphosphate that lead to cell death [33]. Nitrogen-containing compounds (such as alendronate, risedronate, ibandronate, and zoledronate; see Table 1) appear to have a different mechanism of action; they work by interfering with protein prenylation [34] through
Clinical trials
Alendronate was the first bisphosphonate approved by the FDA (1995) for use in osteoporosis. It is approved for prevention and treatment of postmenopausal osteoporosis and for treatment of corticosteroid-induced osteoporosis in men and women and treatment of osteoporosis in men [38].
Alendronate is a nitrogen-containing bisphosphonate (Table 1) [39]. The pivotal phase III study with alendronate involved almost 1000 postmenopausal women who were recruited because of low bone mineral density
Clinical trials
Risedronate is a nitrogen-containing bisphosphonate, with the nitrogen contained in a pyridinyl ring [64]. It is approved for the prevention and treatment of postmenopausal osteoporosis and for prevention and treatment of glucocorticoid-induced osteoporosis [65]. Its effectiveness for prevention of vertebral fractures was shown in two pivotal studies of over 3600 women with prevalent vertebral fractures [66], [67]. The primary end point in these trials was the reduction of new vertebral
Clinical trials
The first bisphosphonate to be studied in osteoporosis was etidronate. Given continuously, etidronate may impair mineralization of new bone [77], so an intermittent cyclical regimen (400 mg daily for 14 days every 3 months) was used that was safe and appeared effective in small trials [78], [79], [80]. As is true for other bisphosphonates, etidronate must be taken on an empty stomach (with water only). Etidronate can be taken between meals (2 hours before and 2 hours after eating) or during the
Bisphosphonates in development
A number of other compounds, including olpadronate and neridronate, have seen clinical use outside the United States, but are not available in the United States and are not being pursued for general commercial development.
Ibandronate, 1 mg given intravenously every 3 months to women with postmenopausal osteoporosis, increased BMD but did not reduce the risk of fracture [129]; perhaps the dose was too low or the interval was too long. Oral ibandronate has recently been reported to prevent bone
How do different bisphosphonates compare in efficacy?
There are no head-to-head trials that compare one bisphosphonate with another for treatment of osteoporosis, except for using surrogate markers such as changes in BMD or biochemical markers. It is tempting to look at increases in bone density in different trials; however, the changes in bone density using the same agent in different trials can vary by 20% to 30% [66], [132], [133], [134], and changes in BMD correlate only weakly with reduction in fractures [135], [136]. Based on available data,
How do bisphosphonates compare with other agents in efficacy?
Again, there are no head-to-head trials with fracture end points that compare bisphosphonates with other agents. Bisphosphonates are the only currently approved agents that have been shown to reduce the risk of hip and other nonvertebral fractures [42], [44], [66], [70]. For this reason, bisphosphonates are considered by most authorities to be the treatment of choice for patients who are at risk for a variety of fractures.
How do bisphosphonates compare with each other in tolerability?
Although alendronate seemed well tolerated in clinical trials [53], daily dosing with alendronate appeared to cause esophageal problems (eg, heartburn, pain on swallowing, and so forth) in about 10% of patients. Tolerability problems with daily dosing of risedronate appear infrequent [75]. There have been a number of head-to-head trials of alendronate and risedronate that looked at gastric lesions (with conflicting results) [140], [141]. A few unpublished studies have looked at rechallenge,
General side effects and toxicity
There has also been concern that potent bisphosphonates might turn off remodeling completely, leading to “frozen bone.” There is no evidence that this actually occurs in humans. There are studies that show increased microcracks but preserved biomechanical properties in dogs treated with very high doses of bisphosphonates [144], [145]. Fracture healing does not appear to be a problem with low doses of etidronate [146], alendronate [147], or any of the newer bisphosphonates [148].
Combination of bisphosphonates with other agents
Should bisphosphonates be used in combination with other agents? Several classes of agents have proven effectiveness in reducing osteoporotic vertebral fractures. Although all current agents are antiresorptive drugs, mechanisms of action differ, which offers the possibility that combining two agents might produce greater benefit than would a single agent. Combining a bisphosphonate with calcitonin is probably safe, although data on BMD response is lacking. Several studies have shown greater
Summary
Bisphosphonates represent the agents of choice for most patients with osteoporosis. They are the best studied of all agents for the prevention of bone loss and reduction in fractures. They increase BMD, primarily at the lumbar spine, but also at the proximal femur. In patients who have established osteoporosis, bisphosphonates reduce the risk of vertebral fractures, and are the only agents in prospective trials to reduce the risk of hip fractures and other nonvertebral fractures.
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2021, Journal of Controlled ReleaseCitation Excerpt :Therefore, osteoporosis therapy is beneficial to solve a severe worldwide public health threat. Until now, there are two commonly used drugs toward osteoporosis in clinic with approval of Food and Drug Administration (FDA): bisphosphonates (BPs) [164] and sCT [165]. The applications of BPs have already been discussed in other reviews. [166–171]
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