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Researchers know that bisphosphonates have an incredible affinity for bone, binding to calcium and building up in the mineralized bone matrix, so that it's more resistant to breakdown by osteoclasts. Still, it's not perfectly clear how they work. It is suspected that bisphosphonates affect signaling between osteoblasts and osteoclasts. Some in vitro studies have suggested that bisphosphonates may initiate macrophage death, thereby also overcoming their deleterious effects on osteoblasts. Macrophages are found on osteoblasts, and are thought to have some responsibility for excessive bone resorption, namely by impeding the activity and survival of osteoblasts. Researchers found that adding bisphosphonates to co-cultures of osteoblasts and macrophages blocked the adverse effects of macrophages on osteoblasts. Bisphosphonates increased the number of osteoblasts by 82%, and reduced the number of macrophages. Also, control co-cultures revealed fewer osteoblasts than the treated ones.
Because of various modes of action observed in studies, bisphosphonates have been classified into two groups. Bisphosphonates that closely resemble pyrophosphate-a normal by-product of human metabolism (such as clodronate and etidronate) are incorporated into adenosine triphosphate (ATP) analogues, which create compounds that are believed to build up and lead to osteoclast death. The newest generation of bisphosphonates, which contain nitrogen (such as pamidronate, alendronate, risedronate and ibandronate), are believed to inhibit protein prenylation (post-translational modification) within the mevalonate pathway. The mevalonate pathway is responsible for the biosynthesis of cholesterol, other sterols and isoprenoid lipids. Isoprenoid lipids are key in the prenylation of intracellular signaling proteins (GTPases) that, when activated, regulate a number of processes, including osteoclast activity. It's believed that by impeding the function of these regulatory proteins, bisphosphonates result in blocking osteoclast functioning and causing apoptosis.
Weighing pros & cons
Besides attempting to unravel how bisphosphonates work, researchers are also aiming to address their benefits and risks. The fact that bisphosphonates bind so strongly to bone and confine their activity to the skeleton has made clinicians confident about their safety profile. The positive aspect of bisphosphonates is that, because their effects are limited to bones, adverse effects elsewhere in other body tissues and organs are minimal. However, thanks to their antiresorptive properties, bisphosphonates have been accused of substantially reducing bone turnover, in turn, impairing microdamage repair and causing increased bone mineralization, which can increase bone fragility. Thus, it's important to weigh how, "Osteoporosis therapies may also affect bone architecture by causing the redistribution of bone structure. Restructuring of bone during treatment may change bone fragility, even in the absence of drug effects on bone mineral density (BMD)."
Bisphosphonates also have some side effects, regardless of their narrow target of action. The most commonly reported side effects of oral bisphosphonates are gastrointestinal complications, such as esophagitis, gastritis and diarrhea. Intravenous delivery of bisphosphonates is being examined as a way to sidestep gastrointestinal adverse effects for those who cannot tolerate oral bisphosphonates, as well as a strategy to reduce dosing frequency significantly. There are adverse effects related to intravenous administration too, such as iritis (inflammatory eye disorder), muscle aches and fever.
Studies are attempting to elucidate how bisphosphonates work best, the question focusing on delivery modes (oral versus intravenous) and dosing amount and frequency. While some research has looked at intermittent dosing, given every few weeks or months, the latest findings reported in the New England Journal of Medicine suggest that just one annual injection of the bisphosphonate, Zometa (zoledronic acid), boosts bone mineral density as well as more frequently dosed oral bisphosphonates. In the study led by a New Zealand team of scientists, 351 postmenopausal women with low bone mineral density were randomized into five different treatment regimen groups: 0.25 milligrams, 0.5 milligrams, or 1 milligram given every three months; a 2-milligram dose every six months; or a single 4-milligram dose; or an inactive placebo. Increases in bone mineral density were reported among all Zometa-treated patients, which were comparable to increases associated with a daily regimen of any of the three oral bisphosphonates: Actonel, Fosamax and Aredia. Larger studies with a 5 milligram dose of Zometa are underway, one involving over 8,000 men and postmenopausal women with osteoporosis, while another includes about 3,000 men and postmenopausal women.
Another question being investigated is whether bisphosphonates are preferable to other treatments for the purpose of preventive therapy in high-risk groups. Some studies have debated whether bisphosphonate therapy is appropriate for patients under 60 with osteopenia (low bone density) without fractures. Generally, bisphosphonates have been indicated for individuals with established osteoporosis or at high risk of the disease. A large UK study called the Early Postmenopausal Intervention Cohort Study Group weighed bisphophonates against hormone replacement therapy (HRT). Investigators looked at the effect of 2.5 versus 5 milligrams of alendronate per day or placebo on bone mineral density in 1,174 postmenopausal women under the age of 60. Also, 435 more women were randomized to receive alendronate, a placebo or combination estrogen-progestin therapy. Results showed that controls lost bone mineral density at all measured sites. Contrarily, women receiving 5 milligrams of alendronate daily had an average increase in bone mineral density of 3.5% at the lumbar spine, 1.9% at the hip and 0.7% for the total body. Women treated with 2.5 milligrams of alendronate daily had smaller increases in bone mineral density. And the estrogen-progestin combination showed a 1% to 2% better response rate than a 5-milligram dose of alendronate. While the study's authors concluded that bisphosphonates were comparable to hormone replacement therapy, others argue that HRT is still the best mode of preventive therapy in postmenopausal women because of additional beneficial effects on other organ systems, and not just bones.
Finally, researchers are still delving further into the question of how appropriate bisphosphonates are for treating osteoporosis in men, as the majority of studies have focused on women. It remains to be seen whether they work as well in men as they do in women, although clinical experience would suggest that's the case. Also, some research now demonstrates that bisphosphonates positively affect bone mineral density in men with idiopathic or secondary osteoporosis.[23-24] Preliminary data from a large, placebo-controlled trial of alendronate in men with osteoporosis also suggests a positive effect on bone mineral density.
1. Greenspan SL, et al. Bisphosphonates: Safety and Efficacy in the Treatment and prevention of Osteoporosis. Am Fam Physician 2000;61:2731-6.