Whole Body Health Sale

Life Extension Magazine

LE Magazine September 2002

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Possible mechanisms

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.[16]

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.[17] 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.[4]

Weighing pros & cons

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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.

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.[2] 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)."[18]

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.[19] 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.[1]

Knowing more

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.[20] 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.[21] 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.[22]

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.[25]


References

1. Greenspan SL, et al. Bisphosphonates: Safety and Efficacy in the Treatment and prevention of Osteoporosis. Am Fam Physician 2000;61:2731-6.

2. Fleisch HA. Bisphosphonates: preclinical aspects and use in osteoporosis. Ann Med 1997;29:55-62.

3. Minne HW, et al. Osteoporosis-evidence based therapy. Z Gastroenterol 2002 Apr;40 Suppl 1:57-61.

4. Wuster C, et al. Bisphosphonate therapy in osteoporosis. Inhibition of trabecular perforation by aminobisphosphonate. Fortschr Med 1997 Oct 20;115(29):37-42.

5. Russell RG, et al. Bisphosphonates: from the laboratory to the clinic and back again. Bone 1999 Jul;25(1):97-106.

6. Reid IR, et al. Continuous therapy with pamidronate, a potent bisphosphonate, in postmenopausal osteoporosis. J Clin Endocrinol Metab 1994 Dec;79(6):1595-1599.

7. Man Z, et al. New spine and non-spine fractures in 871 women/year treated with oral pamidronate plus calcium and vitamin D supplements. Medicina (B Aires) 1997;57 Suppl 1:32-36.

8. Harris ST, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA 1999 Oct 13;282(14):1344-1352.

9. Black DM, et al. Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996 Dec 7;348(9041):1535-41.

10. Cummings SR, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998 Dec 23-30;280(24):2077-82.

11. Diel IJ, et al. Treatment of metastatic bone disease in breast cancer: bisphosphonates. Clin Breast Cancer 2000 Apr;1(1):43-51.

12. Gangji V, et al. Analgesic effect of intravenous pamidronate on chronic back pain due to osteoporotic vertebral fractures. Clin Rheumatol 1999;18(3):266-267.

13. Sambrook PN. Steroid-induced osteoporosis. Ann Acad Med Singapore 2002 Jan;31(1):48-53.

14. Haderslev KV, et al. Alendronate increases lumbar spine bone mineral density in patients with Crohn's disease. Gastroenterology 2000 Sep;119(3):639-646.

15. Reeves HL, et al. Intravenous bisphosphonate prevents symptomatic osetoporotic vertebral collapse in patients after liver transplantation. Liver Transpl Surg 1998 Sep;4(5):404-409.

16. Evans CE. Bisphosphonates modulate the effect of macrophage-like cells on osteoblast. Int J Biochem Cell Biol 2002 May;34(5):554-63.

17. Martin TJ, et al. Bisphosphonates-mechanisms of action. Aust Prescr 2000;23:130-132.

18. Thiebaud D, et al. Two years' effectiveness of intravenous pamidronate (APD) versus oral fluoride for osteoporosis occurring in the postmenopause. Osteoporos Int 1994;4:76-83.

19. Turner CH. Biomechanics of bone: determinants of skeletal fragility and bone quality. Osteoporos Int 2002;13(2):97-104

20. Reid IR, et al. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. New England Journal of Medicine 2002 Feb 28;346:653-661.

21. Hosking D, et al. Prevention of bone loss with alendronate in postmenopausal women under 60 years of age. Early Postmenopausal Intervention Cohort Study Group. N Engl J Med 1998 Feb 19;338(8):485-92.

22. Ravn P. Bisphosphonates for prevention of postmenopausal osteoporosis. Dan Med Bull 2002 Feb;49(1):1-18.

23. 2nd Joint Meeting of the American Society for Bone and Mineral Research and the International Bone and Mineral Society. San Francisco, California, USA. December 1-6, 1998. Bone 1998;23:S149-708.

24. Heilberg IP, et al. Effect of etidronate treatment on bone mass of male nephrolithiasis patients with idiopathic hypercalciuria and osteopenia. Nephron 1998;79:430-7.

25. Anderson FH, et al. Effect of intermittent cyclical disodium etidronate therapy on bone mineral density in men with vertebral fractures. Age Ageing 1997;26:359-65.


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