The action of bisphosphonates is not fully understood, and their long term effects are unknown. What is known is that they effectively poison and kill bone remodelling cells. One hundred and fifty years ago they were used for making soap and de-scaling boilers. In humans they permanently adhere to the surface of bone, particularly on sites where there is active bone turnover. The cells that reabsorb old or damaged bone (osteoclasts) quite literally swallow a dose of the drug when resorbing the bone. Once inside the osteoclast cell the bisphosphonate poisons a key enzyme which switches off the cell’s ability to function and causes it to die. For a time the cells that rebuild bone (osteoblasts) will continue to function – hence the increase in bone density observed with the use of the drugs – but they eventually die as well, as they require the action of osteoclast cells to stimulate their action. Thus although bisphosphonates may favourably influence bone density loss, there are concerns that because their mechanism of action suppresses the bone remodelling process long term use may result in brittle bones that are prone to fracture.
• New evidence links the bisphosphonates with increased micro-fracture, osteonecrosis (bone death) of the jaw, and spontaneous fractures displaying delayed healing. i ii
• Bisphosphonates have an indefinite half-life of at least 10 years duration so the effect of the drug continues for better or worse once stopped. The amount of drug within the bone will accumulate with use thus continuing its effect for better or worse. There is no known method of removing the medication from the bones. iii
• Bisphosphonates can have very unpleasant side-effects. The gastro-intestinal side-effects have been well documented. A lesser known side-effect is now evident. Hundreds of women using Fosamax and Actonel report on patient websites that they are experiencing chronic, often severe, joint and bone pain, swelling of ankles and feet, muscles cramping and stiffness, and difficulty walking. A 2005 Serious Adverse Events report from the U.S. Food and Drug Administration describes Fosamax-related bone joint and muscle pain as ‘severe,’ ‘extreme,’ ‘disabling,’ or ‘incapacitating.’ “Many patients were unable to walk, climb stairs, or perform usual activities. Some became bedridden, and others required walkers, crutches, or wheelchairs.” They caution that “underreporting of pain is probably considerable because of its subjective nature and because physicians may attribute pain to osteoporosis.” iv
• The anti-fracture benefit from bisphosphonates is minimal. Studies have found vertebral fracture benefit with Fosmax, Actonel and Boniva where bone density is very low and there has been a previous vertebral fracture, but even then the drug will not benefit the majority in this category who take it. For example, 22 older women in this category would need to take Fosamax for three years to prevent one vertebral fracture discernible by X-ray in one of them. v Read more…
• Most vertebral fractures are asymptomatic. Hip wrist and rib fractures are more serious, more painful, and more incapacitating than vertebral fractures. A recent review of the intention to treat data for a range of osteoporosis treatments from 11 randomised clinical trials of at least 3 years duration failed to find any non-vertebral fracture benefit at all from alendronate. v
• Bisphosphonates should not be used by younger women of child-bearing years. Dr Susan Ott, Associate Professor of Medicine at the University of Washington warns: “Studies in animals show fetal and maternal abnormalities in bones and calcium metabolism, so it is unethical to study this medication in pregnant women or women who might become pregnant while the bisphosphonate is still in the bones.” vi
The Bisphosphonate Family:
Etidronate (Didronel) and clodronate (Bonefos) were the first bisphosphonates. Neither drug is approved in the
US for the treatment of osteoporosis. Etidronate is approved for subsidy in
Alendronate (Fosamax) and risedronate (Actonel) are two second-generation nitrogen-containing bisphosphonates that have been shown in randomized trials to increase bone mineral density in postmenopausal women. Their anti-fracture benefit is minimal (see above) and limited to those with previous vertebral fracture and very low bone density (i.e. established osteoporosis). Even then it will not benefit the majority who take it. Alendronate or risedronate once weekly has been shown to reduce the rate of gastro-intestinal side-effects.
Ibandronate (Boniva) was approved by the Food and Drug Administration (FDA) in 2005 for both the prevention and treatment of postmenopausal osteoporosis at a dose of 2.5 mg daily or 150 mg monthly, Daily ibandronate has not been shown to be effective in preventing non-vertebral (i.e.hip etc.) fracture and only minimally reduces the incidence of vertebral fractures in people with previous vertebral fractures.
Pamidronate (Aredia) is intravenous. Is used to treat women who cannot tolerate oral bisphosphonates; but its efficacy in reducing fracture has not been established. Acute and delayed hypersensitivity reactions can occur with intravenous pamidronate, and its use is contraindicated in patients with vitamin D deficiency, since the drug can cause a precipitous drop in serum calcium levels
Intravenous zoledronate or zoledronic acid (Zometa), is FDA approved for the treatment of malignant hypercalcemia, multiple myeloma, and skeletal metastases. Research is being conducted in
New Zealand on its role in the treatment of Paget’s disease. It is very potent as it can suppress bone resorption and increase bone mineral density in postmenopausal women for as long as one year from a single 4-mg dose. As yet there is no data to evaluate the safety and efficacy of this drug in reducing osteoporotic fracture. The FDA advised dentists and cancer physicians in May 2005 that the labels or package inserts for the injectable bisphosphonate drugs zoledronic acid (Zometa) and pamidronate (Aredia) had been revised to warn about the possibility of osteonecrosis (bone death) of the jaw. viii
New evidence reveals the potential for serious harm from the bisphosphonates Zoledronate (Zometa) and Fosamax. In a study just published in the New England Journal of Medicine, atrial fibrillation, an abnormal heart rhythm that can increase the risk of stroke, was found to be nearly three times more common among women taking Zoledronate or Reclast. Of 3,889 volunteers using the drug and 3,876 given placebo injections, one in 77 Reclast patients developed the problem.The risk of atrial fibrillation was increased 3 fold over placebo. People with atrial fibrillation have reduced cardiac output and are four times more likley to have a stroke and it is more likely to be fatal than in patients without atrial fibrillation. Overall mortality rates are doubled in atrial fibrillation.
Fosamax, used by an estimated 1.8 million American women has been found to have a 50 percent higher risk of the serious heart rhythm in women who took the daily pill. The Fracture Intervention Trial involving 6,459 women, half of whom took Fosamax while the other didn’t, found there appeared to be 50 percent more risk of the serious heart rhythm in women taking the pill than among those who didn’t take it; about half of the 6,459 women took Fosamax, and 47 developed atrial fibrillation, compared to just 31 cases among the other women.
(Black DM et al. Cummings SR et al. N Engl J Med 2007; 356:1809-1822,1895-1896.)
i Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004 May;62(5):527-34.
ii Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY. Severely suppressed bone turnover: a potential complication of alendronate therapy.
J Clin Endocrinol Metab. 2005 Mar;90(3):1294-301.
iii Ott Susan MD “Osteoporosis and Bone Physiology”.
iv Wysowski DK, Chang JT. Alendronate and risedronate: reports of severe bone, joint, and muscle pain. Arch Intern Med. 2005 Feb 14;165(3):346-7.
vBlack, D.M., Cummings, S.R.et al. ‘Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures.’ Lancet 1996;348:1535-41
vi Boonen,S., Laan, RF., Barton I P.,
Watts, NB. Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies Osteoporosis International Published online: 29 June 2005
vii Ott, Susan MD. ibid