Bisphophonates and SERMs

While doctors most often use expensive medications such as the bisphophonates risedronate (Actonel), ibandronate (Boniva) and alendronate (Fosamax) or the Selective Estrogen Receptor Modulator (SERM) raloxifene (Evista), for treatment or prevention of osteoporosis, their $1,000 per year cost makes them extremely expensive for the limited benefits they give.  These medications should be reserved for those failing on the above recommended strategies and suffering from a fracture or found to have a T-score under -2.5 despite other my other recommended treatment efforts.   Such patients are extremely rare. Bisphosphonates helps lower the risk of breast cancer slightly, but the benefit is not cost-effective.  Risedronate has also been found to help osteoarthritis of the knee.

Most of the research on these heavily prescribed drugs has been carefully biased by big-name academic researchers trying to please wealthy drug companies.  Control groups are put on sugar pills instead of being put on a calcium-magnesium-vitamin D-vitamin K combination or one or two of these inexpensive supplements are used at unreasonably low doses to give the impression of fairness.  It is very unlikely that these expensive medications would be found of much added value if they were compared to standard good health practices, which would include the above combination.  

Actonel may have fewer side-effects than Fosamax.  Evista doubles the frequency of clotting problems, i.e., thromboembolisms.  Thromboembolism can and does cause many deaths in the U.S. each and every year.

Stomach: Protects Against Alendronate Damage: Protective effect of melatonin and omeprazole against alendronate-induced gastric damage in rats. Each did equally well with pretreatment and attributed to anti-oxidant effect. Sener G, et al. Marmara University, Istanbul, Turkey. Dig Dis Sci. 2005 Aug;50(8):1506-12. 

Evista Giant Waste of Money for Osteoporosis: Evista (raloxifene) is $84/mo at Walgreens.com (9/27/04) or $1008 per year. In the industry sponsored raloxifene study of 7705 women with osteoporosis advertised by the company in the 2004 Physician's Desk Reference, after 3 years only 4.3% of elderly women had vertebral fractures with placebo vs. 1.9% with placebo. All received 500 mg of calcium and 400-600 IU of vitamin D. In 3 DB PC studies for prevention of osteo, That's $125,000 and taking pills 40,000 times and filling 1,333 prescriptions to prevent one vertebral fracture.  If it were your money and your time, would you do it?  Even this miniscule benefit is bogus, since taking one vitamin D 1000 IU capsule instead of a 400 IU pill, 1000 mg of calcium instead of 500 mg, and taking one vitamin K tablet daily would have considerably increased the benefits to the control group.  

Unethical Industry-Funded Chinese Study Showed Evista Helped Bones: In a 1-year DB PC study of 204 postmenopausal Chinese women with osteoporosis, raloxifene (60 mg/day) increased lumbar spine BMD by 3.3% vs. 1% for placebo (P < 0.001), hip BMD by 1.4% vs. a decrease of 0.9% for placebo. There were no new vertebral fractures with raloxifene vs. 5 for placebo. Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis: a multi-center, randomized, placebo-controlled clinical trial. Liu JL, Zhu HM, et al. Beijing, China. Chin Med J (Engl). 2004 Jul;117(7):1029-35. Ed: This apparently industry-funded study intentionally unethically deprived the control group of vitamin D, vitamin K, calcium, and magnesium in order to make Evista look good.  If the control group had taken the supplements, it is unlikely any of them would have suffered fractures.  Anything to make money. 

Vitamin K Did Very Well at Preventing Vertebral Fractures; As Well as a Bisphosphonate: In a 2-year DB study, 396 postmenopausal women ages 50 to 75 were divided into six equal groups: hormone replacement therapy, etidronate, eel calcitonin, alfacalcidol, vitamin K-2, or no treatment. The 2-year mean changes in bone mineral density were 2.0% for hormone replacement therapy, -0.5% for etidronate, 1.6% for calcitonin, -3.6% for alfacalcidol, -1.9% for vitamin K, and -3.3% for control. Vertebral fractures occurred in 26% of control patients. Compared with controls, the relative risks of vertebral fracture were 0.35 for hormone replacement therapy, 0.40 for etidronate, 0.41  for calcitonin, 0.56  for alfacalcidol, and 0.44 for vitamin K. Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfacalcidol, and vitamin K in postmenopausal women with osteoporosis: The Yamaguchi Osteoporosis Prevention Study. Ishida Y, Kawai S., Yamaguchi University, Japan. Am J Med. 2004 Oct 15;117(8):549-55.

Bisphosphonate Alendronate (Fosamax) Continued for 10 Years, But Benefit Questionable: In 10 year follow-up of 227 women assigned to receive 5 or 10 mg of alendronate orally or placebo each day, the mean cumulative increase after 10 years in women taking 10 mg daily was 13.7%. There were no significant group differences in new vertebral fractures! The 3 groups also had similar safety profiles. Alendronate therapy continued to be effective over 10 years in these postmenopausal women, as estimated by both BMD measurements and effects on bone remodeling. Ten Years' Experience With Alendronate for Osteoporosis in Postmenopausal Women. The Alendronate Phase III Osteoporosis Treatment Study Group. Obstet Gynecol Surv. 2004 Aug;59(8):597-598. Ed: At $10,000 per patient, this is a drug company’s dream. If you wonder why Medicare is running out of money, here is a big reason. Millions of women are being given this and similar medicines at the cost of billions of dollars every year with absolutely no evidence that this is better than a combination of vitamin D 800 IU, vitamin K 0.5 mg, and calcium 1,000 mg/day which costs only $36 per patient per year with many added health benefits obtained besides just better bones.

Highly Biased Study Promotes Alendronate (Fosamax) for All Post-Menopausal Women: In a 6-year, industry-funded, poor-designed study of 1609 healthy, early postmenopausal women, fractures occurred in 11.5, 10.3, and 8.9% of women taking placebo, 2.5 mg alendronate, or 5 mg alendronate daily. The authors claimed that alendronate is "an effective and promising strategy for the prevention of postmenopausal osteoporosis." Prevention of postmenopausal bone loss: six-year results from the early postmenopausal intervention cohort study. McClung MR, Wasnich RD, Hosking DJ, Christiansen C, Ravn P, Wu M, Mantz AM, Yates J, Ross PD, Santora AC 2nd. Portland, Oregon. J Clin Endocrinol Metab. 2004 Oct;89(10):4879-85. Ed: This is another extremely biased study designed to make sure the sponsor’s medication looks better. Forty women had to take Fosamax for 6 years to prevent one fracture at a cost of $230,000 of medication per fracture prevented. If the controls had been given vitamin D 1000 IU, vitamin K 500 mcg. and calcium 1000 mg/day, it is virtually certain the controls would have done as well or better with many other added health benefits (less cancer, less heart disease, etc.) and an annual cost of $36 vs. $1000.

Alendronate Minimally Better Than Controls: In a 4.2 year DB PC study of 4432 women ages 54-81 years with a femoral neck BMD of 0.68 g/cm² or less but no vertebral fracture and all received at least 500 mg/d calcium and 250 IU vitamin D, those on 5 mg/d of alendronate sodium for 2 years followed by 10 mg/d had increased BMD at all sites studied (P<.001) and reduced clinical fractures from 312 in the placebo group to 272 in the intervention group, but not significantly so (14% reduction). Alendronate reduced clinical fractures by 36% in women with baseline osteoporosis at the femoral neck (>2.5 SDs below the normal young adult mean; RH, 0.64; treatment-control difference, 6.5%; number needed to treat [NNT], 15), but there was no significant reduction among those with higher BMD (RH, 1.08). Alendronate decreased the risk of radiographic vertebral fractures by 44% but the treatment-control difference was only 1.7%; NNT, 60). Effect of Alendronate on Risk of Fracture in Women With Low Bone Density but Without Vertebral Fractures. SR. Cummings; DM. Black, et al. Fracture Intervention Trial Research Group. JAMA. 1998;280:2077-2082. Ed: It is virtually certain that if the controls had received adequate doses of calcium, vitamin D, and vitamin K, that they would have done better than alendronate.

Alendronate Minor Benefit For Women Not Quite Osteoporitic: In a 3.8 year DB PC study of 3737 women ages 55-80 years with BMD T scores between -1.6 and -2.5, alendronate at 5 mg/d for 2 years and 10 mg/d thereafter reduced the risk of clinical vertebral fractures by 60%, but the risk of such fractures was low in either group unless the women had already had vertebral fractures. Effect of alendronate on vertebral fracture risk in women with bone mineral density T scores of-1.6 to -2.5 at the femoral neck: the Fracture Intervention Trial. Quandt SA, Thompson DE, et al. Wake Forest University. Mayo Clin Proc. 2005 Mar;80(3):343-9.

Weekly Alendronate (Fosamax) Did Better than Raloxifene (Evista): In a 12-month 456-patient DB PC study of postmenopausal women with osteoporosis with once-weekly alendronate 70 mg vs. raloxifene 60 mg daily, the weekly alendronate caused a greater increase in lumbar spine BMD (4.4%, P < 0.001) than raloxifene (1.9%). Total hip and trochanter BMD increases were also significantly greater (P </=0.001). Side-effects were similar. Luckey M, Kagan R, Greenspan S, Bone H, Kiel RD, Simon J, Sackarowitz J, Palmisano J, Chen E, Petruschke RA, De Papp AE. Beth Israel Deaconess, George Washington University, and Merck & Co. Menopause. 2004;11(4):405-415

Raloxifene (Evista) Has Benefit for Chinese Women in Biased Research: In a 1-year DB PC study of 204 postmenopausal women with osteoporosis in China, lumbar spine BMD increased in both groups with a mean increase of (3.3)% in the raloxifene group and (1.0)% in the placebo group (P < 0.001). There was a mean increase in total hip BMD of (1.4 )% in the raloxifene group and a mean decrease of (0.9)% in the placebo group (P < 0.001). No subject in the raloxifene group had a new vertebral fracture and 5 placebo subjects had new fractures (P > 0.05) Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis: a multi-center, randomized, placebo-controlled clinical trial. Liu JL, Zhu HM, Huang QR, Zhang ZL, Li HL, Qin YJ, Zhang Y, Wei DL, Lu JH, Liu H, Chen XP, Liu YJ, Ekangaki A, Zheng YM, Diez-Perez A, Harper K. General Hospital of the People's Liberation Army, Beijing. Chin Med J (Engl). 2004 Jul;117(7):1029-35. Ed: Note that women were not given vitamins D and K or calcium and were not placed on low salt diets. This would have been a major benefit and probably would have erased the superiority of the medication. The multinational drug industry has a powerful influence in China, a country even more corrupt than our own.

Raloxifene (Evista) No Help for Hip, Wrist Fractures; Only Spine; Did Reduce Breast Cancer: In the huge 3-year, 7700-postmenopausal woman DB PC "MORE" study, researchers found no impact on hip or other nonvertebral fractures from raloxifene, but there was a 75% decrease in invasive breast cancer and an increase in spinal bone density. Side-effects include leg cramps, clotting, arthralgias, rhinitis, headaches, and hot flashes. JAMA 1999;281:2189-97. Ed: Research suggests that calcium and vitamin D also cause major decreases in breast cancer.

Raloxifene (Evista) Reduces Breast Cancer But Cost Extremely High: Mammograms were routinely done in 10,575 women in DB PC trials. The 7,108 on raloxifene in 19,381 person-years had 10 cases of invasive breast cancer (0.52 per 1000 person-years). For placebo, there was 1.62 per 1000 person-years. (PDR 2004 Evista Insert). At $1000 per year cost, this is roughly $900,000 per case of invasive cancer prevented. Since breast cancer kills roughly 50% of its victims, the cost per life saved would be $1,800,000, a very high figure. The fracture-prevention benefit of raloxifene to women taking vitamin K in addition of adequate doses of vitamin D (800-1000 IU/day) and calcium (1000 mg/day) has never been determined and there may be no benefit at all.

Raloxifene Doubles Thromboembolisms: In the 3.3-year MORE study of 7,705 postmenopausal women with osteoporosis, raloxifene 60 mg/d or 120 mg/d was associated with an increased risk for venous thromboembolism (relative risk [RR] 2.1). The excess event rate was 1.8 per 1,000 woman-years affecting 1 in every 170 women during the study. The thromboembolism occurred during the first two years. Raloxifene did not increase cataracts (RR 0.9), gallbladder disease (RR 1.0), endometrial hyperplasia (RR 1.3), or endometrial cancer (RR 0.9). Safety and adverse effects associated with raloxifene: multiple outcomes of raloxifene evaluation. Grady D, Ettinger B, Moscarelli E, Plouffe L Jr, Sarkar S, Ciaccia A, Cummings S. University of California, San Francisco, California. Obstet Gynecol. 2004 Oct;104(4):837-44

Bisphosphonate Ibandronate (Boniva) Very Slight Benefit for Osteoporosis in Biased University of Washington Study: In a massive 2964 postmenopausal women DB PC study for 3 years of daily (2.5 mg) or intermittently (20 mg every other day for 12 doses every 3 months) ibandronate, new vertebral fractures were reduced with daily (4.7%) and intermittent ibandronate (4.9%), vs. placebo (9.6%)(p = 0.0006). Significant and progressive increases in lumbar spine (6.5%, 5.7%, and 1.3% for daily ibandronate, intermittent ibandronate, and placebo, respectively, at 3 years) and hip BMD, normalization of bone turnover, and significantly less height loss than in the placebo group were also observed for both ibandronate regimens. The incidence of nonvertebral fractures was similar between the ibandronate and placebo groups after 3 years (9.1%, 8.9%, and 8.2% in the daily, intermittent, and placebo groups. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. Chesnut III CH, Skag A, Christiansen C, Recker R, Stakkestad JA, Hoiseth A, Felsenberg D, Huss H, Gilbride J, Schimmer RC, Delmas PD. Osteoporosis Research Group, University of Washington. J Bone Miner Res. 2004 Aug;19(8):1241-9. Ed: This massive study study means doctors must treat 20 patients for 3 years to prevent one vertebral fracture with just the medications costing $60,000 per vertebral fracture prevented! The University of Washington researchers were careful not to give women calcium, vitamin D, and vitamin K because these might have eliminated even this small effect.

Raloxifene Very Minor Beneficial Effect on Cognitive Impairment: In the 3-year DB PC MORE study of 5,386 postmenopausal women with osteoporosis, 3.4% developed mild cognitive impairment, and 1.0% dementia. Compared to those taking placebo, women receiving 120 mg/day of raloxifene had a 33% lower risk of mild cognitive impairment (relative risk, 0.67; 95% confidence interval [CI], 0.46-0.98) and somewhat lower risks of Alzheimer's disease (relative risk=0.52, not significant) and any cognitive impairment (relative risk=0.73, not significant). Risks of mild cognitive impairment, Alzheimer's disease, and any impairment were not significantly different in the group taking 60 mg/day of raloxifene. Effect of Raloxifene on Prevention of Dementia and Cognitive Impairment in Older Women: The Multiple Outcomes of Raloxifene Evaluation (MORE) Randomized Trial. Yaffe K, Krueger K, et al. University of California, San Francisco. Am J Psychiatry. 2005 Apr;162(4):683-90. Ed: Although 33% sounds like a lot, in fact, so few women in the study developed cognitive impairment tht only the massive size of the study was able to detect the effect.  The size of the effect barely reached the level of statistical significance.  Many less expensive ways are available to lower with risk of cognitive impairment.

Risedronate Helped Knee Osteoarthritis: In a 1-year DB PC study of 284 patients with mild to moderate OA of the medial compartment of the knee, those receiving risedronate at 15 mg showed improvement of the WOMAC index, particularly of physical function, significant improvement of the patient global assessment (P < 0.001), and decreased use of walking aids relative to patients receiving the placebo (P = 0.009). A trend towards less joint-space narrowing was observed in the group receiving 15 mg risedronate. Eight percent of patients on placebo and 4% on 5 mg risedronate had detectable progression of disease (joint-space width >or= 25% or >or= 0.75 mm) versus 1% on 15 mg risedronate (P = 0.067). Risedronate (15 mg) significantly reduced markers of cartilage degradation and bone resorption. Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Spector TD, Conaghan PG, et al. St Thomas' Hospital, London, UK. Arthritis Res Ther. 2005;7(3):R625-33.

Thomas E. Radecki, M.D., J.D.

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