Page 1, 2
Long-Term Bisphosphonate Risk-Benefit
Three to five years of bisphosphonate treatment increases bone density by slowing bone resorption and reduces the rate of osteoporotic fractures, but the value of longer treatment is being questioned at the US Food and Drug Administration. The agency recently conducted a systematic review of long-term bisphosphonate efficacy based on three extension trials. Marcea Whitaker, MD, and colleagues summarized the results in a New England Journal of Medicine article (May 31, 2013). The review focused primarily on the Fosamax Fracture Intervention Trial Long-Term Extension (FLEX).
All participants in FLEX had received Fosamax during a previous five-year study that compared Fosamax with placebo. During the extension trial, the FLEX participants either continued to use Fosamax or were given a placebo for an additional 5 years.
Although the initial study showed significantly less osteoporotic fracture incidence in the treatment group (10.6%) compared with the placebo group (21.0%), the extension trial did not: continuous Fosamax treatment had a fracture incidence of 17.7% compared with 16.9% for those who were switched to placebo. Pooled data from all three extension trials in the FDA review showed that " … patients who received continuous bisphosphonate treatment for 6 or more years result in fracture rates ranging from 9.3 to 10.6%, whereas the rate for patients switched to placebo is 8.0 to 8.8%," according to Whitaker et al."These data raise the question of whether continued bisphosphonate therapy imparts additional fracture-prevention benefit, relative to cessation of therapy after 5 years."
Efficacy is only half of the risk-benefit equation. Bisphosphonates have multiple adverse effects. For years, the FDA has been aware of serious but rare adverse events such as atypical femur fractures, osteonecrosis of the jaw, atrial fibrillation, and esophageal cancer. Gastric disorders (i.e., dyspepsia, abdominal pain, nausea, and gastritis) and musculoskeletal pain are more common side effects, according to a 2012 literature review conducted by Pooneh Salari and Mohammed Abdollahi. People's Pharmacy has received multiple reports of muscle aches and spasms, deep bone pain, and back and joint pain from readers who attribute their symptoms to bisphosphonate use. These problems, along with tingling in extremities, fatigue, flu-like feelings, headache, dizziness, skin irritation, and eye damage, are recognized by bisphosphonate manufacturers as possible adverse effects.
At this point, practitioners have no clear guidelines for weighing benefit vs. risk. It does appear, however, that the benefits decrease and the risks increase with long-term bisphosphonate treatment. As bisphosphonate labeling states, "'The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.'"
Reclast side effects incapacitate patient [Web page]. The People's Pharmacy. April 15, 2013. http://www.peoplespharmacy.com/2013/04/15/reclast-side-effects-incapacitate-patient. Accessed November 14, 2013.
Salari P, Abdollahi M. Long term bisphosphonate use in osteoporotic patients; a step forward, two steps back. J Pharm Pharmaceut Sci. 2012;15(2):305–317. Available at www.cspsCanada.org. Accessed November 14, 2013.
Whitaker M, Guo J, Kehoe T, Benson G. Bisphosphonates for osteoporosis – where do we go from here? N Engl J Med. May 31, 2012;366(22):2048–2051.
Breast Hypoplasia and Breast-Feeding
Many women worry that they are not producing enough breast milk to feed their infants; but, for a small percentage of women, that worry is based in reality. To their disappointment and frustration, they are physically unable to produce enough milk to meet their babies' needs. Thyroid disorders, polycystic ovary syndrome, Sjögren's syndrome, and abnormal postpartum bleeding due to retained placenta tissue have all been linked to low milk supply. The most common causes, however, are milk ducts damaged during breast surgery and insufficient milk-producing glandular tissue (IGT).
Insufficient glandular tissue is impossible to diagnose before breast-feeding is attempted. Different-sized breasts (asymmetry), overly large and bulbous areolae, and long, tubelike breasts indicated the possibility of IGT, but not all women with one or more of these characteristics have difficulty producing milk, according to Australian Breastfeeding Association. Breast size, which pertains to fatty rather than glandular tissue, has nothing to do with IGT. The association suggests that women with signs of IGT contact a lactation consultant before giving birth, to discuss options. Some options are discussed in "Living with Chronic Low Milk Supply: A Basic Guide," posted by MOBI Motherhood International. The article explains factors that contribute to low milk supply, ways to increase the supply, and how to build a nursing relationship despite a low milk supply.
As the Australian Breastfeeding Association states, "Breastfeeding is so much more than the amount of milk a mother is able to make. … ."
Australian Breastfeeding Association. Insufficient glandular tissue (breast hypoplasia) [online article]. May 2013. https://www.breastfeeding.asn.au/bfinfo/insufficient-glandular-tissue-breast-hypoplasia. Accessed November 15, 2013.
Cannon A, Jacobson H, Morgan B [online article]. Living with chronic low milk supply: a basic guide. MOBI Motherhood International. www.mobimotherhood.org/MM/portal-lowmilksupply.aspx. Accessed November 15, 2013. (Editor's note: Link now http://www.mobimotherhood.org/low-milk-supply.html)
Schoenberg N. Breast-feeding agonizing for some new mothers. Spartanburg Herald Journal. April 10, 2013.
Strontium for Osteoporosis
European Medicines Agency released a new warning about the use of strontium ranelate (Protelos) for the treatment of osteoporosis in April 2013. (The drug has not been approved in the US or Canada.) People taking the pharmaceutical have an increased risk of developing serious heart problems, including heart attack: "relative risk compared with placebo was 1.6 (95% CI 1.07-2.38)." The drug also increases the risk of venous thromboembolism. The agency recommends that strontium ranelate be given only to postmenopausal women with high fracture risk and at-risk men. People with uncontrolled hypertension, ischemic heart disease, peripheral arterial disease cerebrovascular disease, or a history of these disorders should avoid taking strontium ranelate.
Strontium ranelate inhibits bone loss; and, unlike bisphosphonates, it also increases bone formation. A year-long, double-blind study, presented at the 2011 European Congress on Osteoporosis and Osteoarthritis, found that strontium ranelate "exerts significantly greater bone-forming activity than the bisphosphonate alendronate [Fosamax]," writes Megan Brooks for Medscape. Unlike studies that depend on DEXA (X-ray) to determine bone density, this study used bone biopsies. DEXA evaluations tend to overrate bone mineral density in women taking strontium. Strontium has a greater atomic weight than calcium: " … much of the increase [in BMD] is a purely physical effect due to the increased attenuation of X-ray when some of the calcium in bone is replaced by strontium" (Blake et al.).
Strontium ranelate also decreases fracture risk, but its effectiveness appears to decline with continued use. In his review of a 2008 double-blind study, Dr. Alan R. Gaby says, "The available evidence indicates that high-dose strontium therapy [two grams per day] for up to five years reduces the incidence of [new vertebral] fractures, but the benefit appears to diminish after the first year of treatment."
Although strontium ranelate is not legal in North America, supplements containing high doses of strontium, in the form of salts (e.g., strontium citrate), can be bought over the counter (OTC). These high-dose preparations contain far more strontium than the 1 to 3 milligrams per day provided by food. Positive strontium ranelate studies are often used to promote strontium salts as an alternative to bisphosphonates. A 2013 rat study, using ANOVA statistical models, indicated that bone strontium levels were as high or higher in rats given strontium citrate, compared with rats given the prescription strontium; so OTC strontium supplements may have some of the same bone-building benefits. Does that mean it also has some of the same risks? We don't know; I could find no data showing that strontium salts are safer than strontium ranelate. High-dose strontium is known "to cause mineralization defects resembling rickets and to inhibit the synthesis of 1,25-dihydroxyvitamin D (the biologically active form of vitamin D)," says Gaby. These defects occur even when the rat diet includes recommended amounts of calcium.
As the European Medicines Agency continues to monitor the risk-benefit of strontium ranelate, consumers need to be aware that high-dose strontium salts may have risks of their own.
Blake GM, Lewiecki EM, Kendler DL, Fogelman I. A review of strontium ranelate and its effects on DXA scans. J Clin Densitom. 2007;10(2):113–119. Available at www.cof.org.cn. Accessed December 3. 2013.
Brooks M. Novel study confirms strontium ranelate's bone-forming benefits [online article]. Medscape. March 25, 2011. www.medscape.com/viewarticle/739683. Accessed November 20, 2013.
Gaby AR. Strontium for osteoporosis: how much and for how long? Townsend Lett. November 2009;28.
Medicines and Healthcare Products Regulatory Agency. Strontium ranelate (Protelos): risk of serious cardiac disorders – restricted indications, new contraindications, and warnings [Web page]. April 2013. www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON266148. Accessed November 15, 2013
Wohl GR, Chettle DR, Pejović-Milić A, et al. Accumulation of bone strontium measured by in vivo XRF in rats supplemented with strontium citrate and strontium ranelate [abstract]. Bone. January 2013;52(1):63–69. Available at www.ncbi.nlm.nih.gov/pubmed/22995463. Accessed November 15, 2013.
Page 1, 2
Jule Klotter
jule@townsendletter.com |
