A Recent Systematic Review Study Has Found That Treatment With Prescription Bisphosphonates Quizlet

by Lane Lenard, PhD

Bisphosphonates are at present the most widely marketed and prescribed patented, FDA-approved anti-osteoporosis drugs. Bisphosphonates mimic, to some extent, the effects of estrogen on os in that they work past inhibiting bone resorption [the process by which former bone is removed to brand room for new bone]. However, like estrogen, these drugs accept no ability to build new bone.

Currently FDA-approved bisphosphonates, including Fosamax (alendronate), Actonel (risedronate), Didronel (etidronate), Boniva (ibandronate), and Reclast (Zometa) (zoledronate), are designed to strengthen bone by inhibiting normal osteoclastic bone resorbing activeness, which slows the loss of bone mineral density (BMD), allowing the trabecular architecture to stabilize. Observe that this has nothing to practise with stabilizing the residual between estrogen and progesterone, restoring calcium levels, or any other natural process.

Similar many other patented drugs, bisphosphonates are constructed analogs of an important natural bone-building chemical, pyrophosphate, which normally helps bind calcium to os tissue through a process known as mineralization. Unlike pyrophosphate, however, bisphosphonates actually cake normal mineralization also equally osteoclastic bone resorption.

Large, placebo-controlled trials generally show that these drugs can indeed increment BMD and reduce the risk of vertebral, hip, and other nonvertebral fractures in women with osteoporosis—at least in the curt run. That's the good news. Merck, the company that markets the leading bisphosphonate, Fosamax (at present besides sold generically equally alendronate), seized upon results like these to plow its drug into a blockbuster worth equally much as $3.6 billion per twelvemonth. Apply of Fosamax and other bisphosphonates has been growing at an especially rapid charge per unit since 2002, when the publication of the Women'south Health Initiative (WHI) results scared women abroad from "estrogen" replacement, which until then had been the leading conventional method for preventing osteoporosis.

Unfortunately, all may not be then rosy later on all. Trials lasting up to 10 years are commencement to raise doubts near the long-term safety and efficacy of bisphosphonates. The primary problem is that bisphosphonates not just directly—and unnaturally—inhibit osteoclastic bone resorption, they as well indirectly inhibit the other side of the bone-building coin, osteoblastic bone germination.

How Bisphosphonates Work
In normal bone remodeling, osteoclasts first resorb bone tissue, forming little pits in the os structure. In curt order, osteoblasts come forth—like microscopic route repair crews—to fill in those pits with good for you new bone. Under normal circumstances, osteoblasts remain inactive until the osteoclasts first practise their affair. If osteoclastic activity is suppressed enough, though, as it is past bisphosphonates, osteoblasts take no cavities to fill up, and and so formation of new os ceases. Although estrogens also inhibit osteoclastic action, they do so in a natural way that does not suppress osteoblastic bone edifice, which tin all the same be stimulated by agents like progesterone, testosterone or strontium.

Thus, the physical toll of bisphosphonate-induced bone stabilization is to freeze normal bone remodeling—a highly unnatural state of affairs.

The Long Term Consequences of Suppressing Normal Os Remodeling
What does this mean for bone health in the long term? This is a crucial question, because there's no such matter as short-term treatment with these drugs. A woman who starts taking bisphosphonates at age 55 could easily yet be taking them 25 or 30 years afterwards, if she stays healthy and can tolerate them. The longest trial and then far reported—10 years with Fosamax—plain evidenced no increment in fracture rate in the later years. Notwithstanding, the design of this Merck-sponsored study has been criticized.

Another much smaller clinical trial – conducted independently of straight drug company influence—presented a very different story. The researchers followed nine women with osteopenia or osteoporosis, who had been taking Fosamax for 3 to 8 years (some had also been taking Premarin) and had developed nonspinal fractures (to the lower back, ribs, hip bones, and femur) while performing normal daily activities such every bit walking, continuing, or turning around. The locations of these fractures were unusual for women with osteoporosis, and none of the fractures was related to a fall or other trauma. The fractures occurred earlier in the women taking both Fosamax and Premarin, suggesting an additive effect on os resorption.

Since the women continued taking Fosamax while their fractures were healing, the researchers took the opportunity to written report the drug's effects on the healing process. What they establish was not encouraging. In nigh of the women, fracture healing slowed down considerably, taking months or even years longer than it should have. One woman'southward broken hip (femoral shaft fracture) took more than than ii years to heal, despite the fact that her doctors had treated the fracture aggressively, employing metallic screws and rods also as a os graft. In most of the women, once the drug treatment was discontinued, the fractures healed satisfactorily.

The researchers likewise performed bone biopsies at a site away from the fractures, which was intended to give them an thought of the health of the women'southward bones in general. They found a strikingly severe depression of os formation—about 100-fold lower in some of the patients than has been institute in healthy postmenopausal women. They concluded that the deterioration in bone health was most certainly due to Fosamax treatment, and that it was probably exacerbated by the coadministration of Fosamax with estrogen, since both suppress os turnover.

Ane Woman's Experience with Fosamax
In i instance reported in the medical literature, Jennifer P. Schneider, Doctor, PhD, a medico from Tucson, Arizona, described her personal experience with Fosamax. At historic period 59, Dr. Schneider, who had gone into menopause prematurely in her early 40s, was riding in a New York City subway when the car jolted. Although the femur is normally ane of the strongest basic in the body, she reported in the journal Geriatrics that when the motorcar lurched, she "shifted all her weight to one leg, felt the bone snap, and barbarous to the floor of the railroad train." The photograph shows an X-ray of Dr. Schneider'south shattered femur.

At the time of her fateful subway ride, Dr. Schneider had been experiencing hurting in her correct thigh for about 3 months, and a bone scan the week earlier had shown a stress fracture of her right femur. She had also been taking Fosamax for about seven years, in improver to calcium and conventional HRT (Premarin + Provera).

After the fracture, her doctors persuaded her to continue taking Fosamax, dismissing her concerns about its potential for suppressing bone turnover—that is, healing—as just "a theoretical possibility." Yet despite aggressive treatment over more than nine months, including electrical bone stimulation and two surgeries to implant increasingly larger metal rods, her fracture refused to heal. Finally, she halted the drug on her ain, and within half dozen months the pieces of her broken thighbone finally began to unite.

Dr. Schneider remained off Fosamax for two years, during which time she was able to regain her normal level of action. Withal, since her os scans were showing that her BMD was commencement to decline somewhat, her doctors brash her to beginning taking Fosamax again. Reluctantly, she agreed. About a yr later, though, upon getting out of bed one morning, she felt a pain in her right human foot with each pace. Fearing the possibility of some other nontraumatic stress fracture, she once more stopped taking the Fosamax, but a os browse ii months later revealed that she had indeed suffered a stress fracture in her human foot (the second metatarsal bone).

For the second time in 4 years, Dr. Schneider had fractured a bone due to no particular trauma. This time, instead of Fosamax, she started taking calcium supplements, oral estradiol and oral micronized progesterone [natural progesterone in pill form]. Wearing sturdy shoes to support her human foot, she started walking a mile every twenty-four hours, and later on several months, her fractured foot finally healed. Remaining on this regimen ever since, she has not suffered any new fractures.

Dr. Schneider is not alone in her fracture experience. After she published her ain "case" history in 2006, she was sent numerous unpublished reports of others who had had similar fractures. Continuing to research the consequence, she recently reviewed the current knowledge about this phenomenon. Meanwhile, ii other papers—one from doctors in Singapore and the other from the Hospital for Special Surgery in New York—have independently documented a total of 87 men and women, who had had "low-energy," "low-touch," "fragility," or "atypical" fractures associated with use of Fosamax or other bisphosphonates. It appears that these unusual fractures have several things in mutual:

• Most patients had been taking Fosamax for iv to 7 years prior to the issue.
• The fracture was often preceded by localized pain in the thigh for one week to 2 years.
• Some patients had sustained fractures in their reverse femur 2 to 4 years earlier.
• The fractures were associated with "low-energy" events, like tripping, and patients often could feel the bone snap prior to the fall.

Patients with bisphosphonate-related femoral shaft fractures often show a specific and unusual fracture pattern that is visible on Ten-rays. In 1 survey of  men and women admitted to a trauma center, 70 such fractures were identified over a 5‑year flow. The unusual X-ray pattern was seen in only one patient who was non beingness treated with Fosamax. In other words, the unusual fracture pattern was specific to 98% of Fosamax patients.15

Perchance the oddest aspect of these Fosamax-related fractures is that they tend to occur in the upper femur. Call up, this bone is equanimous primarily of difficult, thick cortical bone, and information technology is ordinarily the strongest bone in the body. In most healthy people, femoral fractures like these occur only after major, high-free energy trauma, like a fall from a high identify or an automobile accident. This is in abrupt dissimilarity to typical osteoporosis-related fractures, which occur in relatively soft, weakened cancellous bone (for example, trochanter of the hip, wrist, ribs) post-obit (or sometimes preceding) relatively mild trauma, like tripping and falling. As Dr. Schneider points out in her recent review, the femur is "unlikely to fracture in low-energy trauma unless extreme osteoporosis is present.14 The reports of multiple cases of depression-impact femoral fractures in patients taking alendronate [Fosamax] for several years, a previously rare effect, accept therefore called for further study of the possible connection between alendronate and such fractures."xiii

How Bisphosphonates Might Promote New Fractures
Given the mode that os remodeling normally takes place, it'southward easy to see why bisphosphonates might inhibit fracture healing (even though many doctors take been reluctant to admit information technology), but how they could actually promote new fractures while they're supposed to be preventing them seems less obvious. Current thinking on this paradox goes as follows:

The typical stresses of every solar day life tend to crusade bones to develop microcracks. Under normal weather condition in otherwise healthy people, these microcracks trigger osteoclasts and osteoblasts to spring into action to repair the impairment, unnoticeably and with no ill effects. However, if bone remodeling (turnover) is strongly inhibited, as it unquestionably is by bisphosphonates, the osteoclasts and osteoblasts cannot exercise their jobs, and so, the microcrack damage—similar a well-traveled but poorly maintained road pounded by heavy traffic over many years—develops ever-widening cracks and potholes. This hypothesis has recently been supported by Czech researchers, who found that, in women with low BMD, Fosamax handling—which keeps the trunk's "road repair crews" off the job—led to an increment in the accumulation of microcracks.

Let's be clear virtually something: despite the fact that Fosamax increases BMD, information technology may still make bones more likely to fracture in the long term. In lab animals, Fosamax-induced oversuppression of bone remodeling increased the appearance of microcracks by 2- to 7‑fold. Aggregating of these microcracks, without subsequent repair—due to the actions of bisphosphonates—appears to increase the risk of fractures while delaying or inhibiting healing.

In summary, even though bone forcefulness appears toincrease due to Fosamax treatment, in fact, use of this patented medicine has been associated with a 20% reduction in bone toughness (that is, its ability to endure bending pressure without breaking). Dr. Susan One thousand. Ott of the Academy of Washington, Seattle, compares bisphosphonate-treated bone to an one-time tree. Under the stress of a strong wind, younger trees are flexible enough to curve easily without breaking. However, older, denser trees, faced with a serious windstorm, are less able to bend and might just snap in two. "Many people believe that these drugs are 'bone builders,'" she wrote in a letter of the alphabet to a medical journal, "simply the evidence shows they are really os hardeners." (Italics added.)

In an editorial in the Journal of Endocrinology and Metabolism, Dr. Ott suggested that bone tissue in Fosamax-treated women resembles a form of "adynamic bone illness" sometimes seen in people whose kidneys are declining. She notes that, one time ensconced in bone tissue, bisphosphonates virtually never leave, and in fact, they accumulate with use. "These drugs are not metabolized, but are either excreted renally [in urine] or deposited within bones. … At that place is no known method of removing the medication from the bones," she wrote.

Dr. Ott urges circumspection in the long-term utilize of bisphosphonates, pointing out that research supports their beneficial effects—but just for the first 5 years. "I believe the current evidence suggests that bisphosphonates should be stopped after 5 years." She added, "The bisphosphonates in doses used today suppress bone formation to a greater extent than the other anti-resorbing medications, and so it is possible that microdamage accumulation would develop after 15 or 20 years—simply about the fourth dimension between menopause and the usual onset of osteoporotic fractures."

More Bisphosphonate Bad News:It's Not Just in Your Bones
GI Toxicity (or How to Lie with Valid Clinical Trials)
As if these problems weren't bad enough, bisphosphonates are also potentially subversive to the upper gastrointestinal (GI) tract, including the rima oris, esophagus, breadbasket, and maybe jawbone. Equally noted in the official FDA-approved Fosamax label, "Fosamax, similar other bisphosphonates, may cause local irritation of the upper gastrointestinal mucosa. Esophageal adverse experiences, such as esophagitis, esophageal ulcers, and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving handling with Fosamax. In some cases, these have been severe and required hospitalization." Contempo reports have even linked its employ to cancer of the esophagus.

It's difficult to know merely how common these kinds of GI complications are. In Merck's original clinical trials, for case, there was little difference in the frequency of GI side effects between the Fosamax and placebo groups. However, in the real world of physicians and patients, GI side furnishings of Fosamax and other bisphosphonates are a serious trouble.22

Is Merck fudging the data about GI complications? Not really. What nosotros have here is a perfect example of how a large-scale, well-controlled, FDA-approved, drug-company-sponsored clinical trial tin can do everything right and nonetheless distort reality past making a drug look safer than it really is. Here's how information technology works:

Serious as the bisphosphonate-related GI side effects are, information technology's pretty simple to forbid them by closely following the recommended procedures for taking the drug, all of which are basically designed to get the pill out of your oral fissure, through your esophagus, and into and out of your stomach as quickly as possible, with as little contact as possible with the delicate linings of these organs. To attain this and too to maximize absorption, Merck recommends the following:

• Take Fosamax first thing in the morning, right after getting out of bed and at least xxx minutes before ingesting any other food, beverage, or medication.
• Accept Fosamax with a full glass (6-eight oz) of ordinary water, but not mineral h2o.
• Later on swallowing the Fosamax pill, beverage another 2 oz (¼ cup) of h2o.
• Do not prevarication down for at to the lowest degree 30 minutes and non until subsequently eating your first nutrient of the mean solar day—at least 30 minutes later.

Taking Fosamax with as well footling h2o tin can expose the esophageal or gastric (stomach) lining to the dangerously irritating drug, which can crusade annihilation from heartburn to perforated ulcers to cancer. Lying downwardly with the drug still in your tummy risks reflux of the acidic, drug-loaded gastric contents back into the esophagus, where they can do serious damage. Moreover, taking Fosamax while food or other meds are all the same in your stomach significantly reduces the drug's absorption, thus inhibiting its effectiveness. Fifty-fifty the minerals in mineral h2o tin can impede Fosamax absorption.

Then, after taking Fosamax in the morning, there'due south no going dorsum to bed for at least 30 minutes (What do you do during this fourth dimension? Watch TV? Have the dog for a walk? Read a volume?); nor are you supposed take it before bedtime at nighttime. You tin can't even have the drug and then have your morning loving cup of coffee or tea. You must take it on an empty stomach, and then y'all need to wait at least one-half an hour earlier consuming anything else. Any deviations from these very stringent procedures can reduce the drug'due south "therapeutic" furnishings and/or increase the chances it will cause serious injury to the lining of your upper GI tract.

Conspicuously, then, taking Fosamax and other bisphosphonates is a far weep from popping an ordinary pill in the morning. These drugs demand a delivery to religiously post-obit the recommended procedures or y'all face potentially dire consequences. For older people, who typically take lots of other meds at different times each twenty-four hours and who may become easily confused well-nigh which is which, Fosamax may be a prescription for disaster. To get around these problems, companies accept been designing new bisphosphonate drugs that can be taken once a week (e.g., Fosamax), once a month (e.g., Boniva), or fifty-fifty once a yr (Reclast – by IV infusion).

Now, back to the clinical trials. We know that the people who run clinical trials for pharmaceutical companies become out of their way to brand sure their participants follow the recommended drug-taking rules to a T. Therefore, information technology'south no surprise that Merck didn't see very many serious side effects during its clinical trials, compared with placebo, thus assuasive it to merits—statistically speaking—that the drug was prophylactic.

Not and so, though, for people who get their prescriptions from the average harried, conventional HMO GP, who may non have the time, agreement, or motivation to carefully instruct his/her patients and to follow up on their drug-taking in a timely style. More probable, it's, "Take these pills and come back in iii to 6 months. Oh, and be sure to read this booklet about the correct and wrong ways to take the pills. What did y'all say your proper name was?"

Nether such real-globe circumstances, bisphosphonate-related GI pathology turns out to be a mutual and potentially very serious problem. In fact, the FDA has recently reported receiving more than than 40 case reports of esophageal cancer related to Fosamax utilize, of which 14 resulted in a patient's decease. Some other 31 cases of esophageal cancer (and 6 deaths) linked to use of Fosamax and other bisphosphonates take been reported in Europe and Japan. The median time from initial drug exposure to cancer diagnosis was but ii.one years in the US and ane.3 years in Europe and Japan.

Beware "Jaw Death"
Recently, a new, very disturbing, rare bisphosphonate side issue—osteonecrosis of the jaw (ONJ), likewise known as jaw death—has emerged. In ONJ, the bone tissue in the jaw fails to heal after minor trauma, such as a molar extraction, which leaves the bone exposed and vulnerable to a especially difficult-to-treat bacterial infection and fracture. Long-term antibiotic therapy and surgery to remove dying bone tissue may be required. Occasionally, a large portion of the jaw may have to be removed.

Ordinarily, ONJ is uncommon and is primarily associated with cancer chemotherapy, radiation of the head or neck, steroid therapy (e.g., cortisone), poor dental health, gum disease, dental surgery, booze abuse, and other conditions. Accustomed to 1 or 2 cases a year, doctors at one infirmary were alarmed to find that, over a iii‑year flow, ONJ had been diagnosed in 63 of their patients. The one thing all these patients had in common was bisphosphonate treatment. While 56 of them (89%) had been receiving Iv bisphosphonates (pamidronate or zoledronate) every bit cancer chemotherapy for at least a year, 7 of the patients (11%) had been taking only oral bisphosphonates (alendronate or zoledronic acid) at standard doses for osteoporosis.

While in that location take been numerous subsequent anecdotal reports of bisphosphonate-related ONJ, Merck, along with the American Dental Association, proceed to insist that oral Fosamax (every bit well as other bisphosphonates) poses minimal risk of ONJ. However, a recent systematic study from researchers at the University of Southern California School of Dentistry suggests otherwise. They evaluated the electronic medical records of patients attending the USC dental school clinic to find out which ones had e'er used Fosamax and which of those later adult ONJ. Of the 208 patients (all women, aged 63 to 80) with a history of once-a-week Fosamax use, 9 were being treated for ONJ – about 4%. (Four cases were associated with tooth extractions, and five with ulceration related to poorly fitting dentures.) This was a far higher incidence than had been suggested by most "government." By dissimilarity, of the 4,384 USC patients who had undergone dental extraction but had never used Fosamax, not a single 1 developed ONJ.

"Nosotros've been told that the risk with oral bisphosphonates is negligible, but four% is not negligible," insisted Dr. Parish Sedghizadeh, who led the USC research team. He points out that near doctors who prescribe bisphosphonates do not tell their patients about the drugs' potential risks, even with short-term utilise.

The trouble is that, as Dr. Ott suggested above, the drug remains locked into bone tissue for a long fourth dimension (information technology may take 10 years for levels to drib by one-half even in one case you stop taking information technology). Thus, continuous use allows the drug to build up to levels previously thought to exist achievable but by high-dose intravenous administration to cancer patients. The USC results showed that ONJ could develop afterward taking oral Fosamax for as little as 1 year.

Several lawsuits have been filed confronting Merck alleging that Fosamax causes ONJ and that Merck has known near the adventure only has been keeping information technology under wraps. "We're not quite sure what we're dealing with over the long booty," Dr. Susan Ott told the Los Angeles Times. "Side effects like this should make ordinary, salubrious women think twice."

Increased Heart Risks, Too
The latest bad news about bisphosphonates concerns their adverse effects on middle office. New research shows that women who accept ever used Fosamax or Reclast (also called Zometa) double their risk of developing serious atrial fibrillation (AF), a form of heart arrhythmia. Common symptoms include lite-headedness, palpitations, chest pain, and shortness of breath; or there may exist no symptoms at all. Untreated AF can lead to fluid collecting in the lungs (pulmonary edema), congestive heart failure, and germination of claret clots that may travel to the encephalon and crusade a stroke. An assay of three studies covering more 16,000 women, most of whom were taking the drugs for osteoporosis, establish that 2.v% to 3% experienced atrial fibrillation; 1% to 2% experienced serious AF, leading to hospitalization or death.

This article was reprinted with permission of the Townsend Letter, the Examiner of Alternative Medicine. It was too extracted, in office, from the book Stay Young and Sexy with Bioidentical Hormone Replacement by Jonathan Wright MD and Lane Lenard PhD (Smart Publications, 2010).

Notes

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2. Rosen CJ. Clinical practice. Postmenopausal osteoporosis. N Engl J Med. 2005;353:595–603.

3. Chemical analogs are molecular look-alikes, only with subtle differences, like the substitution of a carbon atom for an oxygen atom. Bisphosphonates are analogs of the natural substance pyrophosphate in the same way that Provera is an analog of progesterone.

4. Smith A. Merck sales dip; Vioxx blamed [Spider web folio]. CNNMoney.com http://coin.cnn.com/2005/04/21/news/fortune500/merck/alphabetize.htm. 2005. Accessed April 24, 2006.

five. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the adventure of vertebral fracture in women with postmenopausal osteoporosis. North Engl J Med. 2004;350:459–468.

6. Reginster JY, Deroisy R, Dougados Thousand, Jupsin I, Colette J, Roux C. Prevention of early postmenopausal bone loss by strontium ranelate: the randomized, 2-yr, double-masked, dose-ranging, placebo-controlled PREVOS trial. Osteoporos Int. 2002;xiii:925–931.

7. Bone HG, Hosking D, Devogelaer JP, et al. 10 years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199.

viii. Roux C, Fechtenbaum J, Kolta S, Isaia 1000, Andia JB, Devogelaer JP. Strontium ranelate reduces the take chances of vertebral fracture in young postmenopausal women with severe osteoporosis. Ann Rheum Dis. 2008;67:1736–1738.

ix. The researchers had grants from the United states of america Public Health Service and the University of Texas Southwestern Medical Center, Dallas.

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11. Schneider J. Should bisphosphonates be continued indefinitely? An unusual fracture in a healthy woman on long-term alendronate. Geriatrics. 2006;61:31–33.

12. She later on switched to a patented combination of oral estradiol plus a progestin (norethindrone acetate), brand proper noun Activella.

13. Schneider J. Bisphosphonates and depression-impact femoral fractures: Current testify on alendronate-fracture adventure. Geriatrics. 2009;64:18–23.

fourteen. Goh SK, Yang KY, Koh JS, et al. Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Os Joint Surg Br. 2007;89:349–353.

15. Neviaser As, Lane JM, Lenart BA, Edobor-Osula F, Lorich DG. Low-energy femoral shaft fractures associated with alendronate utilize. J Orthop Trauma. 2008;22:346–350.

xvi. Stepan JJ, Burr DB, Pavo I, et al. Depression bone mineral density is associated with bone microdamage accumulation in postmenopausal women with osteoporosis. Bone. 2007;41:378–385.

17. Ott SM. Long-term condom of bisphosphonates. J Clin Endocrinol Metab. 2005;90:1897–1899.

18. Brody J. Plotting to salvage the structure of those aging bones. The New York Times. July v, 2005.

19. Ott Due south. New treatments for breakable bones. Ann Intern Med. 2004;141:406–407.

20. Fosamax (alendronate sodium). Prescribing Information [Web page]. Merck & Co. Inc. http://www.fosamax.com/alendronate_sodium/fosamax/consumer/product_information/pi/index.jsp?WT.svl=1. Accessed April 26, 2006.

21. Wysowski DK. Reports of esophageal cancer with oral bisphosphonate apply. N Engl J Med. 2009;360:89–xc.

22. Greenspan SL, Harris ST, Bone H, et al. Bisphosphonates: prophylactic and efficacy in the treatment and prevention of osteoporosis. Am Fam Physician. 2000;61:3731–2736.

23. Chustecka Z. Esophageal cancer in patients taking oral bisphosphonates [Web page]. Medscape Medical News. 2008. http://world wide web.medscape.com/viewarticle/586127.24.

24. Basu Northward, Reid DM. Bisphosphonate-associated osteonecrosis of the jaw. Menopause Int. 2007;13:56–59.

25. 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;62:527–534.

26. Edwards BJ, Hellstein JW, Jacobsen PL, Kaltman South, Mariotti A, Migliorati CA. Updated recommendations for managing the intendance of patients receiving oral bisphosphonate therapy: an advisory statement from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc. 2008;139:1674–1677.

27. Sedghizadeh PP, Stanley K, Caligiuri M, Hofkes Due south, Lowry B, Shuler CF. Oral bisphosphonate use and the prevalence of osteonecrosis of the jaw: an institutional inquiry. J Am Dent Assoc. 2009;140:61–66.

28. Paddock C. Osteoporosis drug linked to bone death in jaw [Web page]. Medical News Today. January 5, 2009. http://world wide web.medicalnewstoday.com/articles/134381.php.

29. Marsa L. Bone drugs' contrary danger. Los Angeles Times. April 3, 2006. Available at: http://www.latimes.com/features/health/la-he-fosamax3apr03,0,3944007,full.story?coll=la-headlines-business organisation. Accessed April 27, 2006.

30. Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM. Utilise of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med. 2008;168:826–831.

31. Miranda J. Osteoporosis drugs increment gamble of heart problems. Presented at: Breast 2008: the 74th almanac assembly of the American College of Chest Physicians; October 25–30, 2008; Philadelphia, PA.

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Source: https://www.virginiahopkinshealthwatch.com/2010/02/bisphosphonates-bone-strengtheners-or-bone-hardeners/

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