Bisphosphonates: Bone Strengtheners or Bone Hardeners?

by Lane Lenard, PhD

Bisphosphonates are now the most widely marketed and prescribed patented, FDA-approved anti-osteoporosis drugs. Bisphosphonates mimic, to some extent, the effects of estrogen on bone in that they work by inhibiting bone resorption [the process by which old bone is removed to make room for new bone]. However, like estrogen, these drugs have 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 activity, which slows the loss of bone mineral density (BMD), allowing the trabecular architecture to stabilize. Notice that this has nothing to do with stabilizing the balance between estrogen and progesterone, restoring calcium levels, or any other natural process.

Like many other patented drugs, bisphosphonates are synthetic analogs of an important natural bone-building chemical, pyrophosphate, which normally helps bind calcium to bone tissue through a process known as mineralization. Unlike pyrophosphate, however, bisphosphonates actually block normal mineralization as well as osteoclastic bone resorption.

Large, placebo-controlled trials generally show that these drugs can indeed increase BMD and reduce the risk of vertebral, hip, and other nonvertebral fractures in women with osteoporosis—at least in the short run. That’s the good news. Merck, the company that markets the leading bisphosphonate, Fosamax (now also sold generically as alendronate), seized upon results like these to turn its drug into a blockbuster worth as much as $3.6 billion per year. Use of Fosamax and other bisphosphonates has been growing at an especially rapid rate since 2002, when the publication of the Women’s Health Initiative (WHI) results scared women away from “estrogen” replacement, which until then had been the leading conventional method for preventing osteoporosis.

Unfortunately, all may not be so rosy after all. Trials lasting up to 10 years are beginning to raise doubts about the long-term safety and efficacy of bisphosphonates. The main problem is that bisphosphonates not only directly—and unnaturally—inhibit osteoclastic bone resorption, they also indirectly inhibit the other side of the bone-building coin, osteoblastic bone formation.

How Bisphosphonates Work
In normal bone remodeling, osteoclasts first resorb bone tissue, forming little pits in the bone structure. In short order, osteoblasts come along—like microscopic road repair crews—to fill in those pits with healthy new bone. Under normal circumstances, osteoblasts remain inactive until the osteoclasts first do their thing. If osteoclastic activity is suppressed enough, though, as it is by bisphosphonates, osteoblasts have no cavities to fill, and so formation of new bone ceases. Although estrogens also inhibit osteoclastic activity, they do so in a natural way that does not suppress osteoblastic bone building, which can still be stimulated by agents like progesterone, testosterone or strontium.

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

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

Another much smaller clinical trial – conducted independently of direct drug company influence—presented a very different story. The researchers followed 9 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 as walking, standing, 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 bone resorption.

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

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

One Woman’s Experience with Fosamax
In one case reported in the medical literature, Jennifer P. Schneider, MD, PhD, a physician from Tucson, Arizona, described her personal experience with Fosamax. At age 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 one of the strongest bones in the body, she reported in the journal Geriatrics that when the car lurched, she “shifted all her weight to one leg, felt the bone snap, and fell to the floor of the train.” The photograph shows an X-ray of Dr. Schneider’s shattered femur.

At the time of her fateful subway ride, Dr. Schneider had been experiencing pain in her right thigh for about 3 months, and a bone scan the week before had shown a stress fracture of her right femur. She had also been taking Fosamax for about seven years, in addition 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 only “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 own, and within six 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 activity. However, since her bone scans were showing that her BMD was beginning to decline somewhat, her doctors advised her to start taking Fosamax again. Reluctantly, she agreed. About a year later, though, upon getting out of bed one morning, she felt a pain in her right foot with each step. Fearing the possibility of another nontraumatic stress fracture, she again stopped taking the Fosamax, but a bone scan 2 months later revealed that she had indeed suffered a stress fracture in her 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 foot, she started walking a mile every day, and after 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 own “case” history in 2006, she was sent numerous unpublished reports of others who had had similar fractures. Continuing to research the issue, she recently reviewed the current knowledge about this phenomenon. Meanwhile, two 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-impact,” “fragility,” or “atypical” fractures associated with use of Fosamax or other bisphosphonates. It appears that these unusual fractures have several things in common:

  • Most patients had been taking Fosamax for 4 to 7 years prior to the event.
  • The fracture was often preceded by localized pain in the thigh for 1 week to 2 years.
  • Some patients had sustained fractures in their opposite 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 X-rays. In one survey of  men and women admitted to a trauma center, 70 such fractures were identified over a 5‑year period. The unusual X-ray pattern was seen in only 1 patient who was not being treated with Fosamax. In other words, the unusual fracture pattern was specific to 98% of Fosamax patients.15

Perhaps the oddest aspect of these Fosamax-related fractures is that they tend to occur in the upper femur. Remember, this bone is composed primarily of hard, thick cortical bone, and it is usually the strongest bone in the body. In most healthy people, femoral fractures like these occur only after major, high-energy trauma, like a fall from a high place or an automobile accident. This is in sharp contrast to typical osteoporosis-related fractures, which occur in relatively soft, weakened cancellous bone (for example, trochanter of the hip, wrist, ribs) following (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 low-impact femoral fractures in patients taking alendronate [Fosamax] for several years, a previously rare event, have therefore called for further study of the possible connection between alendronate and such fractures.”13

How Bisphosphonates Might Promote New Fractures
Given the way that bone remodeling normally takes place, it’s easy to see why bisphosphonates might inhibit fracture healing (even though many doctors have been reluctant to admit it), 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 day life tend to cause bones to develop microcracks. Under normal conditions in otherwise healthy people, these microcracks trigger osteoclasts and osteoblasts to spring into action to repair the damage, 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 do their jobs, and so, the microcrack damage—like 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 treatment—which keeps the body’s “road repair crews” off the job—led to an increase in the accumulation of microcracks.

Let’s be clear about something: despite the fact that Fosamax increases BMD, it 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. Accumulation 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 strength 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 M. Ott of the University of Washington, Seattle, compares bisphosphonate-treated bone to an old tree. Under the stress of a strong wind, younger trees are flexible enough to bend 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 to a medical journal, “but the evidence shows they are actually bone 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 disease” sometimes seen in people whose kidneys are failing. She notes that, once 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. … There is no known method of removing the medication from the bones,” she wrote.

Dr. Ott urges caution in the long-term use of bisphosphonates, pointing out that research supports their beneficial effects—but only 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, so it is possible that microdamage accumulation would develop after 15 or 20 years—just about the time 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 destructive to the upper gastrointestinal (GI) tract, including the mouth, esophagus, stomach, and possibly jawbone. As noted in the official FDA-approved Fosamax label, “Fosamax, like 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 treatment with Fosamax. In some cases, these have been severe and required hospitalization.” Recent reports have even linked its use to cancer of the esophagus.

It’s hard to know just how common these kinds of GI complications are. In Merck’s original clinical trials, for example, 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 effects of Fosamax and other bisphosphonates are a serious problem.22

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

Serious as the bisphosphonate-related GI side effects are, it’s pretty simple to prevent them by closely following the recommended procedures for taking the drug, all of which are basically designed to get the pill out of your mouth, 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 accomplish this and also to maximize absorption, Merck recommends the following:

  • Take Fosamax first thing in the morning, right after getting out of bed and at least 30 minutes before ingesting any other food, beverage, or medication.
  • Take Fosamax with a full glass (6-8 oz) of ordinary water, but not mineral water.
  • After swallowing the Fosamax pill, drink another 2 oz (¼ cup) of water.
  • Do not lie down for at least 30 minutes and not until after eating your first food of the day—at least 30 minutes later.

Taking Fosamax with too little water can expose the esophageal or gastric (stomach) lining to the dangerously irritating drug, which can cause anything from heartburn to perforated ulcers to cancer. Lying down with the drug still in your stomach risks reflux of the acidic, drug-loaded gastric contents back into the esophagus, where they can do serious harm. Moreover, taking Fosamax while food or other meds are still in your stomach significantly reduces the drug’s absorption, thus inhibiting its effectiveness. Even the minerals in mineral water can impede Fosamax absorption.

So, after taking Fosamax in the morning, there’s no going back to bed for at least 30 minutes (What do you do during this time? Watch TV? Take the dog for a walk? Read a book?); nor are you supposed take it before bedtime at night. You can’t even take the drug and then have your morning cup of coffee or tea. You must take it on an empty stomach, so you need to wait at least half an hour before consuming anything else. Any deviations from these very stringent procedures can reduce the drug’s “therapeutic” effects and/or increase the chances it will cause serious injury to the lining of your upper GI tract.

Clearly, then, taking Fosamax and other bisphosphonates is a far cry from popping an ordinary pill in the morning. These drugs demand a commitment to religiously following the recommended procedures or you face potentially dire consequences. For older people, who typically take lots of other meds at different times each day and who may get easily confused about which is which, Fosamax may be a prescription for disaster. To get around these problems, companies have been designing new bisphosphonate drugs that can be taken once a week (e.g., Fosamax), once a month (e.g., Boniva), or even once a year (Reclast – by IV infusion).

Now, back to the clinical trials. We know that the people who run clinical trials for pharmaceutical companies go out of their way to make sure their participants follow the recommended drug-taking rules to a T. Therefore, it’s no surprise that Merck didn’t see very many serious side effects during its clinical trials, compared with placebo, thus allowing it to claim—statistically speaking—that the drug was safe.

Not so, though, for people who get their prescriptions from the average harried, conventional HMO GP, who may not have the time, understanding, or motivation to carefully instruct his/her patients and to follow up on their drug-taking in a timely manner. More likely, it’s, “Take these pills and come back in 3 to 6 months. Oh, and be sure to read this booklet about the right and wrong ways to take the pills. What did you say your name was?”

Under such real-world circumstances, bisphosphonate-related GI pathology turns out to be a common and potentially very serious problem. In fact, the FDA has recently reported receiving more than 40 case reports of esophageal cancer related to Fosamax use, of which 14 resulted in a patient’s death. Another 31 cases of esophageal cancer (and 6 deaths) linked to use of Fosamax and other bisphosphonates have been reported in Europe and Japan. The median time from initial drug exposure to cancer diagnosis was just 2.1 years in the US and 1.3 years in Europe and Japan.

Beware “Jaw Death”
Recently, a new, very disturbing, rare bisphosphonate side effect—osteonecrosis of the jaw (ONJ), also known as jaw death—has emerged. In ONJ, the bone tissue in the jaw fails to heal after minor trauma, such as a tooth extraction, which leaves the bone exposed and vulnerable to a particularly 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, alcohol abuse, and other conditions. Accustomed to 1 or 2 cases a year, doctors at one hospital were alarmed to notice that, over a 3‑year period, 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) as 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 there have been numerous subsequent anecdotal reports of bisphosphonate-related ONJ, Merck, along with the American Dental Association, continue to insist that oral Fosamax (as 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 ever used Fosamax and which of those later developed 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 “authorities.” By contrast, of the 4,384 USC patients who had undergone dental extraction but had never used Fosamax, not a single one developed ONJ.

“We’ve been told that the risk with oral bisphosphonates is negligible, but 4% is not negligible,” insisted Dr. Parish Sedghizadeh, who led the USC research team. He points out that most doctors who prescribe bisphosphonates do not tell their patients about the drugs’ potential risks, even with short-term use.

The problem is that, as Dr. Ott suggested above, the drug remains locked into bone tissue for a long time (it may take 10 years for levels to drop by half even once you stop taking it). Thus, continuous use allows the drug to build up to levels previously thought to be achievable only by high-dose intravenous administration to cancer patients. The USC results showed that ONJ could develop after taking oral Fosamax for as little as 1 year.

Several lawsuits have been filed against Merck alleging that Fosamax causes ONJ and that Merck has known about the risk but has been keeping it under wraps. “We’re not quite sure what we’re dealing with over the long haul,” Dr. Susan Ott told the Los Angeles Times. “Side effects like this should make ordinary, healthy women think twice.”

Increased Heart Risks, Too
The latest bad news about bisphosphonates concerns their adverse effects on heart function. New research shows that women who have 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 light-headedness, palpitations, chest pain, and shortness of breath; or there may be no symptoms at all. Untreated AF can lead to fluid collecting in the lungs (pulmonary edema), congestive heart failure, and formation of blood clots that may travel to the brain and cause a stroke. An analysis of three studies covering more than 16,000 women, most of whom were taking the drugs for osteoporosis, found that 2.5% 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 also extracted, in part, from the book Stay Young and Sexy with Bioidentical Hormone Replacement by Jonathan Wright MD and Lane Lenard PhD (Smart Publications, 2010).


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