Tag Archives: alendronate

2018: A MedShadow and FDA Year in Review

When the end of the year comes, many use it as a time of reflection. I am no different. I’d like to use my blog this week to reflect on some of the accomplishments MedShadow has achieved in 2018, as well as some observations about the FDA this year.

MedShadow’s Top 3 Achievements of 2018

1. The first thing to highlight about 2018 is that it was another year of growth in terms of people visiting the site and reading our content. We already have more than 1.3 million site visitors year-to-date, and we hope to make it to 1.4 million by Dec. 31. As far as content, we added the bi-weekly “Ask the Pharmacist” column from Dave Walker, who also happens to be on our MedShadow Medical Advisory Board. Also, this column, originally called FDA Watch, became known as Health Pulse and instead of running every other week, comes out weekly.

2. MedShadow also held its first-ever public event in November, Raising Awareness About the Side Effects of Medicines. It brought together patients, patient advocates, healthcare workers and political leaders to listen to medical professionals. The purpose was to improve efforts to inform the public about medications to improve their health care, as well as increase MedShadow’s exposure.

3. Last month, MedShadow filed an amicus curiae (“friend of the court”) brief in a US Supreme Court case, Merck v. Albrecht. The case involves the osteoporosis drug Fosamax (alendronate) and women who say their spontaneous fractures of the thigh bones were caused by the drug. At issue is how Merck dealt with updating the label of Fosamax when it became aware of the issue. Yesterday, Suzanne Robotti, MedShadow’s founder and executive director, had an op-ed piece published in STAT, one of the most well-respected health and medical websites that is followed by many in the pharmaceutical industry, about the case. The decision could impact how patients are able to hold drug companies accountable when they are harmed by a drug and seek damages in court.

Top 3 FDA Actions – and Inactions — of 2018

1. The FDA’s biggest offensive this year came in its assault on e-cigarettes amid growing numbers of young people using the devices. Between 2017 and 2018, the number of high school students using e-cigs increased by 78% from 2.1 million to about 3.6 million. Last month, the agency proposed new restrictions on the sale of flavored e-cigs, which are especially appealing to teens. In September, the FDA ordered the 5 biggest e-cig manufacturers to develop plans to curb use of their devices by teens. Earlier this year, the FDA conducted a surprise inspection of the offices of JUUL Labs, the nation’s largest e-cig manufacturer, seizing more than 1,000 documents.

2. Another product that found itself in the FDA’s crosshairs was kratom. The herb has a loyal following among many Americans who use it for its reported pain-relieving properties, as an alternative to opioids, to deal with the effects of opioid-use withdrawal, and even depression and anxiety. The FDA has issued several warnings on kratom this year. In February, the agency warned kratom has opioid-like qualities and can be potentially addictive. Earlier in the year, the agency issued several warnings about kratom products tainted with salmonella. Last month, the FDA said it found high levels of heavy metals in kratom samples it had tested. The FDA has linked at least 44 death to kratom, though kratom supporters say that is misleading as in nearly all those cases, the kratom was either adulterated with other substances or other potent drugs were found in the person’s system. The Drug Enforcement Agency may essentially ban kratom by making it a Schedule 1 substance – the same as heroin, LSD and marijuana – after the Department of Health and Human Services made the recommendation.

3. One area where the FDA could have – and should have – done more is to tighten regulation of the supplement industry. We have reported on many occasions about supplements being recalled for one reason or another. While drugs are also sometimes recalled, supplements do not have to conduct clinical trials to prove they actually say what they do in order to make it onto the market. Americans spend more than $40 billion a year on supplements, and in many, many cases, they are using products that are likely useless, and potentially harmful. It’s time for the FDA to require more rigorous testing of these products so that the claims on their labels are actually backed by scientific evidence.

Did Merck Circumvent Its Duty To Warn on ‘Fosamax Fractures’?

This article was originally published on STAT on December 18, 2018.

How would you feel if you were harmed by a medicine you took as prescribed and then learned that the drug company wasn’t liable — even though it knew about the risk and didn’t tell you or your doctor?

This is exactly what has happened in the case of Fosamax (alendronate), a drug used to treat bone-thinning osteoporosis and osteopenia. After it was approved by the Food and Drug Administration and women across the country began taking the drug, the FDA and its maker, Merck, started receiving reports about spontaneous fractures of the thigh bone among women taking the drug.

These fractures, dubbed “Fosamax fractures,” happen with no warning and usually require surgery. Although they are a rare side effect of the drug, millions of women have taken the drug. While the true number of Fosamax fractures isn’t known, about 500 women have sued Merck for failing to warn them about the risk of this painful and possibly debilitating side effect. These lawsuits are at the heart of a case, Merck, Sharp & Dohme Corp. v. Doris Albrecht, et al., that will be argued before the U.S. Supreme Court on Jan. 7, 2019.

MedShadow Foundation, the nonprofit organization I founded in 2012 to inform the public about the side effects of medicines, along with three former FDA officials, filed an amicus curiae brief in support of Albrecht, the defendant in the case. Such “friend of the court” briefs are filed by individuals or organizations that aren’t parties in a case.

Merck Admits Fosamax Caused The Fractures

Merck acknowledges that Fosamax caused these fractures and that the company knew about them. In 2008, Merck started the process to get the FDA’s permission to put a warning on the drug label — the inserts that come with all medicines, providing information such as instructions on how to take a drug, what it can be used for, and warnings. The FDA reviews and must approve any information on drug labels for accuracy. These labels are generally considered fair warning to users about possible side effects or adverse events and, in that way, provides legal protection for drug companies from being sued for causing them.

The FDA relies on manufacturers to update and make changes to drug labels throughout the lives of their drugs. That’s because approvals for new drugs are often based on small clinical trials of 1,000 or fewer people that normally last less than a year. Unusual or rare side effects and can’t be detected in such small, short-term trials. Once a drug is approved and thousands or millions of people are taking it, new side effects and adverse events can emerge.

The spontaneous fractures caused by Fosamax didn’t begin appearing until the drug had been on the market for five years. And these fractures aren’t the only significant bone problems linked to the drug. Cases of osteonecrosis (literally “bone death”) of the jaw, a painful condition where jaw bones become exposed, were reported by people taking Fosamax. In 2013, Merck agreed to pay $27.7 million to settle 1,140 lawsuits from individuals who alleged that Fosamax caused them to develop this condition.

If the Supreme Court allows drug companies to circumvent the law … which is what Merck is attempting to do in this case, it would remove the motivation for pharmaceutical companies to provide the FDA with timely and transparent information.

Pharmaceutical companies have the best access to reports of adverse events, and they pay attention to updating drug labels as an important patient-protection safeguard.

When Merck applied to the FDA for a label change to reflect these fractures, the FDA rejected its request. Why? Because Merck described them as stress fractures, which are minor and quite different from far more serious spontaneous fractures. A stress fracture is an incomplete bone break that is generally treated by rest and inactivity. A spontaneous fracture is a complete break that occurs in a seemingly normal bone without any trauma and must often be repaired with surgery.

Although drug companies are responsible for updating labels, the FDA can require updates. In 2010, the FDA convened a panel to review the increasing number of reports of Fosamax-related spontaneous fractures. After reviewing the research, the panel found a clear connection between Fosamax and spontaneous thigh bone fractures. The FDA then ordered Merck to change the label.

Women Suing Merck Claim Drugmaker Failed to Warn Them

The women suing Merck claim that the company failed to warn them about a known adverse event. Merck is claiming that the FDA did not allow the company to change the label, making it impossible for Merck to warn women or their doctors.

If Merck prevails, the disingenuous tactic it used for Fosamax could be replicated by other pharmaceutical companies and have far-reaching effects.

Suppose a pharmaceutical company discovers that one of its drugs causes a serious adverse event. The company files an application for a change to the drug label, but knowingly designs the change so the FDA won’t accept it — either by minimizing the risk of the adverse event or by not accurately reflecting the risk. The drug company could then claim it isn’t liable for not warning consumers about that adverse event because the FDA denied the label change.

If the Supreme Court allows drug companies to circumvent the law this way — which is what Merck is attempting to do in this case — it would remove the motivation for pharmaceutical companies to provide the FDA with timely and transparent information.

MedShadow Foundation is a small nonprofit with limited resources. Yet we have taken on the costly and time-consuming process of filing an amicus brief because we believe that pharmaceutical companies cannot be allowed to obscure the risks, side effects, and adverse events of drugs — or exaggerate their benefits.

The foundation’s mission is to protect quality of life by ensuring that people have all the known information about side effects before deciding to take a prescription or over-the-counter drug. Today, pharmaceutical companies are motivated to reveal previously unknown risks and warn the medical community so they can’t be sued for damages. The FDA and the law must maintain that obligation to protect people from unnecessary harm.

There will always be some risk with medicines, but consumers have the right to all the information about benefits and risks of drugs — whenever that information is discovered — so they can make informed decisions about their health and well-being.

Can Bisphosphonates Stop Breast Cancer from Spreading to Bones?

In 2016, at the age of 44, Susan Leonard was diagnosed with Stage 2 breast cancer. For the last two years, Leonard has gone through a gauntlet of numerous treatments to keep her cancer from returning, including a double mastectomy, chemotherapy, two types of hormone therapy and surgery to remove her ovaries. The treatments put her into menopause — and her bone health at serious risk.

In April, to prevent osteoporosis, Leonard received her first infusion of Zometa (zoledronic acid), an injected medication belonging to a class of medications that aim to stop bone density loss, bisphosphonates. But Leonard and her oncologist hope the twice-yearly infusions will do something more: Prevent her cancer from metastasizing, or spreading, to her bones.

Evidence for Use

For post-menopausal women, there’s strong evidence backing the idea that bisphosphonates can stop cancer spreading to bones, according to a 2015 meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)). While no significant risk reduction was found for pre-menopausal women, among nearly 12,000 post-menopausal women, bisphosphonates reduced the relative risk of bone metastasis by 28%, the spread to other organs by 18%, and breast cancer mortality by 18% over a 10-year-period.

This meta-analysis, and other favorable studies, prompted an expert panel from the American Society of Clinical Oncologists (ASCO) and Cancer Care Ontario to issue detailed guidelines in March 2017 on the use of bisphosphonates in breast cancer. The guidelines recommend bisphosphonates be considered as adjuvant therapy (after surgery or chemotherapy) for post-menopausal women with breast cancer. There are two options. Zometa is recommended every six months for three to five years, while Bonefos (clodronate), an oral medication, can be taken daily for two to three years.

The ASCO guidelines recommend Zometa or Reclast (both zoledronic acid) or Bonefos because they’re the most studied bisphosphonates for breast cancer benefits, but the optimal dose and administration schedule for these drugs haven’t been determined. And while Bonefos is used in some 80 countries worldwide, it hasn’t been FDA approved.

Why Bisphosphonates?

For breast cancer patients, bisphosphonates have already been FDA-approved and prescribed to prevent and treat osteoporosis related to treatment. In those with bone metastasis, they’re also used to prevent the risk of fracture, spinal cord compression and hypercalcemia, a potentially life-threatening condition where blood calcium levels are above normal.

Researchers are still trying to determine how bisphosphonates prevent breast cancer from invading bone. It’s thought that bone metastatic cancer cells stimulate cells known as osteoclasts that are responsible for brittle bones. For bone health, bisphosphonates increase bone density by inhibiting osteoclastic bone resorption, or turnover, while assisting bone-building cells known as osteoblasts. What oncology researchers do know is that previous and ongoing clinical trials continue to point to the efficacy of bisphosphonates for preventing bone metastasis after breast cancer surgery and other systemic therapy.

Not all bisphosphonates provide breast cancer recurrence benefits, however. The EBCTCG study found Aredia (pamidronate) offered no benefit because of its poor absorption by the body. There was also insufficient data to recommend taking Actonel (risedronate) or Fosamax (alendronate), both oral treatments.

Weighing the Side Effects

Bisphosphonates have several common, often debilitating side effects, including flu-like symptoms, and bone and joint pain. Usually these symptoms get better after a few days, or after the first few infusions.

Cancer doctors often suggest taking Tylenol (acetaminophen) to counter the side effects of bisphosphonate-related bone pain. NSAIDs (nonsteroidal anti-inflammatory drugs), such as Advil (ibuprofen) or aspirin are not recommended because they can tax the kidneys.

Leonard’s cancer treatments had already made her arthritic, so she says it was difficult to tell if the Zometa caused any additional bone pain. “I had terrible bloating for four days but otherwise I felt okay,” she says.

Serious side effects, though rare, include impaired kidney function and osteonecrosis (bone death) of the jaw, also known as ONJ. Cancer doctors will assess renal and other vital functions before prescribing a bisphosphonate. Leonard’s doctor advised her to avoid any dental treatment six weeks before and six weeks after her infusions. Anyone considering these drugs should also speak with their dentist about any dental issues that could put them at a greater risk of ONJ.

Despite the temporary belly swelling, Leonard says taking the Zometa gives her additional peace of mind. She had to skip her last two chemotherapy treatments after developing severe neuropathy — nerve pain and numbness — in her hands. “It’s kind of nerve-wracking knowing I didn’t get the chemotherapy dose they recommended, so hopefully the Zometa infusions will pay off,” she says.

Why Target Bone?

Once breast cancer metastasizes beyond the breast and nearby lymph nodes, known as advanced or Stage 4, it’s considered terminal, with most women living three years on average.

“When breast cancer metastasizes…the most common distant organ is bone,” says Catherine Hall Van Poznak, MD, associate professor at the University of Michigan Medical Center and a co-author on the ASCO guidelines.

“In autopsy analysis, approximately 70% of people who have died from breast cancer have bone metastasis. So, the idea of having something that may impact recurrence to the bone is going to be of interest.”

The hope is to keep the cancer from taking hold in the bones in the first place. Of early-stage breast cancer patients (Stage 1 through 3), a median 12.2% developed bone-only metastasis within the first five years after initial diagnosis, according to a 2017 systematic review and meta-analysis of more than 175,000 breast cancer patients worldwide. Bone metastasis was also present in 55% of breast cancer patients whose disease had spread to other organs.

Given the common occurrence of breast cancer-related bone metastasis, the absolute risk reduction conferred by bisphosphonates may matter more when deciding whether to add these drugs to cancer treatment regimens. Post-menopausal women who received bisphosphonates had a 2.2% absolute risk reduction in bone recurrence and a 3.3% absolute risk reduction in death over a 10-year period, the EBCTCG meta-analysis found.

“It’s just going to be a few percent benefit in the absolute numbers,” says Van Poznak. “And that’s where it’s going to be tricky I think, to really weigh is it worth taking for a particular individual.”

Research also hasn’t yet parsed out whether breast cancer patients who develop osteoporosis during treatment are at a greater risk for developing bone metastasis, though that’s a concern, says Van Poznak.

Quick Hits: Drugs That Boost Heart Failure Risk, Crestor Goes Generic, & More

Many commonly used medications can lead to heart failure or worsen existing heart failure, according to a scientific statement from the American Heart Association (AHA). Many of the drugs that the AHA identified increase heart failure risk due to their high sodium content. Some of these drugs are: Fosamax (alendronate), azithromycin, Prilosec (omeprazole), and Zantac (ranitidine). Other drugs the AHA identified are: Onglyza (saxagliptin) and Januvia (sitagliptin), drugs known as DPP-4 inhibitors to treat diabetes; Celexa (citalopram) for depression; certain anti-cancer biologic medications; and Cardizem (diltiazem) and Verelan (verapamil), calcium channel blockers used for high blood pressure and chest pain. The AHA also found that certain over-the-counter medications, including NSAIDs (non-steroidal anti-inflammatory drugs), certain decongestants, NyQuil/DayQuil, and Pepto-Bismol can also boost heart failure risk. Posted July 11, 2016. Via American Heart Association.

Generics of the blockbuster cholesterol-lowering drug Crestor will soon hit the market after the FDA approved applications from 8 generic manufacturers. The approval means the price of Crestor (rosuvastatin) – which has a retail price of $260 per month – will come down dramatically. AstraZeneca, the manufacturer of the statin, had been trying to prevent the launch of the generics by claiming in a lawsuit that the FDA couldn’t approve generic rosuvastatin because it was recently approved to treat children with a rare disease. The drugmaker argued that because of this indication, generic Crestor couldn’t be approved because of the Orphan Drug Act, which protects certain drugs from competition to encourage development of medications for rare diseases. A judge rejected that argument. Crestor had $5 billion in sales last year, making it AstraZeneca’s best-selling drug. Posted July 20, 2016. Via The New York Times.

An FDA advisory committee has unanimously recommended approval of a new biologic medication for psoriasis. The FDA’s Dermatologic and Ophthalmic Drugs Advisory Committee voted 18-0 to approve Siliq (brodalumab) to treat moderate to severe plaque psoriasis. However, many of the panel members also said there should be a warning on the drug’s labeling and a risk management program over concerns about self-injurious behavior and suicide. Valeant Pharmaceuticals, Siliq’s developer, reported 6 suicides among 6,200 patients who took the biologic in its clinical studies. However, 4 of the suicides were in patients with a history of psychiatric issues, while the other 2 were in people with no signs of self-injurious behavior. The FDA is slated to make a decision on Siliq by November 16. Although the agency is not bound by its advisory committees’ recommendations, it usually follows their advice. Posted July 20, 2016. Via MedScape.

Need to Know: Bisphosphonates

Bisphosphonates can be taken by both men and women to treat osteoporosis.

They are often prescribed during cancer treatments because many chemo combinations can tax bone structure and cause osteoporosis.

Common Names

Fosamax (alendronate), Actonel (risedronate), Boniva (Ibandronate), Reclast (zoledronic acid)

Side Effects and What to Do About Them

The biggest issues with oral bisphosphonates (Actonel, Boniva, Fosamax) are nausea, abdominal pain and heartburn. To alleviate these side effects, take the medication with a full glass of water (milk is not recommended) on an empty stomach and remain upright for 30 to 60 minutes to avoid the medicine coming back up into the esophagus. Once the recommended wait time is over, eat to offset the remaining medication. There are other medicines that can be taken to ease digestive discomfort, or you doctor might suggest lowering the dose.

Low calcium in the blood (hypocalcemia) can cause muscle twitching, spasms and cramps, numbness or tingling in feet hands and around the mouth. Don’t ignore these symptoms. If low calcium in the blood is untreated it could lead to depression, dry skin, itching and (rarely) fits.

Increased bone pain can happen for a short time when you start on bisphosphonates. Your doctor will probably suggest Tylenol (acetaminophen) to deal with the pain.

Bisphosphonates given intravenously, such as Reclast, are taken by patients who find it easier to schedule a quarterly or yearly infusion instead of taking a weekly or monthly pill. Infused forms of bisphosphonates can cause 24 to 72 hours of mild flu-like symptoms.

The possible long-term effects of bisphosphonates include atypical femur fracture, osteonecrosis of the jaw (ONJ), atrial fibrillation, damage to the kidneys and esophageal cancer.

Atypical femur (thigh bone) fractures are rare, but these fractures can happen in the hip or the neck of the femur. According to E. Michael Lewiecki, MD, director of the New Mexico Clinical Research & Osteoporosis Center, and clinical assistant professor of medicine, University of New Mexico School of Medicine, these fractures usually occur in patients who have taken bisphosphonates for 7 years or more.

According to Harvard Medical School, there have been some unusual fractures of the femur in long-term Fosamax users. However, there is no concrete evidence yet to make any conclusions. Consequently, doctors do not know how long patients should take Fosamax. Some women and their physicians  consider a drug holiday if using bisphosphonates.

ONJ is a condition in which bone in the jaw that becomes exposed and begins to weaken from a lack of blood. Luckily, oral bisphosphonate users rarely experience ONJ. Current estimates are that between 1 in 10,000 and 1 in 100,000 patients who have taken bisphosphonates have had ONJ. But the research shows the risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates is higher, in the range of 1-10 per 100 patients (depending on duration of therapy).

Always tell your dentist that you are having bisphosphonate therapy or tell your doctor if you need dental treatment.

Atrial fibrillation is a common type of heart rate problem that might be linked to IV bisphosphonates.

Pooled data from randomized controlled trials and observational studies show that there is a higher risk of atrial fibrillation from bisphosphonates, according to the National Center for Biotechnology Information. (Randomized controlled trial are considered very high quality. However, pooling studies means combining findings from studies with different parameters, people tested and goals of the studies. So that makes it a bit less reliable, but still good.)

Your doctor might want to check your kidney functioning before starting bisphosphonates and occasionally after starting. Drinking plenty of fluids can help protect your kidneys. You should alert your doctor if your urine output drops. Kidney damage is rare, but possible.

Additionally, there are some concerns about bisphosphonate treatment and esophageal cancer. However, the National Institutes of Health examined several studies and doesn’t see any correlation.

Drug Interactions

Combining oral bisphosphonates and calcium or acid-suppressant medications can interfere with the absorption of the bisphosphonate. Therefore, calcium supplementation should not be taken while using bisphosphonates. There is also a risk of fracture.

It’s also recommended to be cautious with oral bisphosphonates and over-the-counter pain meds known as NSAIDs (non-steroidal anti-inflammatory drugs)  because this combination can irritate the gastric mucosa, a layer of the stomach.

Effectiveness & Considerations

Bisphosphonates are commonly prescribed for osteoporosis treatment and other bone diseases. There are some studies that show differences in potency or effectiveness at preserving bone density, but all bisphosphonates are generally considered helpful. Bisphosphonates have shown to reduce chance of a fracture.

Experts say patients can take bisphosphonates for 3 to 5 years. There are plenty of studies that prove these drugs are safe and effective at preventing fractures of the hip and spine.

In addition, in order to maximize the benefit of bisphosphonates, people should be sure their intake of calcium and vitamin D is adequate both before and during therapy.

If an individual has not broken any bones and continues to maintain bone density for 5 years while taking bisphosphonates, then experts believe patients should consider taking a break from their medication because there is little research about the drug’s effectiveness beyond 5 years.

Bisphosphonates are used to lower the chance of fracture, but remember they don’t eliminate all risk of breaking a bone. If a patient experiences a fracture while on treatment, the doctor will assess the situation and see what the next step is.

According to The New York Times, the most commonly prescribed osteoporosis drugs like Fosamax fell by 50% from 2008 to 2012 and the trend is continuing. Millions of Americans choose to avoid these drugs because they are terrified by the extremely rare side effects.

Alternatives to Bisphosphonates

For those who have a higher risk of bone loss, a great way to improve bone health is to provide your body with specific bone-building nutrients like vitamin K and vitamin D. Appropriate doses of vitamin D have been shown to reduce fractures as effectively as drug therapies.

Eating an alkaline-forming diet can offset the acid load that comes from large amounts of animal protein, processed foods, refined sugars and poor quality salts. This kind of diet replaces all of the unhealthy acid load with more fruits, vegetables and seeds to build bone. Note that alkalizing your diet is good in the short-term but detrimental in the long run.

Exercising can help prevent bone loss through building muscle and extensive strength training. Taking walks or enrolling in a yoga class are some ways to include exercise in your everyday life to build muscle and bone.

How They Work (Method of Action)

Bones are made of living tissue and constantly change. Healthy bones have specialized bone cells that break down and replace bone tissue. The specialized bone cells are osteoclasts, which break down old bone, and osteoblasts, which build new bone. The job of bisphosphonates are to slow down osteoclasts, allowing less bone loss and osteoclasts to work more effectively.

What Worked for You?

Share your experience with bisphosphonates in the Disqus box below.

MedShadow Coverage on Osteoporosis

Further Reading

Bisphosphonates Method of Action

Has Osteoporosis Been Overtreated?

Since the mid-90s, when Fosamax (alendronate) was first approved, bisphosphonates have been commonly used to effectively treat osteoporosis in millions of patients.

But bisphosphonates (the class of drugs that work to rebuild and strengthen bone tissue), which are taken either orally or as injections, are not without side effects and recently, some of the potential long-term effects of these medications, while rare, have come under scrutiny. Conversations about what those effects might or might not be and who, in fact, should be taking these drugs have been taking place in the media and medical community alike.

One issue is that no one really knows yet what the optimum length of time patients should be taking these drugs. A study by the FDA, published in the New England Journal of Medicine, caused a stir — taking on the question of whether or not continued use of bisphosphonates helps patients or might put them at increased risk for atypical fractures or other side effects.

‘In other therapies we are confident in saying the effects of the medicine are gone, once we stop giving them… Whereas with bone the exact opposite is true.’ — Kurt Kennel, MD

The study suggests that taking bisphosphonates beyond 5 years doesn’t necessarily continue to improve bone density or strength for all patients. One recommendation is that patients who were initially at low-risk for osteoporosis-related fractures would probably benefit from discontinuing the medication after 3 to 5 years, whereas those patients at a greater risk from the outset would benefit from continuing.

Concern About the Unknown

“Bone is a slow-changing tissue and its metabolism is a gradual process,” says Kurt Kennel, MD, assistant professor of medicine in the Division of Endocrinology, Metabolism and Nutrition at the Mayo Clinic. “A big concern I have is the unknown. Will bone strength remain stronger like we think it does in the first years of therapy, or will it paradoxically not be as strong or healthy in the long run because we’ve manipulated it with these rather long lasting medications?”

Dr. Kennel points to the fact that there hasn’t been enough time to study the long-term residual effects of bisphosphonates simply because they haven’t been around for that long. “In other therapies we are confident in saying the effects of the medicine are gone, once we stop giving them,” he says. “So if we have reservations in terms of long-term safety we can always counter that concern with the medicine being out of the body. Whereas with bone the exact opposite is true, it has every reason to still be in the body and every reason it has some impact decades down the road.”

Short-term Side Effects

Oral Bisphosphonates (Fosamax, Boniva, Actimel, all available in generic form)

The biggest complaint is upper gastrointestinal discomfort such as nausea, abdominal pain and heartburn. Patients are encouraged to take the medication with a full glass of water and remain upright for 30 minutes to an hour after consumption.

IV Bisphosphonates (Reclast, or zoledronic acid)

It’s not uncommon for patients to experience flu-like symptoms 24 to 72 hours after receiving the infusion; typically symptoms lessen with the second and subsequent doses. This “acute phase response,” says Dr. Kennel, could occur in as few as 1in 3, but more likely it’s 50% of patients. Often, the symptoms are so minor, people don’t report them to their doctors.

Long-term Effects

Atypical Femur Fracture

This side effect, while statistically rare, has emerged as one of the primary concerns of bisphosphonate use. A typical osteoporosis fracture often happens in the hip or the neck of the femur (the long bone in the thigh). But some osteoporosis patients taking bisphosphonates end up with breaks in the middle of their femur.

While the reason is unclear, Dr. Kennel suggests that since the medicine doesn’t discriminate where in the skeleton it goes, the same dose that is appropriately strengthening the bones weakened by disease, might be too much for other locations, such as the middle of the femur which needs some flexibility for normal walking function. It’s a paradox: The drug makes the bone stronger, but may also leave it less resilient, and more prone to a stress fracture or a break.

Again, these fractures are very rare: “If you treat 1,000 women with osteoporosis with a bisphosphonate for 3 years, you’ll prevent about 100 fractures and perhaps out of those 1,000 patients, 1of them might have a atypical femur fracture,” says  Michael Lewiecki, MD, director of the New Mexico Clinical Research & Osteoporosis Center, and Clinical Assistant Professor of Medicine, University of New Mexico School of Medicine. Most of the atypical femur fractures occur in patients who have taken bisphosphonates for 7 years or more, says Dr. Lewiecki.

In some cases, researchers might consider a drug holiday as an option: “After being treated for 3 to 5 years, if your fracture risk is no longer very high, you could consider stopping taking the drug, and there would presumably be enough of the medication built up in your bones that it would continue to be effective and reduce the risk of fractures for at least a year or two afterwards.” As the level of medication goes down, he explains, you’ll presumably lower your risk of an atypical fracture. That said, a bisphosphonate holiday doesn’t equal bisphosphonate retirement; when bone density decreases again and fracture risk increases, medication will be needed.

Osteonecrosis of the Jaw (ONJ)

ONJ is defined as exposed bone in the jaw that persists at least eight weeks after identification. The occurrence of ONJ among oral bisphosphonate users is quite low — 1 in 100,000 patients — according to a report published by the National Institutes of Health, with the incidence slightly higher among IV patients.

More often than not ONJ doesn’t happen spontaneously but is associated with trauma to the jaw, typically a tooth extraction, says Dr. Kennel. A patient being considered for bisphosphonate therapy who also requires dental treatment probably shouldn’t do both simultaneously. “It just doesn’t make sense to be taking the medicine and having teeth pulled when the teeth could be pulled first and start the medicine later,” says Dr. Kennel.

Atrial Fibrillation

There is some suggestion that IV bisphosphonate use in particular might contribute to increased risk of developing atrial fibrillation, a common type of heart rate problem. There tends to be an overlap in the demographic of patients who have a high risk for osteoporosis and for atrial fibrillation, says Dr. Kennel. As such, “those at high risk for atrial fibrillation might have greater reason to consider this potential adverse effect,” he says.

Esophageal Cancer

Amid some concerns, an evaluation by the NIH examined several studies and refutes direct correlation between bisphosphonate treatment and esophageal cancer.

How Bisphosphonates Work

Normal, healthy bones are constantly breaking down and building themselves back up. Cells called osteoclasts are responsible for the breaking down; osteoblasts are in charge of replacing lost cells. In fact, “all of us probably replace our skeleton about once every ten years through this process of bone remodeling,” says Dr. Lewiecki.

Next: Non-Drug Ways to Build Bone >>