Bisphosphonates and Musculoskeletal Pain

The U.S. Food and Drug Administration (FDA) issued an alert highlighting the possibility of severe and sometimes incapacitating bone, joint and/or muscle (musculoskeletal) pain in patients taking bisphosphonates. Bisphosphonates are a family of non-hormonal drugs that are used to prevent and treat osteoporosis.

Osteoporosis is a disease of the bones that makes them weak and prone to fractures. In the United States, about eight million women and two million men have osteoporosis. Those older than 50 years of have greatest risk of developing osteoporosis and suffering from related fractures. In this age group, an estimated one in two women and one in six men will suffer an osteoporosis-related fracture at some point in their lives.

The FDA explained that although severe musculoskeletal pain is included in the prescribing information for all bisphosphonates, the association between bisphosphonates and severe musculoskeletal pain may be overlooked by healthcare professionals, delaying diagnosis, prolonging pain and/or impairment and necessitating the use of pain-relievers.

Pain is the most common reason individuals seek medical care. Pain is often classified as acute (immediate, short-term) or chronic (long-term). About 30-40 million Americans annually do not experience symptom relief with use of over-the-counter pain-relievers, such as acetaminophen (Tylenol®), aspirin and ibuprofen (Advil®). According to the American Medical Association (AMA), 13-15 million Americans suffer from chronic  and severe pain that is not easily managed. The annual cost of chronic pain in the United States, including healthcare expenses, lost income and lost productivity is estimated to be $100 billion.

The alert stated that the severe musculoskeletal pain may occur within days, months or years after starting a bisphosphonates. While some patients have reported complete relief of symptoms after discontinuing bisphosphonates, others have reported slow or incomplete resolution. The FDA cautioned that the risk factors for and incidence of severe musculoskeletal pain associated with bisphosphonates are unknown.

The FDA elaborated that this severe musculoskeletal pain is in contrast to the acute phase response characterized by fever, chills, bone pain, muscular pains and joint pains that sometimes accompanies initial administration of intravenous (injected into a vein) bisphosphonates and may occur with initial exposure to once-weekly or once-monthly doses of bisphosphonates taken by mouth. The symptoms related to the acute phase response tend to resolve within several days with continued drug use.

The FDA advised healthcare professionals to consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients who present with these symptoms and consider temporary or permanent discontinuation of the drug.

Integrative therapies with good scientific evidence in the prevention and/or treatment of pain include: acupuncture, bromelain, comfrey, guided imagery, hypnotherapy, hypnosis, music therapy, physical therapy and therapeutic touch.

Integrative therapies with strong scientific evidence in the treatment of osteoporosis include calcium and vitamin D. For more information, please visit Natural Standard's Medical Conditions database.

Comments

[Sam]

The bad news about this is that no one seems to know yet what the risk factors or causes are of the musculoskeletal pain resulting from taking bisphosphonates. Some alternatives to taking bisphosphonates are: calcitonin (Miacalcin®), a naturally occurring hormone produced by the thyroid gland and given as a nasal spray or injection to inhibit the cells that break down bones; estrogen, a hormone replacement therapy that can help maintain or increase bone mass in women after menopause; Raloxifenes, a Selective estrogen receptor modulator medication with similar advantages as estrogen therapy without the potential side effects (risk of uterine or breast cancers, blood clots and stroke) and unlike estrogen, it does not need to be combined with progesterone. Teriparatide is an injection of recombinant parathyroid hormone and has been used to treat people with established osteoporosis who have already experienced bone fractures, and people with risk factors or intolerance to bisphosphonates. Unfortunately, teriparatide has also been linked to increased incidence of osteosarcoma. The preferred osteoporosis treatment in Europe has become strontium ranelate, a “dual-action bone agent” that has proven efficacy in reducing osteoclasts (cells that break down bones) while increasing osteoblasts (cells responsible for bone formation). Calcium supplementation and weighted exercise can also be very beneficial in treating osteoporosis.

[Sean]

Calcium is critically important to bone health. However, the average American consumes levels of calcium that are far below the amount recommended.

Multiple studies of calcium supplementation in the elderly and post-menopausal women have found that high doses of calcium can help reduce the loss of bone density. Studies indicate that bone loss can be prevented in many areas, including the ankles, hips and spine.

Vitamin D is also important for good bone health because it helps the body absorb and use calcium.

[Greg]

Although calcium and vitamin D alone are not recommended as the sole treatment of osteoporosis, they are necessary additions to pharmaceutical treatments. The vast majority of clinical trials investigating the efficacy of pharmaceutical treatments for osteoporosis have investigated these agents in combination with calcium and vitamin D. So, even though calcium alone is unlikely to have an effect on the rate of bone loss following menopause, osteoporosis cannot be treated in the absence of calcium.

[Kristen]

As of February 2005, there were 112 reports of severe pain in patients taking Fosamax® and six reports of severe pain in patients taking Actonel® (both of which are bisphosphonates). The FDA is concerned that this adverse effect may be under-reported because patients may think the pain is from the osteoporosis instead.

[Ian]

I've heard that strength training/lifting weights can help prevent osteoporosis. As I understand it, when muscle pulls on bone, it helps builds bone. Therefore, weight-bearing exercises help build denser, stronger bones.

[Cassie]

Here's an interesting tidbit: Smokers lose bone more rapidly than nonsmokers. Among 80 year olds, smokers have up to 10% lower bone mineral density, which translates into twice the risk of spinal fractures and a 50% increase in risk of hip fractures. Fractures heal more slowly in smokers and are more likely to heal improperly.

[Tom]

A diet high in protein or coffee increases calcium loss and may increase the body's calcium needs. Fiber, oxalates (in rhubarb, spinach, beets, celery, greens, berries, nuts, tea and cocoa) and foods that contain a lot of zinc (such as oysters and red meats) decrease absorption, requiring more calcium in dietary supplement form.

The plant estrogens found in soy help maintain bone density and may reduce the risk of fractures, particularly in the first 10 years after menopause.

[Jess]

The musculoskeletal pain symptoms described in the FDA alert may or may not resolve after bisphosphonates are discontinued. Some patients have reported complete relief of symptoms after they stopped taking bisphosphonates, while others have reported slow or incomplete resolution.

[Jade]

Bisphosphonates decrease bone resorption by inhibiting osteoclast activity or through other mechanisms. Alendronate sodium (Fosamax®), ibandronate sodium (Boniva®) and risedronate sodium (Actonel®) are commonly prescribed for the treatment or prevention of osteoporosis in post-menopausal women. Other bisphosphonates that are approved for different uses include etidronate disodium (Didronel®), pamidronate disodium (Aredia®), tiludronate disodium (Skelid®) and zoledronic acid (Reclast® and Zometa®).

[K]

Never mind muscle pain- what about GERD?!! These pills cause major esophagus ulcers too! Also, you can't crush these, and they're hard to swallow. They have to come up with something better soon. Maybe Sally Fields has some ideas? ;). I suppose it's all about prevention...

[Sarah]

According to the product info for Fosamax®, the incidence of musculoskeletal pain ranges from 0.4% to 4.1%, depending on the dose and frequency. Also, the pain is not contained in one general area, and it can be so debilitating that it interferes with a person’s normal, daily activities. Doctors should always be aware that a new symptom could be from a medication, and alerts like this are a good way to remind them to look at the medications a patient is taking instead of adding a new one.

[Carey]

Actually Tom, coffee, or more specifically, caffeine, hasn’t been proved to increase bone loss. It’s been correlated with increased bone loss in people who already had genetic predispositions for bone loss and osteoporosis. However, studies have shown that people who consume milk daily throughout their adult lives were unaffected by caffeine consumption in terms of bone loss. Even people with genetic predispositions for bone loss were unaffected by moderate caffeine consumption. The thinking is that the biggest reason people who drink greater quantities of coffee only tend to have an increased risk for osteoporosis because they tend to substitute drinking coffee for opportunities to consume milk or other calcium-containing beverages.

[concerned]

Apparently, it isn’t only musculoskeletal pain you have to worry about with bisphosphonates. I came across a really horrible story online about a woman who was on Fosamax and developed internal abscesses in her teeth after taking Fosamax for a year and a half. She almost went into septic shock and had to have ALL of her teeth removed! AND because of deterioration of her lower jaw (osteonecrosis), her mouth wouldn’t hold a titanium rod to put in dentures for three whole months. The manufacturer, Merck, is facing lawsuits now from several people who suffered through similar experiences. It’s so scary to think they might have tried to conceal a serious reaction like that, or that it wasn’t made imminently clear to people taking Fosamax that these conditions might develop.

[Carey]

There are actually two different classes of bisphosphonates: N-containing and non-N-containing (N being nitrogen). The nitrogenous class of bisphosphonates includes those that are used to treat osteoporosis. I wonder if this musculoskeletal pain is also a side effect of non-nitrogenous bisphosphonates. Anyone know?

[Stacey]

It seems that both types of bisphosphonates (N-containing and non N-containing) have the similar side effect profiles. Musculoskeletal pain and osteonecrosis have been seen in both types. Osteonecrosis is a devastating adverse event from bisphosphonates. It is usually seen in patients who are receiving intravenous bisphosphonates, and it happens after some sort of dental surgery. However, the story mentioned before shows that it can happen with oral administration as well. So I’m wondering if this means that if you’re taking a bisphosphonate that you shouldn’t have dental surgery, seeing there is a risk. Seeing these adverse effects, it may be more beneficial to increase bone some other way, like taking more calcium and vitamin D!

[Deb]

Menopause is not the only cause of osteoporosis; medications can also cause a loss in bone minerals. Some medications that have been associated with osteoporosis are barbiturates, proton-pump inhibitors (Prilosec®), warfarin, and thiazolindiones (Avandia®). However, glucocorticoids are the main medication known to cause osteoporosis. This is usually when oral glucocorticoids are taken for long periods of time (longer than three months). The only FDA-approved drugs to treat steroid-induced osteoporosis are bisphosphonates and calcitonin.

[Julie]

Three new studies just came out about osteoporosis and how to evaluate your risk of fractures with the condition. Also, they discuss cost-effective solutions.

The first study (PMID: 18292978), FRAXtrade mark and the assessment of fracture probability in men and women from the UK, used a fracture risk assessment tool (FRAXtrade mark) for the prediction of fracture in men and women with the use of clinical risk factors (CRFs) for fracture with and without the use of femoral neck bone mineral density (BMD). The authors concluded that the models provide a framework which enhances the assessment of fracture risk in both men and women by the integration of clinical risk factors alone and/or in combination with BMD.

The second study (PMID: 18292977), Development and application of a Japanese model of the WHO fracture risk assessment tool (FRAXtrade mark) estimated the 10-year probability using the Japanese version of WHO fracture risk assessment tool (FRAXtrade mark) in order to determine fracture probabilities that correspond to intervention thresholds currently used in Japan and to resolve some issues for its use in Japan. The study concluded that the FRAXtrade mark tool approach will need to be supported by appropriate health economic analyses. Femoral neck BMD is suitable for the prediction of fracture risk among Japanese. However, when applying the FRAXtrade mark model to Japan, T-scores and Z-scores should be converted to those derived from the international reference.

And finally, a third study (PMID: 18292976 ), Cost-effective osteoporosis treatment thresholds: the United States perspective, conducted a United States-specific cost-effectiveness analysis, which incorporated the cost and health consequences of clinical fractures of the hip, spine, forearm, shoulder, rib, pelvis and lower leg, to identify the 10-year hip fracture probability required for osteoporosis treatment to be cost-effective for cohorts defined by age, sex, and race/ethnicity. The researchers concluded that the application of the WHO risk prediction algorithm to identify individuals with a 3% 10-year hip fracture probability may facilitate efficient osteoporosis treatment.

Check them all out, very interesting!

[Liv]

The onset of pain for alendronate was anywhere from one day to 52 months, with an average of 91 days. Also, although some patients found relief immediately after stopping the bidphosphonate, others found a much slower relief or only partial relief.

[mo]

Obviously, the goal of osteoporosis therapy is to reduce bone fractures and thereby illness and death. I remember reading a very disturbing statistic about how high death rates were one year following hip fractures! In addition to strengthening bone, however, treatment should focus on preventing falls. While certain exercises can build coordination and bone mass, others, like pilates and yoga, focus on strengthening core muscles and thereby improving balance. This is a huge benefit and should not be discounted!

[Jackie]

Comfrey as an alternative agent may be useful to some of these patients whose pain doesn’t fully disappear with the discontinuation of bisphosphonates. It is rated as having “good scientific evidence” in the treatment of pain, meaning that clinical trials have found statistically significant benefits. It is not recommended to take comfrey orally and is not available this way in the US. Using it as a topical cream may show benefit in patients experiencing pain.

[Deb]

Although there are some unsettling side effects with bisphosphonates, it is extremely important to reduce the risk of fractures. Hip fractures account for 300,000 hospitalizations a year. Although raloxifene (Evista®) can be used, it has not been proved to decrease hip fractures. Another bone-building medication, teriparatide (Forteo®), showed an increase in osteosarcoma in rats. All medications are going to have risks of certain side effects, but what are the risks for having a fracture? Statistics say that 1 in 5 people will die within a year of having a fracture. Also, a fracture could lead to surgeries and other problems. So the risk of developing these effects is small in comparison to the risks of having a fracture.

[Andy]

Strontium ranelate is another drug used for osteoporosis that is approved and commonly used in Europe; however, it has not been approved in the United States yet. It inhibits bone resorption, like bisphosphonates, and also promotes the growth of new bone, like teriparatide. In clinical trials it showed a decrease in vertebral fractures by more than 40% and reduced all no-nvertebral fractures by about 16%. Women with the lowest mineral density scores had the most improvement in non-vertebral fractures with a 39% decrease. The adverse effects seen during these trials were similar to placebo. However, it shouldn’t be used if a patient has kidney disease. Maybe this drug will be approved in the United States so patients who cannot tolerate bisphosphonates have another option.

[cahoneak]

Statistics show that one out of five people will die within a year of having a fracture.

What population do these statistics refer to? ALL people or specifically senior citizens?

IMHO, osteosarcoma is not a trivial side effect - it often requires surgery (like some fractures) and the risk factors there are quite comparable to those of fractures. The complications that may arise with osteosarcoma may require amputation - which is seldom the solution for a bone fracture.

[Hannah]

The statistics are for older Americans and can be found on the FDA Web site (www.fda.gov). Osteoporosis mainly affects adults who are older than 50, and it is estimated that 10 million Americans older than 50 have osteoporosis. These statistics are also from 2004, and the numbers have most likely changed in the last four years.

[Harry]

In response to cahoneak…not sure exactly what the article refers to, but I did find an article that says that one in four people who experience hip fractures due to osteoporosis over the age of fifty die within a year of the injury. Hopefully that gives a little bit better picture.

[Gina]

Bromelain has been used for joint pain and muscle injuries to decrease pain. It has anti-inflammatory properties and can be taken orally or applied topically as a cream. Some people may be allergic to bromelain, and it may cause a rash, GI discomfort, difficulty swallowing or wheezing. It is also believed to have an effect on blood-thinning medications, so it should be used cautiously in patients taking warfarin.

[Jean]

Bisphosphonates have also been used for other conditions besides prevention and treatment of osteoporosis. These include Paget’s disease (large or disformed bones), bone metastasis and multiple myeloma. Intravenous bisphosphonates, like pamidronate, have been shown to modify the progression of skeletal metastasis, especially women with breast cancer. Oral and intravenous bisphosphonates can be used in Paget’s disease.

[Heather]

Nonsteroidal anti-inflammatory drugs (NSAIDs), like ibuprofen, naproxen and acetaminophen (Tylenol®), have been used to treat musculoskeletal pain. If these medications are not enough, acupuncture has been studied as an addition. Acupuncture has been seen to improve pain in most patients. One study from 2002 found that 69% of patients had good or excellent response to acupuncture.

[jeffrey dach md]

Questioning Bisphosphonates:

There are obvious similarities between bisphosphonate adverse side effects and the genetic disease, pycnodysostosis, namely jaw necrosis, phossy jaw, spontaneous femur fracture and severe bone pain.

Pycnodysostosis was Toulous Lautrec’s genetic disease, causing a cathepsin K deficiency in the osteoclasts, which are the bone cells responsible for bone resorption. Similarly, the mechanism of bisphosphonates is to impair the osteoclasts.

Cathepsin K and osteoporosis from Nature:

"Cathepsin K is a lysosomal cathepsin located in osteoclasts, and is the major enzyme involved in bone resorption. The first evidence for this role came from a genetic study on pycnodysostosis, a rare genetic disorder associated with severe defects in bone growth, which revealed that an inactivating mutation in the gene encoding cathepsin K is a causative factor."

Are the bisphosphonate drugs creating a population of women with Toulous Lautrec's Bone Disease?

Increased Fracture Rates

The fracture rates for women with osteopenia (T greater than -2.5) actually increases for women on bisphosphonates. Cummings JAMA 1998 (FIT) Fracture Intervention Trial.

The following is a quote from John Abramson's book, Overdosed America from: Excerpts From Overdosed America Chapter 13

"What about using these drugs to prevent osteoporosis? The study of Fosamax published in JAMA in 1998 also included women with osteopenia. Did Fosamax reduce their risk of fracture? The results show that the risk of hip fractures actually went up 84 percent with Fosamax treatment. The risk of wrist fractures increased by about 50 percent." JAMA.1998;280:2077-2082.Cummings. Quote attributed to John Abramson MD.

http://jeffreydach.com/2008/03/09/bisphosphonates-for-osteoporosis-a-closer-look-at-the-data-by-jeffrey-dach-md.aspx

Bisphosphonates for Osteoporosis, A Closer Look at the Data by Jeffrey Dach MD

Fosamax, Actonel, Osteoporosis and Toulouse Lautrec

Jeffrey Dach MD

[pauline brooks]

I took Fosamax® for six months. I got severe muscle and bone pain in my back and arms. I got over most of the pain but still have severe pain in my right arm and do not have full use of it. Is there a natural cure for pain? I have had pain for two months.

[Cynthia]

I took Fosomax for about six months, and stopped taking it about six months ago when I read about the rare but possible side effect of necrosis of the jaw. I am aware of the fact that Fosomax has a 10-year half life. About three weeks ago I began experiencing severe pains in my elbow, wrists and on the backs of my hands. For two days it kept me awake at night -- it was so severe. Then the pain disappeared as mysteriously as it appeared, with the exception of my left hand. I have no strength in my left hand, especially where my thumb joins the wrist. It's painful to the touch, too. Today I read about the FDA warning about Fosomax and muscular and joint pain. I wonder if Fosomax could affect me months after discontinuation????