Drug Profile

Alendronate (FOSAMAX) and risedronate (ACTONEL) belong to a class of drugs called bisphosphonates, which are used to treat and prevent osteoporosis in postmenopausal women and to increase bone mass in men with osteoporosis. They also are approved for treatment of a bone disease known as Paget's disease.

Bisphosphonates also are approved to treat and prevent osteoporosis caused by prolonged use of corticosteroids, such as prednisone (DELTASONE) or prednisolone (PRELONE), which is known as glucocorticoid-induced osteoporosis. However, they should not be used for this purpose (see the "DO NOT USE" warning box above). Therefore, we have designated these drugs as Limited Use.

Bisphosphonates inhibit activity of the bone cells that break down and reabsorb bone. The breakdown and creation of bone are linked, and because of that, these drugs decrease bone turnover (synthesis and breakdown).

Alendronate and risedronate are not indicated for use in children. The safety and effectiveness of bisphosphonates in children under the age of 18 years is not known. Bisphosphonates should not be used in pregnant or breast-feeding women.[5] Bisphosphonates are not to be used in premenopausal women or by people with mild osteoporosis or severe kidney problems. The drugs should not be given to people with dementia or those who are otherwise unable to follow the instructions on how to take the medication.

For Paget's disease, alendronate is given daily for six months. If a relapse occurs, alendronate is sometimes resumed. Risedronate is given for two months and repeated if necessary.

Alendronate

Alendronate has been shown to reduce the risk of hip fracture by 1% in women who had previously experienced at least one vertebral fracture; 2% of women taking a placebo had hip fractures versus 1% of women taking alendronate, a 50% relative reduction. Vertebral fracture is a spinal fracture that may or may not be symptomatic. Most (more than 85%) of the women who took the placebo in three-year clinical trials did not have a fracture of any type. Fewer studies have been done on men taking alendronate.

A study looking at patients using alendronate for up to 10 years has left many questions unanswered. Three groups of postmenopausal women were studied:

1. Those who had taken alendronate for five years, followed by a placebo for five years;
2. Those who had taken 5 milligrams (mg) per day for 10 years; and
3. Those who had taken 10 mg per day for 10 years.

The main study endpoint was bone mineral density (BMD) at the lumbar spine — not fractures, although fractures also were studied.[6]

Although there were greater increases in BMD with the larger, 10-mg dose, taken for 10 years, this increase was not associated with a lower fracture rate.

Women who had discontinued the drug after five years had about the same number of vertebral fractures as those taking 10 mg for five years. (New "fractures" were defined by examining radiographs and measuring loss of height of the vertebrae.) The loss in height was only very slightly less in the 10-mg group than in the discontinuation group (less than 0.1 inch less loss over the five-year period). As noted in the drug profile for raloxifene (EVISTA), improvements in BMD and fracture reduction are not clearly related; that appears here as well. Yet, women often are treated based on BMD alone.

An accompanying commentary to the 10-year trial raised concerns about what happens to bone structure with continuing increases in BMD. There is evidence from animal studies that with prolonged alendronate use, bones become more brittle and susceptible to fracture. Unfortunately, it is currently unknown at what point that occurs in people. The commentary stated that it was not known how long women should stay on alendronate or how long benefits might last after the drug is stopped.[7]

A more recent study concluded that for many women, discontinuation of alendronate after five years for up to five more years does not significantly increase fracture risk. The product labeling for alendronate now states that optimal duration of use of the drug has not been determined and that for patients at low risk of fracture, drug discontinuation after three to five years of use should be considered. However, women at high risk of clinical vertebral fractures, such as those with previous vertebral fracture or very low BMD, may benefit by continuing treatment beyond five years.[8]

Risedronate

Risedronate, like alendronate, is associated with a modestly favorable effect on the risk of vertebral fracture. The absolute reduction in the risk of a new vertebral fracture in women taking risedronate is 5% (compared with women taking an inactive placebo). The most benefit was seen in women with two or more vertebral fractures before they started taking risedronate.[9]

A published study sponsored by risedronate manufacturer Procter & Gamble suggests that risedronate may reduce the risk of hip fracture, the most serious consequence of osteoporosis, in elderly women with low BMD by about 1% (the same result as alendronate).[10] However, this study has been criticized on a number of grounds, including the fact that follow-up information was not available for 3,324 of the 9,331 women in the study.[11] This could have biased the results in favor of risedronate by leaving out women who eventually had fractures.

Risedronate is retained in bones for many years, but its long-term effects remain uncertain. Concern exists because some bisphosphonates increase the occurrence of spontaneous fractures in animals.[12] The product labeling for risedronate now states that optimal duration of use of the drug has not been determined and that for patients at low risk of fracture, drug discontinuation after three to five years of use should be considered.

Adverse effects

Since alendronate came on the market, there have been reports of serious adverse effects associated with its use, including several cases of bone, joint and muscle pain.

Other common adverse effects include stomach pain, nausea, indigestion, constipation and diarrhea.[13] Rare adverse effects include changes in vision.[14] Bisphosphonates are retained in bones for many years, even after patients stop taking them.[15],[16] Uncertainty exists as to when therapy should begin and how long it should continue, as well as the impact on nonspinal fractures for those with low risk.[17]

Reports of very rare allergic and skin reactions (including hive-like swelling under the skin, especially around the face and mouth [angioedema], generalized rash and severe blistering of the skin) have been associated with risedronate since it has been on the market.

Osteonecrosis of the jaw

Severe musculoskeletal pain and death of the bone tissue of the jaw (osteonecrosis) also have been reported.[18] The typical signs and symptoms of osteonecrosis of the jaw include pain, swelling or infection of the gums; loosening of the teeth; poor healing of the gums; numbness or a feeling of heaviness in the jaw; drainage; and exposed bone. Patients with the least serious form of this condition may not show any symptoms, but in the most serious cases, some patients may require the removal of sections of the jaw.

An Annals of Internal Medicine review of medical literature shows that there have been hundreds of reported cases of osteonecrosis of the jaw linked to drugs commonly used to treat osteoporosis. According to the review, osteonecrosis was more common in the lower jaw than the upper jaw. More than half of all cases (60%) occurred after dentoalveolar surgery (such as tooth extraction) to treat infections, and the remaining 40% were probably related to infection, denture trauma or other physical trauma occurring in the absence of dental surgery.

The authors of the review stated, "The concern is that with more women aging and taking bisphosphonates for longer periods of time, more cases of osteonecrosis may develop even in patients receiving alendronate or ibandronate [BONIVA] therapy."[19]

Ninety-four percent of the patients who developed osteonecrosis of the jaw were those with cancers such as multiple myeloma, as well as patients with cancers that have spread to the bone and patients who are receiving intravenous bisphosphonates. The remaining cases were in people using oral bisphosphonates such as alendronate or risedronate.

Osteonecrosis of the external ear canal

In November 2015, the Food and Drug Administration (FDA) updated the drug product label of alendronate to include a warning about reports of osteonecrosis of the external ear canal. In December 2015, the Medicines and Healthcare Regulatory Agency (MHRA), a regulatory agency in the U.K., also issued an update that osteonecrosis of the external ear canal has been reported rarely with bisphosphonate use. Signs of osteonecrosis of the external ear canal may include ear pain, ear discharge and ear infection. [20]

Interactions with other drugs

Emerging evidence suggests a possible harmful interaction between nonsteroidal anti-inflammatory drugs and bisphosphonates. The combination can result in an increased risk of ulcers and other gastrointestinal adverse effects. Read more in the July 2010 Worst Pills, Best Pills News.

In 2020, an article in Medicine reported two cases of increased bleeding in patients treated with warfarin who start taking alendronate.[21] The patients had marked increases in their levels of anticoagulation within 24 hours of starting the alendronate.

How to take these drugs

Bisphosphonates such as alendronate and risedronate can irritate the esophagus (the tube that connects the mouth and stomach), causing ulcers and bleeding. Because of this, the drugs must be taken with water on an empty stomach. Patients should stay upright for at least half an hour after each dose to ensure that the tablet does not get stuck in the esophagus before reaching the stomach. Also, to get the maximum absorption of the drug, patients should not eat or drink anything but water during this half-hour period.

Studies show ...

There have been multiple case reports of synovitis (inflammation and pain in a joint) associated with alendronic acid, used in alendronate, and one published case report of myalgia (muscle pain) and arthritis. A comparison of the patients receiving alendronic acid with the patients receiving a placebo during clinical trials found that bone, joint or muscle pain occurred in about 4% of the patients treated with alendronic acid and in about 2.5% of the patients treated with placebo.[22]

A July 15, 2008, New York Times article discussed a study documenting growing evidence for the long-held concern that long-term use of bisphosphonates can actually make bones brittle and more likely to fracture. Although the evidence is far from conclusive, emerging reports of a unique type of fracture in patients receiving bisphosphonates for many years point toward the drug as a possible culprit.[23]

In September 2011, the Center for Adverse Reactions Monitoring in New Zealand reported that as of June 30, 2011, it had received reports of eye inflammatory effects associated with bisphosphonate drugs.[24]

In December 2020, the Journal of the American Medical Association Network Open published a systematic review showing that bisphosphonate therapy did not lead to an improvement in hip fracture rates when the medication was used for more than five years .[25]

Regulatory actions surrounding bisphosphonates

2004: The FDA updated the adverse reaction section of the product label for alendronate to include post-marketing reports of bone, joint and muscle pain.[26]

2006: The FDA required manufacturers of bisphosphonates to add information about severe musculoskeletal pain and osteonecrosis to the adverse reaction section of their product labels.[18]

2008: The FDA issued an alert to highlight the possibility of severe and sometimes incapacitating bone, joint and muscle pain in patients taking bisphosphonates. The alert informed health care professionals that they should consider whether bisphosphonate use might be responsible for severe musculoskeletal pain in patients.[27]

In January, the FDA issued an early communication of an ongoing safety review concerning the association of atrial fibrillation with the use of bisphosphonates. The agency had reviewed some safety data and requested additional data to further evaluate this risk.[28]

In November, the FDA issued an update to the review of atrial fibrillation associated with bisphosphonate use, saying:

The occurrence of atrial fibrillation was rare within each study, with most studies containing two or fewer events. Across all studies, no clear association between overall bisphosphonate exposure and the rate of serious or non-serious atrial fibrillation was observed. Additionally, increasing dose or duration of bisphosphonate therapy was not associated with an increased rate of atrial fibrillation.[29]

2010: The FDA issued information relating to bisphosphonate use and a risk of atypical subtrochanteric femur (leg) fractures. The FDA stated that the data it reviewed did not show a clear connection between bisphosphonate use and this risk. The agency said it would continue to gather more information and evaluate the issue further.[30]

In October, the FDA issued another advisory relating to bisphosphonate use and a risk of leg fractures. It required that this information be added to the "Warnings and Precautions" section of the drug product labels and that a Medication Guide be given to patients when they pick up or refill their bisphosphonate prescriptions.[31]

Alendronate and risedronate are two of a limited number of drugs for which the FDA requires an FDA-approved Medication Guide be dispensed when the prescription is filled or refilled.

2011: The FDA released information regarding whether the use of oral bisphosphonate drugs is associated with a potential increased risk of cancer of the esophagus. The agency stated that it was conducting an ongoing review of data and, so far, had not concluded that a risk was present. The agency said that it would continue to update the public when more information became available.[32]

In September, Public Citizen testified before the FDA's Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. The testimony stated that given the effects of underreported rare stress fractures, osteonecrosis of the jaw and other serious risks, bisphosphonates should be restricted to patients who would actually benefit from them. The testimony contended that bisphosphonates have not been shown to decrease fracture risk in postmenopausal women with osteopenia (decreased bone density that is less severe than that seen with osteoporosis) and all patients remaining on these drugs beyond five years.