Bisphosphonates have been used for decades to treat various conditions. But they can have risks and side effects in certain patients.
Bisphosphonates, also known as diphosphonates, are a class of drugs that have been used commonly for more than two decades for the treatment and prevention of osteoporosis. Bisphosphonates slow bone resorption by reducing osteoclast function. Many studies have shown that this class of medication can improve bone density and reduce the risk of fracture in patients with a reduced bone density. They are administered in two ways: orally and intravenously.
Bisphosphonates include the following medications:
Alendronate (Fosamax), risedronate (Actonel) and ibandronate (Boniva) are available orally. The former two agents can be taken daily or weekly; the latter two agents can be taken daily or monthly.
Pamidronate (Aredia), ibandronate (Boniva) and zoledronic acid (Reclast) are available intravenously. The former two agents are generally given every three to four months, and the latter agent yearly. Pamidronate was the first available intravenous bisphosphonate. Although it has been used to treat osteoporosis, it along with is FDA-approved for hypercalcemia (too much calcium in the blood) caused by cancer, as well as for and Paget’s disease. Zoledronic acid is also FDA-approved to treat both of these conditions.
These drugs reduce the risk of osteoporosis-related fractures as quickly as six months after institution of the drug. Alendronate has been FDA-approved since 1995 and hundreds of millions of prescriptions have been written. Fewer people have used risedronate and ibandronate, primarily because they have not been available as long as alendronate. Zoledronic acid attained FDA-approval for the treatment of osteoporosis in 2007, but it has also been used since the 1990s for the treatment of other conditions such as Paget’s disease, malignancy metastatic to bone and early on (off-label) for the treatment of osteoporosis.
There has been concern about a possible association between esophageal cancer and oral bisphosphonate use, however the FDA has not concluded that patients taking bisphosphonates have an increased risk of esophageal cancer.
Bisphosphonates are known to cause esophageal and gastric irritation in a small percentage of patients. Because of this, patients are instructed to remain upright for 30 to 60 minutes after ingestion. This is felt to improve both absorption and to promote gastric motility and reduce the time available for these agents to irritate the upper gastrointestinal tract. Patients who report gastric side effects may well be non-compliant with dosing instructions, as incidence of side effects is very low if instructions are followed correctly.
Review of large Medicare databases have not shown increased risk of esophageal cancer in patients taking oral bisphosphonates. However, from October 1995 to May 2008, the FDA reviewed reports of 23 patients in the US with a new diagnosis of esophageal cancer in patients taking alendronate. In Europe and Japan, 31 cases of esophageal cancer were identified as possibly related to bisphosphonate use. A few of these patients had a diagnosis of Barrett’s esophagitis, which is known to increase the risk of esophageal cancer.
There have been case reports of finding crystalline material similar to ground alendronate in biopsies of patients who have endoscopy for erosive esophagitis. This raises the question of a possible carcinogenic role of bisphosphonates associated with gastrointestinal irritation.
Obviously, millions of patients have taken oral bisphosphonates since alendronate was FDA-approved in 1995. If there is an increased risk of esophageal cancer associated with use of these drugs, it does seem to be low; the increased risk may be associated with the patients having chronic gastrointestinal irritation, which has been described with this class of drug.
The FDA recommends avoiding oral bisphosphonates in patients with a history of Barrett’s esophagitis. Any patients who describe gastrointestinal symptoms related to bisphosphonate use should be evaluated. These patients may well be candidates for intravenous zoledronic acid, which is FDA-approved for the treatment of osteoporosis and is not associated with gastrointestinal irritation.
There has been a lot written on a possible relationship between bisphosphonates and a condition called osteonecrosis of the jaw (ONJ), which refers to an area of bone that has lost its blood supply. However, there is lack of rigorous scientific evidence to support a cause-and-effect relationship between bisphosphonates and ONJ.
Patients with ONJ (also known as avascular necrosis of the jaw) develop exposed bone in the jaw. The overlying tooth often falls out and a non-healing, often painful lesion remains. Also, an associated drainage tract may be present, connecting the area of damaged bone to the gum surface. Osteonecrosis of the jaw is more common in the lower than in the upper jaw.
Reports emerged first in oncology patients receiving 12 times the dose of zoledronic acid used to treat osteoporosis. Cases of non-healing maxillofacial bone lesions were recognized primarily in patients on chemotherapy who had poor dental hygiene. Controlled studies in patients with osteoporosis and Paget’s disease have failed to show an increased risk of ONJ, even after years of treatment with alendronate.
In 2011, an American Dental Association (ADA) expert panel estimated the prevalence of ONJ in patients receiving bisphosphonates for osteoporosis to be very low, about 0.10% at most. The ADA recommended that necessary dental work be done, regardless of the use of bisphosphonates.
When avascular necrosis of the jaw develops, it remains unclear how best to treat it. This has led to the great concern that both patients and healthcare providers are experiencing. Treatment protocols are being designed, but they have not been tested.
It is prudent for all patients to have a dental exam and cleaning prior to beginning bisphosphonate therapy, and regular dental cleaning should continue throughout the duration of use. As infection possibly triggers ONJ, the hope is that proper dental care will reduce the incidence of osteonecrosis of the jaw.
Discontinuing bisphosphonate therapy for low turnover state of bone may help prevent this condition (one way to measure turnover state in bone is the urinary N-Telopeptide, and some physicians suggest stopping bisphosphonate therapy if this result is less than 10). However, this remains controversial, and there is little evidence to support this approach.
If ONJ develops in any patient, patients should be treated with conservative debridement of affected bone, antibiotics, antimicrobial mouth washes, and pain control. Bisphosphonate therapy is generally discontinued if this condition occurs, although there is no data to show that this leads to resolution of the problem.
Uncommon side effects of bisphosphonate therapy include fractures of the femur (such as a hip fracture) and inflammatory eye disease.
Stresss fracture of the femur (thighbone), is an uncommon side effect believed to occur as a result of slow bone turnover and a lack of remodeling of “old” bone into new bone. The risk of this rare complication increases with duration of treatment. It almost never occurs in patients who have been treated with bisphosphonates for less than five years. The fracture has a classic appearance on X-ray.
If a patient receiving bisphosphonate therapy notes thigh pain, a femur X-ray should be obtained. The radiologist may be able to see signs suggestive of patients at risk for this type of fracture. If a patient is on a bisphosphonate at the time of an atypical femur fracture, the bisphosphonate should be held and the fracture repaired. The patient may be a good candidate for teriparatide.
Data suggests that scleritis and uveitis, which are types of eye inflammation, may also be rare side effects of bisphosphonate therapy. Symptoms are often a red, painful eye that is sensitive to light. The condition can usually be treated with eye drops. Patients on bisphosphonates should be instructed to call their provider if these signs are noted.
As when any medication is prescribed, the risks and benefits of that medication must be considered. For the treatment of osteoporosis, patients must understand that hip fractures can lead to significant disability and death (e.g., from clots in the lung related to leg clots that develop after fracture), and that multiple vertebral fractures can cause very significant pain and disability. This must be weighed against what appears to be a probably very low risk of osteonecrosis of the jaw, atypical stress fractures of the femur, esophageal irritation, and inflammatory eye disease.
Oncologists treating patients with multiple myeloma and metastatic cancer have a different set of concerns, and the use of bisphosphonates in a patient who has cancer requires that a different set of issues be weighed. In patients being treated for osteoporosis, the consequences of untreated disease, with resultant fractures must not be forgotten when striking the proper balance.
Osteoporosis remains a significant problem for society. The number of osteoporotic fractures is expected to rise as the population ages. The risk of an osteoporotic fracture in a patient at risk is much greater than the risk of ONJ in that patient. Most cases of ONJ can be treated conservatively. This area requires additional study so that we can all better understand the risk and appropriate treatment of ONJ.
After balancing the risks and benefits, bisphosphonates will likely remain the best choice for many patients with osteoporosis. However, the decision regarding the optimal drug for managing osteoporosis in each patient is quite individual and should be determined on a case-by-case basis. Patients on bisphosphonate therapy should be reevaluated annually to see if continued use of the medication is indicated.
Assistant Attending Physician, Hospital for Special Surgery
Assistant Professor of Clinical Medicine, Weill Cornell Medical College
Assistant Attending, NewYork-Presbyterian Hospital