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Symptoms And Side Effects - Bisphosphonates


Bisphosphonates

What are bisphosphonates?

Bisphosphonates are medicines that are used in the treatment of myeloma bone disease and are usually used in conjunction with other cancer therapy. Bone disease is common in multiple myeloma, with 85% of patients having bone problems.

Bisphosphonates have been shown to:

  • Help slow the advancement of bone disease

  • Decrease bone pain

  • Reduce fractures

  • Improve overall survival (one large study)

Bisphosphonates are also used in the treatment of bone metastases and hypercalcemia of malignancy (increased calcium levels in the blood). They are also used in other cancers where the bone is affected (e.g. breast cancer, prostate cancer).

In addition, bisphosphonates are commonly used to treat osteoporosis (bone thinning) and are used in the treatment of a bone disease called Paget's disease.

What are the different types of bisphosphonates?

Two types of bisphosphonates are approved in the US for the treatment of myeloma bone disease—pamidronate (Aredia®) and Zometa® (zoledronic acid). Zometa is also approved to treat patients with metastatic bone disease regardless of what type of cancer led to the bone disease whereas pamidronate is only also approved for patients with breast cancer. Both of these drugs are given intravenously (into the vein) monthly. Pamidronate is given over 2-4 hours while Zometa is given over 15 minutes. There has only been one large, randomized study comparing both drugs for myeloma patients with bone disease and both drugs were equally effective.

There are many oral bisphosphonates available, but these medicines are mainly used in osteoporosis and other bone diseases unrelated to multiple myeloma or other cancers.

How do bisphosphonates work?

Bisphosphonates block the activity of bone-destroying cells called osteoclasts. Normally, osteoclasts work in harmony with bone-forming cells called osteoblasts in order to rebuild areas of bone that need replacing. However, in myeloma, bone destruction by the osteoclasts is increased and exceeds bone formation, resulting in loss of bone. This can lead to pain, bone fractures, spinal cord compression (a condition where the vertebrae of the spine are compressed putting patients at risk for fractures), and increased levels of calcium in the blood and urine.

Who should take bisphosphonates?

All patients with symptomatic multiple myeloma should receive monthly intravenous bisphosphonate therapy along with their myeloma treatments. Bisphosphonates may also be considered in patients with smoldering multiple myeloma especially among patients demonstrating bone loss in x-rays or in a special bone test that measures bone density (bone densitometry or DEXA).

A large study in the United Kingdom has reported that after 4 years of follow-up both patients with and without bone disease benefitted from Zometa. Both groups had a reduced incidence of skeletal complications. However, it still recommended that only patients with bone disease receive Zometa.

How are bisphosphonates given?

Both Zometa and pamidronate are given intravenously (into a vein) once a month.

Zometa is given as a 15 minute infusion whereas pamidronate is given over a 2- to 4- hour period. In addition, patients should also take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.

How long should bisphosphonates be taken?

Patients should take bisphosphonates monthly for at least 2 years. Some physicians recommend that patients whose myeloma is stable or in remission stop therapy after 2 years. It is important to keep in mind that there is no data evaluating these drugs after 2 years of therapy.

What are the possible side effects and how are they managed?

In general, bisphosphonates are well tolerated. If side effects occur they are usually mild.

Common side effects include:

  • Fever

  • Fatigue

  • Flu-like symptoms

  • Bone / Muscle pain

  • Stomach problems

  • Anemia

  • Low levels of calcium

The flu-like symptoms along with fever and bone/muscle pain occur in approximately 15% of patients following the first dose. These symptoms usually begin 1-2 days following the first dose and the symptoms persist for approximately 8 12 hours. These symptoms do not continue beyond the first dose except in rare cases.

Rare, but serious side effects include:

  • Kidney problems

  • Osteonecrosis of the jaw (damage to the jawbone)

  • Unusual types of bone fractures

Kidney problems have been seen in patients taking intravenously administered bisphosphonates for long periods of time. The risk of kidney problems may be increased in patients who are taking other drugs that affect the kidney (e.g. Thalomid, non-steroidal anti-inflammatory drugs also known as NSAIDs) or have other conditions associated with kidney problems such as hypertension or diabetes mellitus.

  • Because of the potential for kidney problems, patients taking bisphosphonates should have a blood test to monitor their kidney function (creatinine levels) prior to each treatment. In addition, other blood tests should be performed periodically

  • Although it has been recommended that patients with mild or moderately reduced kidney function (renal impairment) receive lower doses of Zometa, there are no clinical trials to support this recommendation. Since zoledronic acid has not been evaluated among patients with severe renal impairment, pamidronate should be used in patients with this condition.

If you develop kidney problems while taking bisphosphonates, your therapy will be stopped temporarily and may be re-started once the problem is resolved.

Another rare, but serious side effect, called osteonecrosis of the jaw (ONJ) has been reported some studies. ONJ is a painful condition that involves damage to the jaw bone. Symptoms of ONJ include pain, swelling, infection of the jaw and exposed bone. ONJ seems to be related to the length of time patients are on bisphosphonates and the type of bisphosphonate. It has been seen more frequently in patients taking Zometa.

The majority of patients who develop ONJ have had recent dental or oral surgery or dental injuries (such as a broken tooth). It is important to maintain good oral health while taking bisphosphonates in order to avoid infections in the jaw that might require surgery impacting the jaw bones.

Keeping Your Mouth Healthy While Taking Bisphosphonates

  • Before taking bisphosphonates, patients should have a comprehensive dental exam and complete major dental work.

  • Practice good daily oral hygiene with brushing, flossing and use of an special type of toothbrush called a proxy brush

  • Schedule regular dental visits and let your dentist know you are receiving bisphosphonates

  • Report all dental problems promptly

  • Avoid tooth extractions and dental procedures that impact the jawbone unless absolutely necessary. However, procedures such as repair of cavities, root canals, crown placement, and dental cleaning are not associated with a risk of ONJ

  • If a dental procedure that impacts the jaw bone is required, bisphosphonate therapy should be stopped for 3 months prior to the procedure and should not be re-started until the mouth is completely healed and not in less than 3 months following the procedure


Recently, reports of unusual fractures of the hip bone and bones in the feet have been reported with long term use of these drugs.

Do bisphosphonates have an anti-myeloma effect?

A large Phase III trial in the United Kingdom showed that Zometa compared to a weak oral bisphosphonate (clodronate) had an anti myeloma effect. Zometa was not only superior to clodronate in its impact on skeletal problems but also significantly improved overall survival by an average of 5.5 months in patients with bone disease (50 months with Zometa vs. 44.5 months with clodronate). The beneficial effect of Zometa on overall survival could not be explained by bone effects alone, raising the possibility that the drug may have other favorable anti myeloma effects. There is much laboratory data to support the direct, indirect and immune-based anti-myeloma effects of Zometa.

How are bisphosphonates being studied in clinical trials?

A large national study is evaluating whether Zometa can be given less frequently—once every 3 months versus once a month. The goal of this study is to determine if less frequent dosing is safer than the standard dose as well as to compare the effectiveness of these two schedules.

In addition, due to a possible anti myeloma effect, Zometa is being studied in combination with Thalomid (an anti-myeloma drug) in early stage multiple myeloma to determine whether or not this combination is more effective than Thalomid alone in slowing the progression of myeloma.

What new bone drugs are in development?

A new drug available for treatment of bone disease is Xgeva (denosumab, Amgen). Xgeva is not a bisphosphonate. It is a novel agent approved by the FDA for many types of cancer, but it is not approved for use in multiple myeloma.

This drug was compared with Zometa in a Phase III trial of 1,756 people with advanced cancers, including 190 patients with multiple myeloma. Overall, the study showed that Xgeva was similar to Zometa in preventing bone complications. However, mortality was significantly higher among the myeloma patients treated with Xgeva. The limited number of myeloma patients in this study makes it difficult to definitively determine its effect. As a result, a larger randomized trial is now planned to evaluate monthly Xgeva compared to Zometa.

There are other new drugs in early stage clinical development (Phase I or Phase II) that may have the ability to not just strengthen bones but to also re-build them. They include ACE-011 and BHQ880.

To find a clinical trial call 1-866-603-MMCT (-6628) or click here to go to the MMRF Patient Navigator Program.

For more information on Zometa visit www.Zometa.com

For more information on pamidronate visit www.pamidronate.com

Reviewed by
William I. Bensinger, MD
Member, Fred Hutchinson Cancer Research Center
Professor of Medicine, University of Washington