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Bisphosphonates Overview
What They Are
Bisphosphonates are a group of compounds that are used in the treatment of myeloma bone disease. They are used specifically to
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Help reduce the advancement of bone disease
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Decrease bone pain
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Reduce fractures
Examples of Bisphosphonates
Bisphosphonates that are approved in the US for the treatment of bone metastases and myeloma bone disease include the following intravenous agents:
You may be aware of other oral bisphosphonates on the market, such as Actonel® (risendronate), Boniva® (ibandronate), Didronel® (etidronate; also available as an intravenous formulation), Fosamax® (alendronate), and Skelid® (tiludronate). These are mainly used in the treatment of osteoporosis and other bone diseases rather than myeloma. In general, these bisphosphonates are not absorbed as completely in the body and are less potent, so they are not as effective in treating myeloma bone disease.
Ibandronate (Boniva, SmithKline/Roche) has been studied for use in myeloma in a Phase III trial, but the dose tested (2 mg) did not appear to be sufficient to demonstrate significant effects on preventing skeletal complications. (Menssen et al. J Clin Oncol. 2002;20:2353-2359.)
Other bisphosphonates, such as incadronate (Yamanouchi Pharmaceutical) are being studied in the laboratory for their effects on myeloma cells. The oral bisphosphonate minodronate (YM529, Yamanouchi) is in late-stage clinical trials in Japan for use in myeloma bone disease.
What They Do
Bisphosphonates inhibit 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 resorption by the osteoclasts is increased and exceeds bone formation, resulting in loss of bone. This can lead to pain, bone fractures, spinal cord compression, and increased levels of calcium in the blood and urine. Different bisphosphonates appear to inhibit osteoclasts in slightly different ways. Some bisphosphonates appear to inhibit production of factors that stimulate osteoclasts, while others inhibit the actual development of the osteoclast cells or inhibit attachment of the osteoclasts to the bone surface. Some bisphosphonates do several of these things.
Benefits in Myeloma
In patients with myeloma, intravenous bisphosphonates delay and reduce the number of skeletal events (bone complications such as fractures, radiation therapy to bone, surgery to bone, or spinal cord compression) and reduce bone pain. They also normalize levels of calcium in patients with hypercalcemia of malignancy. Details about the benefits of specific intravenous agents can be found here:
Guidelines for Use of Bisphosphonates in Myeloma
In September 2002, the American Society of Clinical Oncology (ASCO) published clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone disease in myeloma. (Berenson et al. J Clin Oncol. 2002;20:3719-3736.) Upon review of published literature, the expert panel agreed that bisphosphonates reduce skeletal complications and provide a meaningful support benefit to myeloma patients with bone disease. Key points of the guidelines are summarized here.
| Summary of Guidelines for Use of Bisphosphonates in Myeloma
|
Potential Antitumor Effects
Certain bisphosphonates, particularly the newer, more potent nitrogen-containing compounds (eg, ibandronate, pamidronate, risedronate, and zoledronic acid), also appear to have antitumor activity. For example
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Bisphosphonates have been shown to reduce production of the growth factor interleukin 6 (IL-6) by bone marrow cells from patients with multiple myeloma. IL-6 is known to play an important role in the growth and survival of myeloma cells
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Recent reports also show that pamidronate can stimulate an immune response against myeloma that is mediated by T-cells
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The bisphosphonates pamidronate and zoledronic acid (Zometa) have been shown to induce apoptosis (programmed cell death) in human myeloma cell lines grown in the laboratory
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In laboratory studies, the bisphosphonates pamidronate, incadronate, and zoledronic acid inhibited myeloma cell growth and caused tumor cell death
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In animal models of myeloma, pamidronate and zoledronic acid exert antimyeloma effects
However, it is not known whether these bisphosphonates have the same effects in patients with myeloma.
Pamidronate
What It Is
Pamidronate, which is available as Aredia® (Novartis) and other generic brands, is an intravenous, nitrogen-containing bisphosphonate. It is approved in the US for the treatment of bone metastases of breast cancer, bone lesions in myeloma, hypercalcemia of malignancy (HCM), also known as tumor-induced hypercalcemia (TIH), and a bone disease called Paget's disease.
What It Does
Pamidronate inhibits bone resorption. Although the exact mechanism of action is not completely understood, several things are thought to occur. Pamidronate binds to bone and may block resorption. In addition, it inhibits osteoclast activity. Lastly, in animal studies, pamidronate inhibits the accelerated bone resorption that results from osteoclast hyperactivity induced by various tumors.
How It Is Administered
Pamidronate is administered as an intravenous infusion. The recommended dosage in patients with myeloma is 90 mg administered as a 2- to 4-hour infusion, given on a monthly basis. The optimal duration of therapy is not yet known. However, a study in myeloma that included up to 21 months of therapy showed there was benefit with continued treatment.
Benefits in Myeloma
Studies have shown that
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Pamidronate reduced the rate of skeletal events and provided rapid reduction in bone pain in patients with Stage III myeloma who already had at least 1 bone lesion. In addition, therapy helped maintain the quality of life in these patients. (Berenson et al. N Engl J Med. 1996;334:488-493.)
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Long-term pamidronate therapy (21 monthly cycles) in combination with chemotherapy was more effective than chemotherapy alone in reducing the number of skeletal events in patients with Stage III disease who already had at least 1 bone lesion. The results suggested that pamidronate may also improve the survival of patients receiving salvage therapy. (Berenson et al. J Clin Oncol. 1998;16:593-602.)
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Prophylactic administration of pamidronate in the asymptomatic, initial phases of myeloma may limit the extent of bone disease in this patient population
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The combination of chemotherapy and pamidronate appears to enhance the activity of the individual drugs. In a study involving 62 newly diagnosed patients with myeloma (Terpos et al. Eur J Haematol. 2000;65:331-336.), the combination appeared to have a synergistic (additive) effect in
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Reducing the activity of osteoclasts
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Reducing markers of myeloma activity
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Reducing myeloma-related pain
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Improving patient quality of life
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Guidelines for Use of Pamidronate in Myeloma
In September 2002, the American Society of Clinical Oncology (ASCO) published clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone disease in myeloma. (Berenson et al. J Clin Oncol. 2002;20:3719-3736.) Upon review of published literature, the expert panel agreed that bisphosphonates reduce skeletal complications and provide a meaningful support benefit to myeloma patients with bone disease.
For patients who have bone lesions or bone loss, the guidelines recommend the use of intravenous pamidronate 90 mg infused over 2 hours or zoledronic acid (Zometa®) 4 mg infused over 15 minutes every 3 to 4 weeks. These bisphosphonates may also be used as part of a pain management strategy. The guidelines recommend that therapy, once started, be continued until the likely benefit is believed to be less than the inconvenience of receiving the treatment or until significant side effects are experienced.
For patients who have bone lesions or bone loss, the guidelines recommend the use of intravenous pamidronate 90 mg infused over 2 hours or zoledronic acid (Zometa®) 4 mg infused over 15 minutes every 3 to 4 weeks. These bisphosphonates may also be used as part of a pain management strategy. The guidelines recommend that therapy, once started, be continued until the likely benefit is believed to be less than the inconvenience of receiving the treatment or until significant side effects are experienced.
Potential Antitumor Effects
Pamidronate also appears to have several potential antitumor effects. For example:
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It has been shown to reduce production of the growth factor interleukin 6 (IL-6) by bone marrow cells from patients with multiple myeloma. IL-6 is known to play an important role in the growth and survival of myeloma cells
-
Pamidronate appears to stimulate an immune response against myeloma that is mediated by T cells
-
It has been shown to induce apoptosis (programmed cell death) in human myeloma cell lines grown in the laboratory
-
In laboratory studies, pamidronate inhibited myeloma cell growth and caused tumor cell death
-
Pamidronate exerted antimyeloma effects in mice that had implants of human myeloma cells growing in human bone fragments. (Yaccoby et al. Br J Haematol. 2002;116(2):278-290.)
Potential Side Effects
Pamidronate is generally well tolerated. Some patients may experience mild and transient side effects, including fatigue, gastrointestinal effects, anemia, and skeletal pain, which may be related to their underlying disease. Although rare, long-term use of the drug at higher doses or pamidronate infused in less than 2 hours can affect the kidneys. For this reason, patients who receive pamidronate should have serum creatinine assessed prior to each treatment. In addition, blood tests such as calcium, electrolytes, phosphate, magnesium, and CBC, differential, and hematocrit/hemoglobin should be performed periodically. There is animal data to suggest there can be a problem when bisphosphonates are administered during pregnancy. Therefore, pamidronate should not be used during pregnancy unless a physician feels the benefits outweigh the risks.
Long-term therapy with pamidronate appears to be safe. Results of a study of 22 patients who received intravenous pamidronate or zoledronic acid for up to 6 years found that prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were seen. A clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine were observed. There were no stress fractures of long bones with prolonged therapy and the fracture rate beyond 2 years was no greater than during the first 2 years of treatment. (Ali et al. J Clin Oncol. 2001;19:3434-3437.)
A number of cases of painful exposed bone in the jaw (a condition called osteonecrosis of the jaw) have been reported in patients receiving intravenous bisphosphonates (pamidronate or zoledronic acid) for hypercalcemia of malignancy related to myeloma or breast cancer. (Marx RE. J Oral Maxillofax Surg. 2003;61:1115-1118.) However, cancer patients in general are at increased risk for this condition due to other therapies they may receive, such as radiation, chemotherapy, and medications such as steroids. (Tarassoff P. J Oral Maxillofax Surg. 2003;61:1238-1239.) Although no cause and effect relationship between bisphosphonates and osteonecrosis has been established, it is recommended that cancer patients take adequate steps to maintain their oral health. This includes practicing good oral hygiene and scheduling regular dental visits. Patients may want to complete major dental procedures before they begin treatment with bisphosphonates. If a dental problem does occur, the least invasive conservative management strategy is preferred.
Long-term therapy with pamidronate appears to be safe. Results of a study of 22 patients who received intravenous pamidronate or zoledronic acid for up to 6 years found that prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were seen. A clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine were observed. There were no stress fractures of long bones with prolonged therapy and the fracture rate beyond 2 years was no greater than during the first 2 years of treatment. (Ali et al. J Clin Oncol. 2001;19:3434-3437.)
A number of cases of painful exposed bone in the jaw (a condition called osteonecrosis of the jaw) have been reported in patients receiving intravenous bisphosphonates (pamidronate or zoledronic acid) for hypercalcemia of malignancy related to myeloma or breast cancer. (Marx RE. J Oral Maxillofax Surg. 2003;61:1115-1118.) However, cancer patients in general are at increased risk for this condition due to other therapies they may receive, such as radiation, chemotherapy, and medications such as steroids. (Tarassoff P. J Oral Maxillofax Surg. 2003;61:1238-1239.) Although no cause and effect relationship between bisphosphonates and osteonecrosis has been established, it is recommended that cancer patients take adequate steps to maintain their oral health. This includes practicing good oral hygiene and scheduling regular dental visits. Patients may want to complete major dental procedures before they begin treatment with bisphosphonates. If a dental problem does occur, the least invasive conservative management strategy is preferred.
Clinical Trials
Pamidronate is being evaluated as an integral part of a treatment regimen for patients with smoldering or indolent myeloma to see if it can help prevent or delay the development of bone lesions.
| Ongoing Pamidronate Clinical Trials in Myeloma as of May 2005
A Phase II Trial of Combination Bisphosphonate and Anti-angiogenesis Therapy With Pamidronate and Thalidomide in Patients with Smoldering/Indolent Myeloma
Note: For the latest trials please visit the new MMRF Clinical Trial Matching and Referral Service |
Zometa (zoledronic acid)
What It Is
Zometa® (zoledronic acid) is an intravenous, nitrogen-containing bisphosphonate marketed by Novartis Pharmaceuticals. It was initially approved in the US in 2001 for the treatment of hypercalcemia of malignancy (HCM), also known as tumor-induced hypercalcemia (TIH). It was approved in 2002 for the treatment of bone lesions in myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard cancer therapy.
Zoledronic acid is 100-fold more potent than pamidronate. Because of this fact, the dose of zoledronic acid required is substantially lower and can be administered in a shorter period of time than pamidronate (15 minutes versus 2-4 hours).
Zoledronic acid is 100-fold more potent than pamidronate. Because of this fact, the dose of zoledronic acid required is substantially lower and can be administered in a shorter period of time than pamidronate (15 minutes versus 2-4 hours).
What It Does
Zoledronic acid inhibits bone resorption, which is the breakdown of bone by osteoclasts. Although the exact mechanism of action is not completely understood, several things are thought to occur. In the laboratory, zoledronic acid inhibits osteoclast activity and induces apoptosis (programmed cell death) of osteoclasts. It also binds to bone and may block resorption. In addition, zoledronic acid inhibits the increased osteoclast activity and skeletal calcium release induced by various stimulatory factors released by tumors.
How It Is Administered
Zoledronic acid is administered as an intravenous infusion. The recommended dosage in patients with myeloma is 4 mg administered as a 15-minute infusion, given every 3 to 4 weeks. The optimal duration of therapy is not yet known. However, in clinical studies in myeloma, patients were treated for up to 12 months, and patients have received the drug for longer periods of time. Data from long-term administration (24 months of therapy) have been submitted to the regulatory authorities.
It is recommended that patients with reduced renal function (mild or moderate renal impairment) receive reduced doses of Zometa upon treatment initiation as indicated in the table below.
It is recommended that patients with reduced renal function (mild or moderate renal impairment) receive reduced doses of Zometa upon treatment initiation as indicated in the table below.
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Patients receiving zoledronic acid should also take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily.
Benefits in Myeloma
Zoledronic acid has been shown to be more effective than pamidronate in normalizing serum calcium levels in patients with hypercalcemia of malignancy. In 2 studies that were analyzed together, zoledronic acid (4 mg) normalized calcium by day 10 in 88% of patients compared to 70% with pamidronate. In addition, the median duration of response was significantly longer with zoledronic acid (32 days compared to 18 days). (Major et al. J Clin Oncol. 2001;19:558-567.)
In patients with myeloma, various studies have shown that zoledronic acid is as effective as pamidronate in treating bone lesions. For example
In patients with myeloma, various studies have shown that zoledronic acid is as effective as pamidronate in treating bone lesions. For example
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Zoledronic acid and pamidronate each reduced the number of skeletal events and the need for radiation therapy to bone in a study of patients with myeloma. (Berenson et al. Cancer. 2001;91:1191-2000.)
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Results of a Phase III trial comparing zoledronic acid and pamidronate showed equal efficacy and tolerability of the drugs in the treatment of bone lesions in myeloma and breast cancer over the period of 1 year. (Rosen et al. Cancer J. 2001;7(5):377-387). Long-term (25 month) data from the study showed that both agents reduced the overall proportion of patients with a skeletal event. However, compared with pamidronate, zoledronic acid reduced the risk of developing skeletal complications (including hypercalcemia) as determined by multiple event analysis by an additional 16%. In patients with breast cancer, zoledronic acid was significantly more effective than pamidronate, reducing the risk of skeletal events by an additional 20% compared with pamidronate and by an additional 30% in patients receiving hormonal therapy. (Rosen et al. Cancer. 2003;98(8):1735-1744.)
Guidelines for Use of Zometa in Myeloma
In September 2002, the American Society of Clinical Oncology (ASCO) published clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone disease in myeloma. (Berenson et al. J Clin Oncol. 2002;20:3719-3736.) Upon review of published literature, the expert panel agreed that bisphosphonates reduce skeletal complications and provide a meaningful support benefit to myeloma patients with bone disease.
For patients who have bone lesions or bone loss, the guidelines recommend the use of intravenous zoledronic acid (Zometa) 4 mg infused over 15 minutes or pamidronate (Aredia®) 90 mg infused over 2 hours every 3 to 4 weeks. These bisphosphonates may also be used as part of a pain management strategy. The guidelines recommend that therapy, once started, be continued until the likely benefit is believed to be less than the inconvenience of receiving the treatment or until significant side effects are experienced.
For patients who have bone lesions or bone loss, the guidelines recommend the use of intravenous zoledronic acid (Zometa) 4 mg infused over 15 minutes or pamidronate (Aredia®) 90 mg infused over 2 hours every 3 to 4 weeks. These bisphosphonates may also be used as part of a pain management strategy. The guidelines recommend that therapy, once started, be continued until the likely benefit is believed to be less than the inconvenience of receiving the treatment or until significant side effects are experienced.
Potential Antitumor Effects
Zoledronic acid also appears to have several potential antitumor effects. For example,
-
It reduces the secretion of the growth factor interleukin 6 (IL-6) by myeloma cells grown in the laboratory. IL-6 is known to play an important role in the growth and survival of myeloma cells
-
In laboratory studies, zoledronic acid inhibited growth and induced apoptosis (programmed cell death) in human myeloma cell lines
-
Zoledronic acid exerted antimyeloma effects in mice that had implants of human myeloma cells growing in human bone fragments. (Yaccoby et al. Br J Haematol. 2002;116(2):278-290.)
-
When combined with dexamethasone in the laboratory, the effect of zoledronic acid on inhibiting growth and inducing apoptosis of myeloma cells was enhanced. (Tassone et al. Leukemia. 2000;14:841-844.)
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The drug inhibited angiogenesis (the growth of new blood vessels) in an animal model. (Wood et al. Proc 36th ASCO Annual Meeting, New Orleans. 2000;19:664a.)
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It is able to prevent the development of bone disease in a mouse model of myeloma. In this model, treatment with zoledronic acid was associated with a decrease in tumor burden and a significant increase in disease-free survival. (Croucher et al. J Bone Miner Res. 2003;18(3):482-492.)
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Zoledronic acid appears to affect bone marrow stromal cells taken from patients with active myeloma, which could contribute to its antitumor effects. In the lab, the agent reduced bone marrow stromal cell proliferation, increased apoptosis, and modified the expression of adhesion molecules on their surface. (Corso et al. Blood. 2003;102(11). Abstract 1619.)
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In blood cells taken from patients with myeloma, zoledronic acid induced anti-myeloma activity by activating a particular type of T cell. Zoledronic acid also enhanced the sensitivity of myeloma cells to killing by these T cells. (Mariani S et al. Leukemia. 2005 Mar 3. [Epub ahead of print])
Potential Side Effects
Zoledronic acid is generally well tolerated and the side effects are similar to those seen with pamidronate. Some patients may experience mild and transient side effects, such as fever, flu-like symptoms, fatigue, gastrointestinal effects, or anemia, which may be related to their underlying disease. Although rare, long-term use of the drug at higher doses or zoledronic acid infused in less than
15 minutes can affect the kidneys. For this reason, patients who receive zoledronic acid should have serum creatinine assessed prior to each treatment. In addition, serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly.
Upon treatment initiation, dosage adjustments are recommended in myeloma patients with mild or moderate kidney impairment. (See How It Is Administered.) Treatment with zoledronic acid is not recommended in patients with severe kidney impairment because studies in this patient population have not been conducted. In myeloma, the risk of kidney dysfunction may be increased when it is used in combination with thalidomide or drugs known to affect kidney function (ie, nonsteroidal antiinflammatory drugs). There are animal data to suggest there can be a problem when bisphosphonates are administered during pregnancy. Therefore, zoledronic acid should not be used during pregnancy unless a physician feels the benefits outweigh the risks.
Long-term therapy with zoledronic acid appears to be safe. Results of a recent study of 22 patients who received intravenous zoledronic acid or pamidronate for up to 6 years found that prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were seen. A clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine were observed. There were no stress fractures of long bones with prolonged therapy and the fracture rate beyond 2 years was no greater than during the first 2 years of treatment. (Ali et al. J Clin Oncol. 2001;19:3434-3437.)
15 minutes can affect the kidneys. For this reason, patients who receive zoledronic acid should have serum creatinine assessed prior to each treatment. In addition, serum calcium, electrolytes, phosphate, magnesium, and hematocrit/hemoglobin should also be monitored regularly.
Upon treatment initiation, dosage adjustments are recommended in myeloma patients with mild or moderate kidney impairment. (See How It Is Administered.) Treatment with zoledronic acid is not recommended in patients with severe kidney impairment because studies in this patient population have not been conducted. In myeloma, the risk of kidney dysfunction may be increased when it is used in combination with thalidomide or drugs known to affect kidney function (ie, nonsteroidal antiinflammatory drugs). There are animal data to suggest there can be a problem when bisphosphonates are administered during pregnancy. Therefore, zoledronic acid should not be used during pregnancy unless a physician feels the benefits outweigh the risks.
Long-term therapy with zoledronic acid appears to be safe. Results of a recent study of 22 patients who received intravenous zoledronic acid or pamidronate for up to 6 years found that prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were seen. A clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine were observed. There were no stress fractures of long bones with prolonged therapy and the fracture rate beyond 2 years was no greater than during the first 2 years of treatment. (Ali et al. J Clin Oncol. 2001;19:3434-3437.)
A number of cases of painful exposed bone in the jaw (a condition called osteonecrosis of the jaw) have been reported in patients receiving intravenous bisphosphonates (pamidronate or zoledronic acid) for hypercalcemia of malignancy related to myeloma or breast cancer. (Marx RE. J Oral Maxillofax Surg. 2003;61:1115-1118.) However, cancer patients in general are at increased risk for this condition due to other therapies they may receive, such as radiation, chemotherapy, and medications such as steroids. (Tarassoff P. J Oral Maxillofax Surg. 2003;61:1238-1239.) Although no cause and effect relationship between bisphosphonates and osteonecrosis has been established, it is recommended that cancer patients take adequate steps to maintain their oral health. This includes practicing good oral hygiene and scheduling regular dental visits. Patients may want to complete major dental procedures before they begin treatment with bisphosphonates. If a dental problem does occur, the least invasive conservative management strategy is preferred.
Ongoing Clinical Trials
Trials are evaluating the use of zoledronic acid as an integral part of a treatment regimen for patients with early-stage or newly diagnosed myeloma to see if it can help prevent or delay the development of bone lesions. An additional trial is being conducted to determine the effect of zoledronic acid on the bone density of patients with bone loss with monoclonal gammopathy of undetermined significance (MGUS).
A study is also being conducted to investigate if lengthening the duration of infusion, in conjunction with increased volume of liquid the zoledronic acid is administered in, will provide renal protective effects.
The combination of zoledronic acid and the targeted radiotherapeutic Quadramet® (Samarium Sm-153 lexidronam, Cytogen) is being evaluated for the treatment of pain associated with metastatic bone disease in patients with recurrent or refractory myeloma.
Ongoing zoledronic acid clinical trials in myeloma are listed in the table below.
Note: For the latest trials please visit the new MMRF Clinical Trial Matching and Referral Service
A study is also being conducted to investigate if lengthening the duration of infusion, in conjunction with increased volume of liquid the zoledronic acid is administered in, will provide renal protective effects.
The combination of zoledronic acid and the targeted radiotherapeutic Quadramet® (Samarium Sm-153 lexidronam, Cytogen) is being evaluated for the treatment of pain associated with metastatic bone disease in patients with recurrent or refractory myeloma.
Ongoing zoledronic acid clinical trials in myeloma are listed in the table below.
|
Ongoing Zometa Clinical Trials in Myeloma as of May 2005
|
Reviewed by:
James R. Berenson, MD
Institute for Myeloma & Bone Cancer Research
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