What Other Information Should I Know
Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body’s response to zoledronic acid.
It is important for you to keep a written list of all of the prescription and nonprescription medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.
Inhibition Of Cell Migration By Zoledronic Acid
ZA decreases the migration of mesenchymal stem cells invitro and lowers their production of CCL5 chemokine . Mesenchymal stem cells migrate from bone marrow to the primary tumor, where they are induced to produce CCL5 that promotes breast cancer migration and meta-stases – suggesting that anti-tumor effects of ZA could be mediated in part through suppression of mesenchymal stem cell movement and activity. ZA also decreases breast cancer invasion and endothelial cell migration .
Candidate Estrogen And Progesterone Effects Opposite To Zoledronic Acid On Macrophage Polarization
Estrogen has been posited as supportive of the M2 phenotype , consistent with reports that it down-regulates the M1-promoting cytokine migration inhibitory factor . Like estrogen, progesterone has been found to promote alternative activation of macrophages . Whereas ZA repolarizes macrophages to nitric-oxide-producing M1 macrophages, progesterone has been found to downregulate nitric oxide synthase activity in bone marrow macrophages . Additional studies are necessary to fully understand the potential interaction between sex steroids, effect of ZA, and macrophage polarization.
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Estrogen Modulation Of Hsp27
Estrogen has been shown to transcriptionally upregulate the hsp27 chaperone in both cancer cells and osteoblasts , bolstering cell survival in the presence of apoptotic stimuli. Given the finding that hsp27 was required for acquired resistance of osteosarcoma cells to ZA , it is possible that heightened hsp27 in pre-menopausal women contributes to ZA resistance among those not treated with anti-endocrine therapy.
Useful Information For Doctors And Patients
This study provides information that physicians can use when talking to their patients, Dr. Gralow said. When we talk about the benefits and harms of giving zoledronic acid, we now have more accurate numbers. And we can also better talk about who might be at higher risk, such as smokers or patients who have dental problems and can to reduce the risk of side effects, she continued.
Ultimately, Dr. Gralow said, researchers hope to develop better ways to treat osteonecrosis of the jaw as well as to prevent it.
Some key questions that remain are: How often, and how long, should patients with bone metastases be given zoledronic acid?
Although some experts have suggested that people get the drug for 2 years and then stop, there is no universal agreement on this because no one has done a definitive study, Dr. Loprinzi said.
In addition, the study did not provide data on whether the risk of developing osteonecrosis of the jaw continues to rise after more than 3 years on zoledronic acid, said study leader Catherine Van Poznak, M.D., of the University of Michigan in an interview for JAMA Oncology. However, Dr. Van Poznak expressed concern that the risk of osteonecrosis of the jaw will indeed continue to increase with time.
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Effects Of Zoledronic Acid On Macrophage Polarization
While tumor infiltration by macrophages is common, the function of these macrophages can either be immune suppressive and tumor promoting or be tumor suppressive . ZA seems to promote the tumor-suppressive phenotype for example, it promoted a switch of pro-tumorigenic M2 macro-phages in co-culture with prostate cancer cells to M1 polarization . In an erb-B2 mouse model, Coscia and colleagues have shown that the ability of ZA to inhibit cancer was correlated with its ability to impair the recruitment of macrophages into tumors and to support M1 polarization of macrophages in tumors as manifested by decreased IL-10 and increased IFN production . The contribution of macrophages to the anti-cancer effect of bisphosphonates has been reviewed recently .
Zoledronic Acid Induces Significant And Long
To whom requests for reprints should be addressed, at UniversitaÌ Campus Bio-Medico, Via Emilio Longoni, 83, 00155 Rome, Italy. Phone: 0039-06-22541738 Fax: 0039-06-22541445 E-mail:
Daniele Santini, Bruno Vincenzi, Giordano Dicuonzo, Giuseppe Avvisati, Cristian Massacesi, Fabrizio Battistoni, Michele Gavasci, Laura Rocci, Maria Cristina Tirindelli, Vittorio Altomare, Massimo Tocchini, Maurizio Bonsignori, Giuseppe Tonini Zoledronic Acid Induces Significant and Long-Lasting Modifications of Circulating Angiogenic Factors in Cancer Patients. Clin Cancer Res 1 August 2003 9 : 2893â2897.
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Clinical Efficacy Of Zoledronic Acid And Potential Hormone
In patients, ZA has been effective against both lytic and blastic bone disease, reducing bone symptoms and skeletal-related events in bone-metastatic prostate cancer, bladder cancer, hepatocellular cancer, breast cancer, lung cancer, and multiple myeloma . The ability of ZA to decrease the cancer burden in bone is understandable, given its high concentration and long half-life in the bone environment. For instance, liberation of ZA from hydroxyapetite during bone turnover could allow accumulation of the high ZA concentrations required invitro for direct anti-cancer cell effects. More surprising have been results from recent clinical studies identifying anti-cancer efficacy of ZA beyond the setting of bone metastases, leading to increased disease-free survival .
Table 1 Zoledronic acid trials and disease-free survival
Study Design And Treatment Schedule
This was a phase IIIb, multicentre, randomised, open-label, crossover study. The objective of the study was to determine efficacy and safety of zoledronic acid administered in the community setting vs the hospital setting. Patients received zoledronic acid via 15-min intravenous infusion every 3 weeks for up to 9 months. All patients received treatment in the hospital setting for up to three cycles to ensure disease stabilisation on hormone therapy. Patients were then randomised to receive treatment for three cycles in either the community setting or the hospital setting. After the three cycles, patients were crossed over to receive three cycles of treatment in the opposite setting. Thus, patients received a total of nine infusions over the course of the study . Infusion of zoledronic acid in the community setting was carried out by nurses from Healthcare at Home Limited . This study adhered to Good Clinical Practice and was approved by Multi-Research Ethics Committee. All patients signed informed consent.
Figure 1
Study design. Zoledronic acid was administered intravenously via 15-min infusion every 34 weeks for a maximum of nine infusions. The study was divided into a hospital lead-in phase with three infusions and two community vs hospital crossover phases with three infusions in each setting for a total of nine infusions.
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More About This Trial
Doctors usually treat breast cancer with surgery and then one or more of the following standard treatments – radiotherapy, chemotherapy, biological therapy and hormone therapy.
Zoledronic acid is one of a group of drugs called bisphosphonates. Bisphosphonates are often used to control symptoms caused by cancer that has spread to the bone. Doctors hoped that if women had zoledronic acid after surgery, it would help stop the cancer coming back.
All the women who took part in this trial had standard treatment after surgery. One group had zoledronic acid as well, and the other group didnt.
The aim of this trial was to see if zoledronic acid helped stop breast cancer coming back.
Side Effects Of Zoledronic Acid
Like any drug zoledronic acid can cause side effects. Everyone reacts differently to drugs and some people have more side effects than others.
If youre taking other drugs while having zoledronic acid, you may also have side effects from these and its sometimes difficult to know which drug causes which side effects.
If you have any questions about side effects, whether they are listed here or not, talk to your treatment team.
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Bone Drugs May Help Fight Breast Cancer
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A drug of a class commonly used to combat bone loss may reduce by a third the chance that some breast cancers will spread or recur, a large study has found.
While it may sound odd to treat cancer with a drug that acts on bone, evidence is accumulating that such drugs may do more than just prevent the loss of bone. Other studies are testing the drugs in patients with prostate or lung cancer.
The new study, published in Thursdays New England Journal of Medicine, involved 1,803 premenopausal women with tumors that were fueled by estrogen. As part of their treatment, all received drugs that shut down their ovaries, preventing them from making estrogen, along with drugs that stymie cancer cells from using estrogen to grow.
Half also got the bone drug zoledronic acid, or Zometa, as an intravenous infusion twice a year for three years. Those who took the drug had a 36 percent reduction in cancer recurrences and metastases, compared with women who did not get it. After nearly four years, 54 women who received zoledronic acid and 83 who did not had a recurrence of their cancer or had a new cancer in the opposite breast or a metastasis to their bones.
Others are more persuaded.
I think you have to give it, he said.
Promotion Of Migration By Estrogen
In contrast to ZA, estrogen has been noted to increase endothelial cell migration . Estrogen can directly increase cancer cell migration and also can increase the ability of mesenchymal stem cells to promote the migration of ER-positive MCF7 breast cancer cells . These pro-migratory activities would probably be antagonized by ZA, however, because the migration is supported by prenylation of Rho and Rac .
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Less Common Side Effects
Low calcium levels in the blood
Zoledronic acid can cause calcium levels in the blood to drop too low. This is called hypocalcaemia. Youll have regular blood tests to check the calcium levels.
Early symptoms of hypocalcaemia include tingling around the mouth and lips and in the hands and feet. Let your treatment team know if you experience any of these.
Your treatment team may recommend calcium and vitamin D supplements.
Allergic reaction
Zoledronic acid can cause an allergic reaction. If you become breathless or start to develop an itchy rash let your treatment team know straight away.
Bone, joint or muscle pain
Some people have bone, joint or muscle pain for a short time after having zoledronic acid. Let your treatment team know if you experience any of these symptoms.
Headaches
Let your treatment team know if you get headaches. They can advise you about what medicines to take.
Osteonecrosis
Zoledronic acid can cause some of the jaw bone to lose its blood supply and die. This is called osteonecrosis of the jaw . Its an uncommon but serious side effect of zoledronic acid.
Symptoms include:
- swelling, redness or ulcers on the gums
Let your treatment team and dentist know straight way if you have any of these symptoms.
ONJ is hard to treat so trying to prevent it is very important. Good dental hygiene can help reduce the risk of developing it. This includes brushing your teeth and flossing, making sure dentures fit well and having regular dental check-ups.
Fracture
Immunosuppressive Function Assay Of Regulatory T
The immunosuppressive activity of Tregs was analyzed with a Human Regulatory T-cell Function Kit . Tregs were cultured with pure Tregs culture medium or half C.M. of ZA -pretreated MDA-MB-231 cells and co-cultured with the responding effector T cells in PBMC stimulated using anti-CD3/CD28 beads to express activation marker CD69. After 7h of activation, the percentage of CD69-positive effector T-cells was determined by flow cytometry, and the reduced expression of CD69 in the presence of Tregs indicated Treg suppressive capacity. The percent suppression was calculated using the following formula: 100 .
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Isolation And Expansion Of Regulatory T
Tregs were immediately purified from peripheral blood mononuclear cells, which were isolated from 100ml of fresh heparinized peripheral blood collected from healthy volunteers by Ficoll-Hypaque gradient centrifugation and by immunomagnetic separation using the Dynabeads® Regulatory CD4+CD25+ T-cell Kit , according to the manufacturers instructions. The procedure yielded a highly pure preparation of regulatory CD4+CD25+ T-cells, more than 80% of which expressed the intracellular transcription factor Foxp3. The isolated Tregs were expanded with Dynabeads® Human Treg Expander containing 100U/ml recombinant human interleukin . Each batch Tregs was treated with a standard protocol. After isolation, they were cultured for 10days and expanded to more than 2×106. Each experiment was performed by three independent batches in duplicate. The study was approved by the Institutional Review Committee of E-DA Hospital, and volunteer donors provided written informed consent.
Candidate Estrogen Effects Opposite To Zoledronic Acid On Pro
There is a well-established crosstalk between estrogen signaling and growth factor pathways, including reports on estrogen-mediated induction of a number of growth factors in peritumoral stroma. For example, estrogen has been noted to induce hepatocyte growth factor secretion by macrophages and mammary fibroblasts . Hepatocyte growth factor signaling through the c-met receptor activates mitogen-activated protein kinases independently of Ras, and could represent a rescue pathway around Ras inactivation by ZA .
The Kuperwasser group provides another example of indirect tumor-promoting effects of hormones acting on stroma or marrow rather than on cancer cells themselves. Briefly, they showed that estrogen can promote growth of ER-negative tumors in a stromal-dependent fashion. Interestingly, enhanced growth of ER-negative breast cancer was transferable with bone marrow from estrogen-treated mice . The relevance of these studies to human disease is still somewhat unclear given that the benefit of hormonal blockade as monotherapy clearly depends on the ER expression in the patient’s tumor cells.
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Microarray Gene Expression Profiling
Total cellular RNA was isolated from MDA-MB-231 cells treated with 25M ZA and with or without 100ng/ml IFN- for 24h by TRIzol according to the manufactures protocol, and the total amount was quantified by measuring the optical density at 260nm. Five micrograms of total RNA was reverse transcribed using the high capacity cDNA archive kit according to vendors instructions. Human OneArray Plus was used for comparing gene expression profiles between cells treated with ZA and control. Labeling of cDNA, hybridization of labeled cDNA to genome probes, and scanning were performed according to the manufacturers instructions. Normalized spot intensities were transformed to gene expression log2 ratios between the control and ZA-treatment groups. The spots with log2 ratio1 or log2 ratio1 and p-value < 0.05 were analyzed.
Resistance To Zoledronic Acid
There are limited reports of ZA-resistant cell lines arising from long-term low-dose exposure to ZA. An MCF-7 cell line resistant to ZA exhibited cross-resistance to several chemotherapeutic agents, and expressed an increased Bcl2/Bax ratio and increased ABC transporters BRCP and LRP . Analysis of ZA-resistant osteosarcoma cells arising from culture in low-dose ZA disclosed a farnesyl diphosphate synthase-dependent resistance mechanism in one instance and a heat shock protein-27-dependent mechanism in the other . These few reports suggest that intrinsic cancer cell resistance to ZA may be multifactorial. Whether extrinsic resistance to ZA arises through restoration of pro-tumorigenic paracrine or juxtacrine factors in the tumor microenvironment is unknown.
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Zoledronic Acid Effects On T Cells And Natural Killer Cells
ZA increases the immunogenicity of cancer cells by increasing presentation of the prenyl phosphate antigens isoprenyl pyrophosphate and ApppI on the cell surface . Prenyl phosphate antigens promoted anti-tumor immunity by activating the tumor-suppressive T-cell subset. T-cell expansion and activation has been confirmed in cancer patients after ZA administration , leading to a phase I trial of ZA plus IL-2 to augment T-cell activity in women with late-phase breast cancer. In addition to promoting IFN production by T cells, ZA has been shown to induce IFN production by natural killer cells . Anti-cancer effects of ZA have been eliminated in a mouse breast cancer model when IFN was knocked out . The relative importance of macrophage-generated, NK cell-generated or T-cell-generated IFN in ZA effectiveness against cancer is unknown.
The Adverse Effects Of Bisphosphonates In Breast Cancer: A Systematic Review And Network Meta
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Roles Formal analysis, Methodology, Writing original draft, Writing review & editing
¶ These authors are joint senior authors on this work
Affiliation MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom
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* E-mail:
¶ These authors are joint senior authors on this work
Affiliation Department of Pure Mathematics & Mathematical Statistics, Winton Centre for Risk & Evidence Communication, University of Cambridge, Cambridge, United Kingdom
- Zofia Szlamka,
Roles Data curation, Writing review & editing
Affiliation Department of Pure Mathematics & Mathematical Statistics, Winton Centre for Risk & Evidence Communication, University of Cambridge, Cambridge, United Kingdom
- David J. Spiegelhalter
Roles Conceptualization, Formal analysis, Writing review & editing
Affiliation Department of Pure Mathematics & Mathematical Statistics, Winton Centre for Risk & Evidence Communication, University of Cambridge, Cambridge, United Kingdom
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Migration Assay Of Regulatory T
Migration assays were performed in 24-well transwell chambers using 8-m pore polycarbonate filters. Expanded Tregs were added to the top chamber in serum-free RPMI medium at 5×104 cells/100l. Various chemo-attractants, including 2% serum-containing DMEM with ZA or 2% FBS C.M. of MDA-MB-231 cells pretreated with ZA were added to the bottom chamber of the transwells in a volume of 650L. In certain experiments, the C.M. was preincubated with anti-CCL2 antibody , anti-CCL5 antibody , or both for 1h. The migrated cells in the lower chamber were counted after incubation for 2h at 37°C. The chemotaxis index was calculated relative to the value obtained in response to 2% FBS-containing DMEM medium only.