Bisphosphonates and Bone Metastasis [6.3.1]
Curator: Stephen J. Williams, Ph.D.
General Structure of Bisphosphonates
One of the hallmarks of advanced cancer is the ability to metastasize (tumor cells migrating from primary tumor and colonize in a different anatomical site in the body) and many histologic types of primary tumors have the propensity to metastasize to the bone. One of the frequent complications occurring from bone metastasis is bone fractures and severe pain associated with these cancer-associated bone fractures. An additional problem is cancer-associated hypercalcemia, which may or may not be dependent on bone-metastasis. The main humoral factor associated with cancer-related hypercalcemia is parathyroid hormone–related protein, which is produced by many solid tumors (Paget’s disease). Parathyroid hormone–related protein increases calcium by activating parathyroid hormone receptors in tissue, which results in osteoclastic bone resorption; it also increases renal tubular resorption of calcium {see (1) Bower reference for more information). This curation involves three areas:
- The Changing Views How Bone Remodeling Occurs
- Early Development of Agents that Alter Bone Remodeling and Early Use in Cancer Patients
- Recent Developments Regarding Use of Bisphosphonates in Cancer Patients
As there are numerous articles (1360; more than to manually curate) on “bone”, “metastasis” and “bisphosphonates” the following link is to a Pubmed search on the terms
http://www.ncbi.nlm.nih.gov/pubmed/?term=bone+metastasis+bisphosphonates
In addition there are subset searches to show use of bisphosphonates in common cancers and files given below with numbers of articles:
| Search terms with Pubmed link | # citations | |
| bone metastasis bisphosphonates | 1360 | |
| “ + breast | 559 | |
| “ + prostate | 349 | |
| “ + colon | 9 | |
| “ + lung | 222 |
- The Changing Views How Bone Remodeling Occurs
Bone remodeling (or bone metabolism) is a lifelong process where mature bone tissue is removed from the skeleton (a process called bone resorption) and new bone tissue is formed (a process called ossification or new bone formation). These processes also control the reshaping or replacement of bone following injuries like fractures but also micro-damage, which occurs during normal activity. Remodeling responds also to functional demands of the mechanical loading.
In the first year of life, almost 100% of the skeleton is replaced. In adults, remodeling proceeds at about 10% per year.[1]
An imbalance in the regulation of bone remodeling’s two sub-processes, bone resorption and bone formation, results in many metabolic bone diseases, such as osteoporosis. Two main types of cells are responsible for bone metabolism: osteoblasts (which secrete new bone), and osteoclasts (which break bone down). The structure of bones as well as adequate supply of calcium requires close cooperation between these two cell types and other cell populations present at the bone remodeling sites (ex. immune cells).[4] Bone metabolism relies on complex signaling pathways and control mechanisms to achieve proper rates of growth and differentiation. These controls include the action of several hormones, including parathyroid hormone (PTH), vitamin D, growth hormone, steroids, and calcitonin, as well as several bone marrow-derived membrane and soluble cytokines and growth factors (ex. M-CSF, RANKL, VEGF, IL-6 family…). It is in this way that the body is able to maintain proper levels of calcium required for physiological processes.
Subsequent to appropriate signaling, osteoclasts move to resorb the surface of the bone, followed by deposition of bone by osteoblasts. Together, the cells that are responsible for bone remodeling are known as the basic multicellular unit (BMU), and the temporal duration (i.e. lifespan) of the BMU is referred to as the bone remodeling period.
For a good review on bone remodeling please see Bone remodelling in a nutshell
- Early Development of Agents that Alter Bone Remodeling and Early Use in Cancer Patients
Bisphosphonates had been first synthesized in the late 1800’s yet their development and approval for the indication of osteoporosis occurred over 100 years later, in the 1990’s. For a good review on the history of bisphosphonates please see the following review:
Historical perspectives on the clinical development of bisphosphonates in the treatment of bone diseases. Francis MD1, Valent DJ. J Musculoskelet Neuronal Interact. 2007 Jan-Mar;7(1):2-8.
For a good reference on bisphosphonates as a class, as well as indication, contraindication and side effects see University of Washington web page at http://courses.washington.edu/bonephys/opbis.html
Please view slideshow in the following link: The Evolving Role of Bisphosphonates for Cancer Treatment-Induced Bone Loss presentation by Richard L. Theriault, DO, MBA at MD Anderson Cancer Center
- Recent Developments Regarding Use of Bisphosphonates in Cancer Patients
Bone Metastasis Treatment with Bisphosphonates; A review form OncoLink
Source: From University of Pennsylvania OncoLink® at http://www.oncolink.org/types/article.cfm?c=708&id=9629
Julia Draznin Maltzman, MD and Modified by Lara Bonner Millar, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 18, 2014
Introduction
Bone metastases are a common complication of advanced cancer. They are especially prevalent (up to 70%) in breast and prostate cancer. Bone metastases can cause severe pain, bone fractures, life-threatening electrolyte imbalances, and nerve compression syndromes. The pain and neurologic dysfunction may be difficult to treat and significantly compromises the patients’ quality of life. Bone metastases usually signify advanced, often incurable disease.
Osteolytic vs. osteoblastic
Bony metastases are characterized as being either osteolytic or osteoblastic. Osteolytic means that the tumor caused bone break down or dissolution. This usually results in loss of calcium from bone. On X-rays these are seen as holes called “lucencies” within the bone. Diffuse osteolytic lesions are most characteristic of a blood cancer called Multiple Myeloma, however they may be present in patients with many other types of cancer.
Osteoblastic bony lesions, by contrast, are characterized by increased bone production. The tumor somehow signals to the bone to overproduce bone cells and result in rigid, inflexible bone formation. The cancer that typically causes osteoblastic bony lesions is prostate cancer. Most cancers result in either osteolytic or osteoblastic bony changes, but some malignancies can lead to both. Breast cancer patients usually develop osteolytic lesions, although at least 15-20 percent can have osteoblastic pathology.
Why the bone?
The bone is a common site of metastasis for many solid tissue cancers including prostate, breast, lung, kidney, stomach, bladder, uterus, thyroid, colon and rectum. Researchers speculate that this may be due to the high blood flow to the bone and bone marrow. Once cancer cells gain access to the blood vessels, they can travel all over the body and usually go where there is the highest flow of blood. Furthermore, tumor cells themselves secrete adhesive molecules that can bind to the bone marrow and bone matrix. This molecular interaction can cause the tumor to signal for increased bone destruction and enhance tumor growth within the bone. A recent scientific discovery showed that the bone is actually a rich source of growth factors. These growth factors signal cells to divide, grow, and mature. As the cancer attacks the bone, these growth factors are released and serve to further stimulate the tumor cells to grow. This results in a self-generating growth loop.
What are the symptoms of bone metastasis?
It must be recognized that the symptoms of bone metastasis can mimic many other disease conditions. Most people with bony pain do not have bone metastasis. That being noted, the most common symptom of a metastasis to the bone is pain. Another common presentation is a bone fracture without any history of trauma. Fracture is more common in lytic metastases than blastic metastases.
Some people with more advanced disease may come to medical attention because of numbness and tingling sensation in their feet and legs. They may have bowel and bladder dysfunction – either losing continence to urine and/or stool, or severe constipation and urinary retention. Others may complain of leg weakness and difficulty moving their legs against gravity. This would imply that there is tumor impinging on the spinal cord and compromising the nerves. This is considered an emergency called spinal cord compression, and requires immediate medical attention. Another less common presentation of metastatic disease to the bone is high levels of calcium in the body. High calcium can make patients constipated, result in abdominal pain, and at very high levels, can lead to confusion and mental status changes.
Diagnosis of bone metastasis
Once a patient experiences any of the symptoms of bone metastasis, various tests can be done to find the true cause. In some cases bone metastasis can be detected before the symptoms arise. X-rays, bone scans, and MRIs are used to diagnose this complication of cancer. X-rays are especially helpful in finding osteolytic lesions. These often appear as “holes” or dark spots in the bone on the x-ray film. Unfortunately, bone metastases often do not show up on plain x-rays until they are quite advanced. By contrast, a bone scan can detect very early bone metastases. This test is done by injecting the patient with a small amount of radio-tracing material in the vein. Special x-rays are taken sometime after the injection. The radiotracer will preferentially go to the site of disease and will appear as a darker, denser, area on the film. Because this technique is so sensitive, sometimes infections, arthritis, and old fractures can appear as dark spots on the bone scan and may be difficult to differentiate from a true cancer. Bone scans are also used to follow patients with known bone metastasis. Sometimes CT scan images can show if a cancer has spread to the bone. An MRI is most useful when examining nerve roots suspected of being compressed by tumor or bone fragments due to tumor destruction. It is used most often in the setting of spinal cord compromise.
There are no real blood tests that are currently used to diagnose a bone metastasis. There are, however, a number of blood tests that a provider can obtain that may suggest the presence of bone lesions, but the diagnosis rests with the combination of radiographic evidence, clinical picture, and natural history of the malignancy. For example, elevated levels of calcium or an enzyme called alkaline phosphatase can be related to bone metastasis, but these lab tests alone are insufficient to prove their presence.
Treatment
The best treatment for bony metastasis is the treatment of the primary cancer. Therapies may include chemotherapy, hormone therapy, radiation therapy, immunotherapy, or treatment with monoclonal antibodies. Pain is often treated with narcotics and other pain medications, such as non-steroidal anti-inflammatory agents. Physical therapy may be helpful and surgery may have an important role if the cancer resulted in a fracture of the bone.
Bisphosphonates
Bisphosphonates are s category of medications that decrease pain from bone metastasis and may improve overall bone health. Bisphosphonates man-made versions of a naturally occurring compound called pyrophosphate that prevents bone breakdown. They are a class of medications widely used in the treatment and prevention of osteoporosis and certain other bone diseases (such as Paget’s Disease), as well as in the treatment of elevated blood calcium. These drugs suppress bone breakdown by cells called osteoclasts, and, can indirectly stimulate the bone forming cells called osteoblasts. It is for this reason, and for the fact that bisphosphonates are very effective in relieving bone pain associated with metastatic disease, that they have transitioned to the oncology arena. However, treatment of bone metastases is not curative. There is increasing evidence that bisphosphonates can prevent bony complications in some metastatic cancers and may even improve survival in some cancers. Most researchers agree that these drugs are more helpful in osteolytic lesions and less so in osteoblastic metastasis in terms of bone restoration and health, but the bisphosphonates are able to alleviate pain associated with both types of lesions. The appropriate time to start treatment is once a bone metastasis has been identified on imaging.
Bisphosphonates can be given either orally or intravenously. The latter is the preferred route of administration for many oncologists as it is given monthly as a short infusion and does not have the gastrointestinal side effects that the oral bisphosphonates have. There are currently two approved and commonly used IV bisphosphonates –Pamidronate disodium (Aredia, Novartis) and zolendronic acid (Zometa, Novartis). Their side effect profile is fairly mild and includes a flu-like reaction during the first 48 hours after the infusion, kidney impairment and osteonecrosis of the jaw with long term use. Patients with renal impairment may not be candidates for this therapy.
Bisphophonates may have some level of anti-tumor activity in breast cancer. A recent Phase III clinical trial revealed that the addition of Zometa to endocrine therapy, improves disease-free survival, but not overall survival, in pre-menopausal patients with estrogen-receptor postive early breast cancer. Another trial called AZURE found no effect from the bisphosphonate zolendronic acid (Zometa, Novartis) on the recurrence of breast cancer or on overall survival. However, several other studies on bisphosphonates and breast cancer are ongoing, and for now, their use is not recommended in patients without metastases.
In addition to bisphosphonates, osteoclast inhibition can also be achieved through other means. Another medication, Denosumab (XGEVA, Amgen), targets a receptor called receptor activator of nuclear factor kappa B ligand (RANKL), is able to block osteoclast formation. A few studies comparing Denosumab to bisphosphonates have found Denosumab results in a longer time to skeletal events, on the order of a few months, compared to bisphosphonates, however many experts believe that the evidence is not strong enough to support one class of drug over another. The most common side effects of Denosumab are fatigue or asthenia, hypophosphatemia, hypocalcemia and nausea. Patients receiving bisphosphonates or denosumab should also be taking calcium and vitamin D supplementation.
The future
Skeletal metastases remain one of the more debilitating problems for cancer patients. Research is ongoing to identify the molecular mechanisms that result in both osteolytic and osteoblastic bone lesions. Perhaps the use of proteomics and gene array data may permit us to identify some factors specific to the tumor or to the bony lesion itself that could be used as therapeutic targets to teat or even prevent this complication.
In summary
- there is well established evidence in preclinical models that bisphosphonates:reduce the total tumor burden in bone
- it is unclear as to the mechanisms of this preclinical finding as bisphosphonates have been shown to directly have antitumor activity
- as the review by Holen I1, Coleman RE.show “Bisphosphonates as treatment of bone metastases” (abstract given below) there is conflicting clinical evidence of this effect found in preclinical models
Accelerated bone loss is a common clinical feature of advanced breast cancer, and anti-resorptive bisphosphonates are the current standard therapy used to reduce the number and frequency of skeletal-related complications experienced by patients. Bisphosphonates are potent inhibitors of bone resorption, acting by inducing osteoclast apoptosis and thereby preventing the development of cancer-induced bone lesions. In clinical use bisphosphonates are mainly considered to be bone-specific agents, but anti-tumour effects have been reported in a number of in vitro and in vivo studies. By combining bisphosphonates with chemotherapy agents, growth and progression of breast cancer bone metastases can be virtually eliminated in model systems. Recent clinical trials have indicated that there may be additional benefits from bisphosphonate treatment, including positive effects on recurrence and survival when added to standard endocrine therapy. Whereas the ability of bisphosphonates to reduce cancer-induced bone disease is well established, their potential direct anti-tumour effect remain controversial. Ongoing clinical trials will establish whether bisphosphonates can inhibit the development of bone metastases in high-risk breast cancer patients. This review summarizes the main studies that have investigated the effects of bisphosphonates, alone and in combination with other anti-cancer agents, using in vivo model systems of breast cancer bone metastases. We also give an overview of the use of bisphosphonates in the treatment of breast cancer, including examples of key clinical trials. The potential side effects and future clinical applications of bisphosphonates will be outlined.
References
- Bower M, Cox S. Endocrine and metabolic complications of advanced cancer. In: Doyle D, Hanks G, Cherny NI, Calman K, editors. Oxford textbook of palliative medicine. 3rd ed. New York, NY: Oxford University Press; 2004. p. 688-90.
Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29(9):1125-32.
Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29(9):1221-7.
West, H. Denosumab for prevention of skeletal-related events in patients with bone metastases from solid tumors: incremental benefit, debatable value. J Clin Oncol. 2011;29(9):1095-8.
Gnant M, Mlineritsch B, Schippinger W et al.: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 360(7),679–691 (2009).
Treatment Guidelines by Cancer Organizations
For Immediate Release
February 22, 2011
Contact:
Steven Benowitz
571-483-1370
steven.benowitz@asco.org
ALEXANDRIA, Va. – The American Society of Clinical Oncology (ASCO) today issued an update to its clinical practice guideline on the use of bone-modifying agents, in particular, osteoclast inhibitors, to prevent and treat skeletal complications from bone metastases in patients with metastatic breast cancer. The new guideline includes recommendations on the use of a new drug option, denosumab (Xgeva), and addresses osteonecrosis of the jaw, an uncommon condition that may occur in association with bone-modifying agents. The updated guideline also provides new recommendations on monitoring of patients who undergo treatment with bone-modifying agents and highlights priorities for future research on these drugs.
ASCO’s Bisphosphonates in Breast Cancer Panel conducted a systematic review of the medical literature to develop the new recommendations. The updated guideline, American Society of Clinical Oncology Clinical Practice Guideline Update on the Role of Bone-Modifying Agents in Metastatic Breast Cancer, was published online today in the Journal of Clinical Oncology.
The guideline recommends that patients with breast cancer who have evidence of bone metastases be given one of three agents – denosumab, pamidronate or zoledronic acid – approved by the U.S. Food and Drug Administration. It does not support use of any one drug over the others. These drugs are all considered osteoclast inhibitors, but they belong to different drug families: pamidronate and zoledronic acid are part of a class of drugs called bisphosphonates, while denosumab is a monoclonal antibody that targets receptor activator of nuclear factor-kappa beta ligand (RANKL).
The guideline also recommends against initiating bone-modifying agents in the absence of bone metastases outside of a clinical trial. It notes that an abnormal bone scan result alone, without confirmation by a radiograph, CT or MRI scan, is not sufficient evidence to support treatment with these drugs.
“The updated recommendations take into account recent progress in controlling potential bone damage in metastatic breast cancer,” said Catherine Van Poznak, MD, co-chair of the Bisphosphonates in Breast Cancer Panel and assistant professor of medicine at the University of Michigan. “We’ve established that a growing number of osteoclast inhibitors can have a positive effect and decrease of the risk of skeletal-related events in women with bone metastases. Because many factors – including medical and economic – must be considered when selecting a therapy for an individual, it’s good to have several effective choices.”
Bone is one of the most common sites to which breast cancer spreads. Bone metastases occur in approximately 70 percent of patients with metastatic disease. These metastases can cause bone cells (osteoclasts) to become overactive, which can result in excessive bone loss, disrupting the bone architecture and causing skeletal-related events (SREs), such as fracture, the need for surgery or radiation therapy to bone, spinal cord compression and hypercalcemia of malignancy.
This document updates guideline recommendations that were first issued in 2000 and revised in 2003, and focused on the use of bisphosphonates. The current guideline uses the more inclusive term, bone-modifying agents, to reflect a wider category of therapeutic agents such as monoclonal antibodies that use different mechanisms of action to prevent and treat damage from bone metastases. The guideline notes that research remains to be conducted to address several areas where questions remain.
“The guideline considers new data in a variety of areas, including studies showing that denosumab has equivalent effectiveness compared with other currently available drug therapies,” explained bisphosphonates panel co-chair Jamie Von Roenn, MD, professor of medicine at Northwestern University. “The guideline also provides guidance on preventing a rare, but significant complication of therapy with bone-modifying agents, osteonecrosis of the jaw.”
Denosumab is a human monoclonal antibody that targets a receptor, RANKL, involved in the regulation of bone remodeling. The guideline cites evidence from a randomized Phase III trial showing that denosumab appears to be comparable to zoledronic acid in reducing the risk of SREs in women with bone metastases from breast cancer. Denosumab is given subcutaneously, and can have side effects such as hypocalcemia.
The guideline also addresses the recently discovered osteonecrosis of the jaw. The first reports of this degenerative condition were published in the medical and dental literature in 2003. The committee recommended that all patients with breast cancer get dental evaluations and receive preventive dentistry care before beginning treatment with bone-modifying osteoclast inhibitors.
The panel updated its recommendations regarding the effects of bisphosphonates on kidney function, particularly for those taking either pamidronate or zoledronic acid, which have been associated with deteriorating kidney function. It said that clinicians should monitor serum creatinine clearance prior to each dose of pamidronate or zoledronic acid according to FDA-approved labeling.
The panel did not recommend using biochemical markers to monitor bone-modifying agent effectiveness and use outside of a clinical trial.
While many of the 2003 recommendations remain the same, the guideline notes several research directions to be addressed, including:
- Duration of therapy with bone modifying agents, and the timing or intervals between delivery.
- The development of a risk index for SREs, and better ways to stratify patient risk of SRE or risk of toxicity from a bone-modifying agent. Individual risk may guide selection of timing for use of a bone-modifying agent therapy.
- Trials specifically examining whether stage IV breast cancer patients who do not have evidence of bone metastases would benefit from bone-modifying agents.
- The role of biomarkers in treatment selection and monitoring drug effectiveness.
- Understanding the optimal dosing of calcium and vitamin D supplementation in patients treated with bone-modifying agents.
The meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) was published in Lancet and suggested that “Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began”.
Results
- Of 18, 206 women in trials of 2-5 years of bisphosphonate3453 first recurrences, and 2106 subsequent deaths.
- Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance
- Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). “This was iregardless of age or bisphosphonate type.
Lancet. 2015 Jul 23. pii: S0140-6736(15)60908-4. doi: 10.1016/S0140-6736(15)60908-4. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials.
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
This Study was reported at the 36th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract S4-07. Presented December 12, 2013 and Medscape Medical News journalist Kate Johnson covered the finding with author interviews in the following article:
Bisphosphonates: ‘New Addition’ to Breast Cancer Treatment?
Kate Johnson
December 13, 2013
Editors’ Recommendations
SAN ANTONIO — Adjuvant bisphosphonate treatment significantly improves breast cancer survival and reduces bone recurrence in postmenopausal women with early breast cancer, according to a meta-analysis reported here at the 36th Annual San Antonio Breast Cancer Symposium.
“We have finally defined a new addition to standard treatment,” announced lead investigator Robert Coleman, MD, professor of oncology at the University of Sheffield in the United Kingdom. He emphasized that, as hypothesized, the benefits of this therapy were confined to postmenopausal women.
“There is absolutely no effect on mortality in premenopausal women, with a hazard ratio [HR] of 1.0,” he reported. “But for postmenopausal women, we see a 17% reduction in the risk of death [HR, 0.83], which is highly statistically significant.”
In terms of the absolute benefit, bisphosphonates decreased the breast cancer mortality rate from 18.3% to 15.2% in postmenopausal women (P = .004).
The separation of benefit by menopausal status was also seen in the bone recurrence data.
In premenopausal women, there is no significant effect on bone recurrence (HR, 0.93), whereas in postmenopausal women, there was a 34% reduction. The difference was “highly significant,” said Dr. Coleman.
“I personally believe adjuvant bisphosphonates should be standard treatment in postmenopausal women with breast cancer,” said Michael Gnant, MD, professor of surgery at the Medical University of Vienna, who was one of the study investigators. He spoke during a plenary session before the results were formally announced. (Please click this LINK to See VIDEO Interview with Dr. Gnant)
“This is an important analysis,” said Rowan Chlebowski, MD, PhD, medical oncologist from the Harbor-UCLA Medical Center in Los Angeles.
“There will be a substantial increase in the use of bisphosphonates,” he told Medscape Medical News after the presentation.
“The only question is whether people will accept this analysis as the final word.” Dr. Chlebowski explained that some people might criticize the study as being a post hoc analysis of previous findings.
“You might find some mixed feelings about whether this should be accepted, but I think this will get people thinking,” he said. Dr. Chlebowski previously reported a large observational study that demonstrated that postmenopausal women taking oral bisphosphonates for osteoporosis had a significantly lower risk for breast cancer.
Bisphosphonates were originally indicated for the treatment of osteoporosis, and include agents such as alendronate (Fosamax, Merck), ibandronate (Boniva, Genentech), risedronate (Actonel, sanofi-aventis), and zoledronic acid (Reclast, Novartis). But they are also indicated for bone-related use in breast cancer patients, Dr. Chlebowski pointed out.
Because bisphosphonates “also have an indication for preventing bone loss associated with aromatase inhibitor use, they are already approved in this setting, and would prevent recurrences. It will be interesting to see if guideline panels” like these findings, he noted.
Why Postmenopausal Women Benefit
In the plenary session, Dr. Gnant acknowledged that the data on bisphosphonates to date have been mixed.
There are “many trials showing controversial results” for bisphosphonates in the context of breast cancer, he said. “When we put them all together in an unselected population, some show beneficial effects and some do not.”
Dr. Gnant explained why bisphosphonates appear to be effective in older but not younger women. “When you confine your analysis to the low-estrogen environment, postmenopausal women, or women rendered menopausal by ovarian function suppression, we see that all these trials show a consistent benefit for these patients,” he said.
“Essentially, this low-estrogen hypothesis as a prerequisite for adjuvant bisphosphonate activity means that we believe these treatments can silence the bone marrow microenvironment. However, this only translates to relevant clinical benefits in low-estrogen environments,” he added.
More Study Details
The meta-analysis involved 36 trials of adjuvant bisphosphonates in breast cancer with 17,791 pre- and postmenopausal women.
The primary outcomes of the study were time to distant recurrence, local recurrence, and new second primary breast cancer (ipsilateral or contralateral), time to first distant recurrence (ignoring any previous locoregional or contralateral recurrences), and breast cancer mortality.
Planned subgroup analyses based on hypotheses generated from previous findings included site of recurrence, site of first distant metastasis, menopausal status, and type and schedule of bisphosphonate therapy, said Dr. Coleman.
With bisphosphonate therapy, there was a nonsignificant 1% reduction in breast cancer recurrence at 10 years in postmenopausal women, compared with premenopausal women (25.4% vs 26.5%), and “a small borderline advantage” for distant recurrence (20.9% vs 22.3%), he reported.
However, there was a significant benefit of bisphosphonates in bone recurrence in postmenopausal women (6.9% vs 8.4%; P = .0009), with no effect on nonbone recurrence.
There was no impact of bisphosphonates on local recurrence or cancer in the contralateral breast.
For distant recurrence, there was a 3.5% absolute benefit in postmenopausal women (18.4% vs 21.9%; P = .0003); for distant recurrence, there is was a significant improvement of 2.9% in bone recurrence (5.9% vs 8.8%; P < .00001).
There was no significant reduction in first distant recurrence outside bone, and risk reductions were similar, irrespective of estrogen-receptor status, node status, or use or not of chemotherapy.
“Adjuvant bisphosphonates reduce bone metastases and improve survival in postmenopausal women,” concluded Dr. Coleman. “We have statistical security in this result, with a 34% reduction in the risk of bone recurrence (P = .00001), and a 17% — or 1 in 6 — reduction in the risk of breast cancer death (P =.004).”
The analysis struck a clear line between pre- and postmenopausal women — something that was revealed in a subgroup analysis the AZURE trial, which Dr. Coleman was involved in (N Engl J Med. 2011;365:1396-1405).
Because of this, he was asked about the validity of basing the current analysis on the AZURE hypothesis-generating population.
“We repeated the analysis without the AZURE patients, because they are the hypothesis-generating population, and the P values and risk reductions did not change,” he explained.
Source: Medscape Medical News at http://www.medscape.com/viewarticle/817787#vp_1
Updated on 10/20/2015: Other articles for reference on Bisphosphonates and Metastasis
Human breast cancer bone metastasis in vitro and in vivo: a novel 3D model system for studies of tumour cell-bone cell interactions.
Author information
- 1Academic Unit of Clinical Oncology, Department of Oncology, Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, S10 2RX, UK.
- 2Department of Human Metabolism, Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, S10 2RX, UK.
- 3Academic Unit of Clinical Oncology, Department of Oncology, Mellanby Centre for Bone Research, Medical School, University of Sheffield, Sheffield, S10 2RX, UK. p.d.ottewell@sheffield.ac.uk.
Abstract
Bone is established as the preferred site of breast cancer metastasis. However, the precise mechanisms responsible for this preference remain unidentified. In order to improve outcome for patients with advanced breast cancer and skeletal involvement, we need to better understand how this process is initiated and regulated. As bone metastasis cannot be easily studied in patients, researchers have to date mainly relied on in vivo xenograft models. A major limitation of these is that they do not contain a human bone microenvironment, increasingly considered to be an important component of metastases. In order to address this shortcoming, we have developed a novel humanised bone model, where 1 × 10(5) luciferase-expressing MDA-MB-231 or T47D human breast tumour cells are seeded on viable human subchaodral bone discs in vitro. These discs contain functional osteoclasts 2-weeks after in vitro culture and positive staining for calcine 1-week after culture demonstrating active bone resorption/formation. In vitro inoculation of MDA-MB-231 or T47D cells colonised human bone cores and remained viable for <4 weeks, however, use of matrigel to enhance adhesion or a moving platform to increase diffusion of nutrients provided no additional advantage. Following colonisation by the tumour cells, bone discs pre-seeded with MDA-MB-231 cells were implanted subcutaneously into NOD SCID mice, and tumour growth monitored using in vivo imaging for up to 6 weeks. Tumour growth progressed in human bone discs in 80 % of the animals mimicking the later stages of human bone metastasis. Immunohistochemical and PCR analysis revealed that growing MDA-MB-231 cells in human bone resulted in these cells acquiring a molecular phenotype previously associated with breast cancer bone metastases. MDA-MB-231 cells grown in human bone discs showed increased expression of IL-1B, HRAS and MMP9 and decreased expression of S100A4, whereas, DKK2 and FN1 were unaltered compared with the same cells grown in mammary fat pads of mice not implanted with human bone discs.
Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma.
Abstract
BACKGROUND:
Bone, which abundantly stores a variety of growth factors, provides a fertile soil for cancer cells to develop metastases by supplying these growth factors as a consequence of osteoclastic bone resorption. Accordingly, suppression of osteoclast activity is a primary approach to inhibit bone metastasis, and bisphosphonate (BP), a specific inhibitor of osteoclasts, has been widely used for the treatment of bone metastases in cancer patients. To obtain further insights into the therapeutic usefulness of BP, the authors studied the effects of BP on bone and visceral metastases in animal models of metastasis.
METHODS:
The authors used two animal models of breast carcinoma metastasis that they had developed in their laboratory over the last several years. One model uses female young nude mice in which inoculation of the MDA-MB-231 or MCF-7 human breast carcinoma cells into the left cardiac ventricle selectively develops osteolytic or osteosclerotic bone metastases, respectively. Another model uses syngeneic female mice (Balb/c) in which orthotopic inoculation of the 4T1 murine mammary carcinoma cells develops metastases in bone and visceral organs including lung, liver, and kidney.
RESULTS:
BP inhibited the development and progression of osteolytic bone metastases of MDA-MB-231 breast carcinoma through increased apoptosis in osteoclasts and breast carcinoma cells colonized in bone. In a preventative administration, however, BP alone increased the metastases to visceral organs with profound inhibition of bone metastases. However, combination of BP with anticancer agents such as uracil and tegafur or doxorubicin suppressed the metastases not only in bone but also visceral organs and prolonged the survival in 4T1 mammary tumor-bearing animals. Of interest, inhibition of early osteolysis by BP inhibited the subsequent development of osteosclerotic bone metastases of MCF-7 breast carcinoma.
CONCLUSIONS:
These results suggest that BP has beneficial effects on bone metastasis of breast carcinoma and is more effective when combined with anticancer agents. They also suggest that the animal models of bone metastasis described here allow us to design optimized regimen of BP administration for the treatment of breast carcinoma patients with bone and visceral metastases.
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Amandeep Kaur
Aashir Awan, Phd
Abhisar Anand
Adina Hazan
Alan F. Kaul, PharmD., MS, MBA, FCCP
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David Orchard-Webb, PhD
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