Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In various common cancers, the skeleton is a preferred site of metastasis. It is also threatened by bone loss resulting from anti-cancer therapy. Like bone metastases in advanced cancer, cancer treatment induced bone loss (CTIBL) substantially increases fracture risk and dramatically decreases quality of life and patient autonomy. Both chemotherapy and endocrine deprivation therapy (EDT) can significantly decrease bone mineral density (BMD). This is aggravated by the often long duration of EDT, particularly in the adjuvant setting. Cumulative bone loss can put patients at risk of osteopenia and osteoporosis. With their known efficacy in preventing skeletal complications in metastatic disease, bisphosphonates (BP) lend themselves to exploring their extended use, notably in preventing CTIBL. Clinical trials have shown BPs to effectively prevent and treat CTIBL, for which they are recommended by ASCO guidelines. Whether BPs also have the potential to prevent metastatic dissemination to bone remains to be determined. Zoledronic acid, a third-generation BP with a favourable efficacy/safety record, was shown by ongoing large clinical trials to not only prevent or reduce CTIBL in early stage cancer, but to actually increase BMD. The current evidence of the potential of zoledronic acid in addressing CTIBL and preventing bone metastases is reviewed.
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PMID:Moving into the future: treatment of bone metastases and beyond. 1624 57

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < -2.5) and considered on an individual basis for those with osteopenia (T score < -1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.
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PMID:Aromatase inhibitors and bone loss. 1698 48

Solid tumors frequently metastasize to bone. This results in debilitating skeletal complications such as intractable bone pain, pathologic fractures, spinal cord compression, and hypercalcemia. Patients frequently require palliative radiation therapy or orthopedic surgery. Bisphosphonates have been shown to delay the incidence and decrease the frequency of skeletal-related events. Zoledronic acid is the only bisphosphonate that has provided benefits for patients with bone metastases secondary to a broad range of solid tumors. Among patients with metastatic breast or prostate cancer, zoledronic acid has demonstrated significant reductions in pain and skeletal morbidity compared with placebo. Zoledronic acid has also shown significant reductions in skeletal morbidity in patients with lung cancer or other solid tumors compared with placebo. Zoledronic acid is generally well tolerated. Flu-like symptoms which are manageable with standard treatment can occur. Renal monitoring is recommended, with dose reductions for patients with renal dysfunction. Osteonecrosis has been reported in patients receiving bisphosphonates and might be avoidable with appropriate dental care.
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PMID:Efficacy and safety of intravenous bisphosphonates in patients with bone metastases caused by metastatic breast cancer. 1768 49

Metastasis to the bone is seen in 56% of patients with neuroblastoma and contributes to morbidity and mortality. Using a murine model of bone invasion, we have reported previously that neuroblastoma cells invade the bone by activating osteoclasts. Here, we investigated the antitumoral and antiosteolytic activities of zoledronic acid, a bisphosphonate inhibitor of osteoclasts, in combination with cytotoxic chemotherapy in our model. We first show that zoledronic acid given at the same time (early prevention) or 2 weeks after tumor cell injection (late prevention) significantly prevented the formation of severe osteolytic lesions. It also prevented formation of these lesions when given 4 weeks after tumor cell injection (intervention) when combined with chemotherapy including cyclophosphamide and topotecan. The combination of zoledronic acid + cyclophosphamide/topotecan also significantly improved survival (P < 0.001). In mice treated with zoledronic acid, we observed a marked inhibition of osteoclasts inside the bone associated with a decrease in tumor cell proliferation and increase in tumor cell apoptosis. In vitro, zoledronic acid inhibited neuroblastoma cell proliferation and induced apoptosis, and these effects were significantly enhanced by the addition of 4-hydroxyperoxycyclophosphamide (4-HC). The proapoptotic effect of zoledronic acid and zoledronic acid in combination with 4-HC on tumor cells was associated with an increase in caspase-3 activity and a decrease in phosphorylated Bcl-2, Bcl-2, and Bcl-X(L) expression. Zoledronic acid inhibited the association of Ras with the plasma membrane and activation of c-Raf, Akt, and extracellular signal-regulated kinase 1/2. The data indicate that zoledronic acid, in addition to inhibiting osteoclasts, is active against tumor cells and suggest that zoledronic acid in combination with cytotoxic chemotherapy may be effective in children with neuroblastoma that has metastasized to the bone.
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PMID:The activity of zoledronic Acid on neuroblastoma bone metastasis involves inhibition of osteoclasts and tumor cell survival and proliferation. 1790 43

Background. The aim of this study was to evaluate the effectivness of connected therapy using strontium 89 or Sm153 (osteoblastic component) and bisphosphonate therapy (osteolytic component) in the group of breast cancer patients with multiple osteoblastic-osteolytic (mixt) bone metastases. <br /> Material and methods. The study included 16 patients with breast cancer and multiple bone painful metastases detected by scintigraphy and by radiogram or CT or MRI (the type of metastases). Each patient received a standard dose of strontium 89 (Metastron) or samarium 153 (Quadramet) combined with intravenous infusion of pamidronate (Aredia) or zoledronate (Zometa). The bisphosphonate therapy was repeated every month. For assessment of therapy effectivness; pain relief (VAS scale), a reduction in analgesic requirements and motor activity (ECOG and Karnofsky scale) were evaluated. The group of 10 patients treated with bisphosphonate only in the same time was observed. <br /> Results. We conclude that connected palliative therapy using strontium 89 and bisphosphonates is effective (66-75% "good" and "moderate" response rate) and safe for bone pain palliation in patients with multiple osteoblastic-osteolytic bone metastases from breast cancer. We have observed that the analgesic requirments decreased to 30% of dose on average. The motor activity of the points evaluated according to ECOG scale increased from 3 to 2 and from 50 to 60 to Karnofsky scale. <br /> Conclusions. The results of treatment in the group with radioisotope and bisphosphonate were better than in the group treated with bisphosphonates or radioisotope only.
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PMID:Preliminary results of combined application of radioisotopes and biphosphonates in the management of pain associated with osteoblastic-osteolytic bone metastases of breast cancer. 1803 12

Many solid tumors metastasize to bone, leading to debilitating skeletal complications such as intractable bone pain and pathologic fractures. Patients who experience a skeletal-related event (SRE) are at higher risk for subsequent events. After an SRE such as a pathologic fracture, spinal cord compression, or the requirement for orthopedic surgery or palliative radiation therapy, a patient's quality of life and functional independence could decline substantially. Prevention or delay of skeletal complications provides clinical benefit to patients with bone metastases secondary to solid tumors. Treatment for the prevention of the first SRE might substantially improve patients' quality of life, functional independence, and pain throughout the course of their disease. Bisphosphonates have shown a palliative benefit in this setting. In particular, zoledronic acid is the only bisphosphonate that has provided benefits for patients with bone metastases secondary to a broad range of solid tumors. Among patients with metastatic breast or prostate cancer, zoledronic acid has demonstrated significant reductions in pain and skeletal morbidity compared with placebo. Zoledronic acid has also shown significant reductions in skeletal morbidity in patients with lung cancer or other solid tumors compared with placebo. Pamidronate, oral clodronate, and ibandronate compared with placebo have each shown significant benefits in reductions of pain and skeletal complications for patients with metastatic breast cancer. Further improvements in the management of skeletal health in patients with malignant bone disease could be achieved through ongoing bisphosphonate investigations to optimize dose, timing, and duration of treatment.
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PMID:Treatment of bone metastases and bone pain with bisphosphonates. 1863 73

Bone metastases are common in patients with advanced-stage cancer; they can lead to skeletal complications (ie, pathologic fractures, spinal cord compression, tumor-induced hypercalcemia, and severe bone pain) that often require orthopedic surgery or palliative radiation therapy and negatively affect quality of life. The primary role of bisphosphonates for the management of bone metastases in patients with advanced-stage cancer is the prevention of these painful skeletal complications. In placebo-controlled trials, a number of bisphosphonates, including oral clodronate, oral and intravenous (I.V.) ibandronate, I.V. pamidronate, and I.V. zoledronic acid, have been shown to significantly reduce skeletal complications in patients with bone metastases from breast cancer. Furthermore, zoledronic acid provided benefit compared with pamidronate in patients with bone metastases from breast cancer in a large, comparative trial. Zoledronic acid also provided long-term benefits in randomized placebo-controlled trials in patients with bone metastases from prostate cancer, lung cancer, and other solid tumors, whereas other bisphosphonates that have been investigated have failed to demonstrate objective long-term benefits in placebo-controlled trials. In addition, although systemic analgesics and radiation therapy are primary treatments for the management of bone pain, bisphosphonates can also play an important secondary role in reducing bone pain associated with skeletal metastases. Notably, several economic analyses of bisphosphonate therapy have demonstrated that these agents are cost-effective by reducing health-care costs associated with skeletal complications and providing clinically significant quality of life benefits to patients with malignant bone disease.
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PMID:Role of bisphosphonates for the management of skeletal complications and bone pain from skeletal metastases. 1863 88

Many patients with advanced cancer experience decreased bone strength due to metastatic foci, underlying osteoporosis and/or cancer treatment induced bone loss. The clinical consequences of metastatic disease involving the skeleton are widespread. This review focuses on the efficacy, pharmacology, and safety when using intravenous biphosphonate such a zoledronic acid for cancer bone metastases. Zoledronic acid is the gold standard for the medical management of metastatic bone disease. The indications for treatment include prevention of skeletal relevant events (SRE), osteoporotic complications, and palliation of bone pain, among others. Zoledronic acid is the only bisphosphonate effective in decreasing SREs associated with bone metastases from advanced renal cell carcinoma and prostate cancer. Regarding prostate cancer, zoledronic acid effectively prevents both bone loss in patients with locally advanced disease receiving androgen deprivation therapy and SREs in men with hormone-refractory or hormone-sensitive metastatic disease. Zoledronic acid has an acceptable safety profile and tolerability, and has been effective at significantly decreasing the incidence, delaying the onset, and reducing the overall risk of experiencing an SRE compared to placebo. It is the only bisphosphonate currently approved for the prevention and treatment of skeletal complications in patients with bone metastases due to all solid tumors.
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PMID:Zoledronic acid in the management of metastatic bone disease. 1872 15

Bisphosphonates (BPs), as inhibitors of osteoclasts, are widely used in the management of metastatic bone disease and in the prevention of osteomalacia and osteoporosis. Recent cases of bone necrosis of the jaws have been associated with the use of bisphosphonate therapy. A case is presented of a patient with osteonecrosis of the maxilla with a history of long-term bisphosphonate therapy for metastatic breast cancer. The authors treated the patient and suggest appropriate patient management guidelines with reference to current knowledge. Although a definitive treatment for bisphosphonate-associated osteonecrosis has not yet been established, clinicians must be aware of the pharmacologic properties of several bisphosphonates currently available and their indications, susceptible risk factors in the development of osteonecrosis of the jaws, the clinical signs and symptoms, and recommendations for patient management, including prevention and early recognition. BPs, potent inhibitors of osteoclast-mediated bone resorption, were first introduced more than 20 years ago. Since then, they have been used widely in the management of bone diseases, including hypercalcemia related to malignancy, myeloma-related bone disease, Paget's disease and osteoporosis. They have also been shown to inhibit tumor cell proliferation and inhibit angiogenesis. These additional features have made BPs useful in the treatment of metastatic disease, including breast and prostate cancer, resulting in a rise in the medical use of these drugs. However, recent reports suggest that BPs, particularly the nitrogen-containing BPs pamidronate (Aredia) and zoledronic acid (Zometa), both manufactured by Novartis of East Hanover, NJ, are capable of causing bisphosphonate-associated osteonecrosis of the jaw (BON). With 2.5 million patients treated with pamidronate and/or zoledronate worldwide, BON occurs in about one per 10,000 treated patients (Novartis, unpublished data, 2004). Currently, the total number of reported cases associated with alendronate (Fosamax, Merck and Co. Inc., White-house Station, NJ) the most commonly prescribed oral bisphosphonate, is approximately 170 worldwide (C. Arsver, oral communication, March 2006). This corresponds to a spontaneous BON incidence of approximately 0.7 cases per 100,000-years exposure. However, there is insufficient data to determine why the osteonecrosis reported seems to particularly affect the jaw, with a slightly higher rate in the mandible than the maxilla. This report concerns the management of a patient with BON. Information provided includes: the pharmacologic properties of the several bisphosphonates currently available; the pathobiological mechanism; the clinical presentation of the oral lesions; and recommendations for the oral management of patients who have received BP therapy, with consideration of a preventative approach based on current knowledge.
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PMID:Bisphosphonate-associated osteonecrosis: a clinician's reference to patient management. 1876 52

Bisphosphonates are widely used as therapeutic agents in bone disorders including cancer metastasis due to their osteoclast inhibitory effect. Recent data shows that bisphosphonates may also induce bone-building by stimulating osteoblast activity. Clinical observations, however, have revealed that bisphosphonates may cause necrosis in the oral cavity which questions their usefulness in bone regeneration during the consolidation of inorganic implants. Here we report the investigation of bone neogenesis following chronic amine bisphosphonate (Zometa) treatment in a novel experimental model, using the rat tail vertebra as a support. This method involves (1) implantation of titan screw into the tail vertebrae, (2) systemic bisphosphonate treatment and (3) quantitative biophysical measurements which mirrors consolidation of implant, i.e. strength of fixation and changes in newly formed bone architecture using micro Computer Tomograph (micro-CT). The degree of fixation of titan implants (osseointegration) increased by 36% on the effect of Zometa and the structure of newly formed bone became robust. The mass of new bone increased 3.1-fold at 6 weeks of regeneration, as compared to controls. Thus, Zometa, a potent aminobisphosphonate used in therapy of cancer metastases, osteoporosis and bone marrow transplantation, significantly increased bone neogenesis and enforced osseointegration of titan implants as measured quantitatively in the rat tail vertebra. Our data support the usefulness of aminobisphosphonates in the rehabilitation of bone loss as well as in improvement osseointegration of implants. We emphasise that this novel method may open up new possibilities for screening the effects of local and systemic treatments.
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PMID:Aminobisphosphonate stimulates bone regeneration and enforces consolidation of titanium implant into a new rat caudal vertebrae model. 1926 22


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