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PubMed1997

[New drugs in metastatic breast cancer--1997].

The introduction of new drugs may offer significant hope for improvement in the treatment of breast cancer. They include new cytotoxic agents such as Taxanes, Topoisomerase inhibitor, MDR modulator, new hormone such as 3rd generation nonsteroidal aromatase inhibitor, pure antiestrogen for patients with refractory metastatic breast cancer and new bisphosphonates for those who have metastases to bone. Therefore, some reports evaluating such new drugs were reviewed. Japanese studies revealed response rate of Taxanes in the treatment of metastatic breast cancer as follows; Six out of 22 (27%) with 1 CR for 24 hours infusion, 21 out of 52 (34%) with 2 CR for 3 hours infusion of paclitaxel respectively, 21 out of 31 (41%) with 2 CR for 1 hour infusion, and 32 out of 72 (44%) with 5 CR for 1 hour infusion of Docetaxel, In addition, the MTD of the combination was reached at dose level with 60 mg/sqm of Docetaxel and 400 mg/sqm of cyclophosphamide. As regards hormone therapy, thirty four out of 176 (19%) with 5 CR were observed in phase II study of Fadrozol but results from the phase II study of 3rd generation aromatase inhibitor is not yet accomplished in Japan. However, any european reports did not show a difference in response rate in patients with tamoxifen refractory breast cancer between newer aromatase inhibitor and megasterol, and a good choice of hormones in the treatment of metastatic breast cancer appears to be difficult.

Antineoplastic Agents↗
PubMed2003

Injectable bisphosphonates in the treatment of postmenopausal osteoporosis.

Osteoporosis is a "silent" disease and the patient has usually no clue of it until the occurrence of a fragility fracture. Prevention requires a continuous daily treatment that could be uncomfortable to the patient. Besides the recently introduced weekly oral schedules, injectable bisphosphonates have often been used as an off-label option to ameliorate compliance. In general, although with different efficiency, almost all injectable bisphosphonates can improve bone mineral density and suppress bone resorption markers. The effect of intravenous infusions of bisphosphonates are, to a large extent, similar to equivalent intramuscular administrations, but doses and dosing intervals represent the critical issues. Pain at the injection site and acute phase reactions are relatively common to intramuscular clodronate and intravenous infusions of nitrogen-containing bisphosphonates, respectively. Under certain circumstances, intermittent treatment with injectable bisphosphonates might represent a feasible alternative when compliance is at risk.

Anti-Inflammatory Agents↗
PubMed1994

Effects of two novel bisphosphonates on bone cells in vitro.

Bisphosphonates are now widely used in the treatment of bone diseases, particularly where there is uncontrolled bone resorption, as they are known to be potent inhibitors of osteoclasis. It is still unclear whether the bisphosphonates act by inhibiting osteoclast maturation or by blocking the mechanism of bone resorption, and little is known of their effects on osteoblasts. Recent studies with 3-amino-1, hydroxypropylidene-1,1-bisphosphonic acid (APD) in the treatment of osteolytic metastases in breast cancer have suggested that APD may affect osteoblasts directly. We have now investigated the effects of two novel bisphosphonates, CGP 47072 and CGP 42446A on osteoclastogenesis in fetal rat calvariae cultured on collagen gels and on human osteoblasts (hOB) cultured as explants from bone taken from patients at surgery. We also compared the action of these new bisphosphonates with that of APD, which at concentrations of 2.5 x 10(-6) M to 2.5 x 10(-10) M inhibited osteoclast recruitment, even when this was stimulated by conditioned medium from MCF7 breast cancer cells. This bisphosphonate was particularly potent if cultured with calvaria taken at 19 days gestation, when more immature osteoclast precursors are present. If calvariae from 20 days gestation were used, which contain more mature cells, it produced less inhibition. In contrast, CGP 42446A (2.5 x 10(-6) M to 2.5 x 10(-8) M) was more effective in inhibiting osteoclast maturation in calvariae from 20 days gestation than in those from 19 days. CGP 47072 had a similar pattern of effects but was less potent than either of the other two compounds. APD or CGP 42446A at 10(-5) M significantly inhibited hOB numbers and DNA synthesis, but lower concentrations had little effect. CGP 47072 did not inhibit human osteoblast replication. It is unlikely that these effects are due to calcium chelation, as none of these compounds mimicked results obtained with EDTA, which was effective only at 2.5 x 10(-6) M in reducing osteoclast size and 10(-4) M in human osteoblast cultures. These results demonstrate that all three bisphosphonates are able to inhibit osteoclast formation at low concentrations. APD may be able to influence less mature osteoclast precursors and CGP 42446A and CGP 47072 may exert their effects on the fusion of more mature precursor cells on the bone surface. At these concentrations, however, there is little or no effect on osteoblasts.

Animals↗
PubMed2003

Aetiology of bone disease and the role of bisphosphonates in multiple myeloma.

Osteolytic bone disease is a major cause of morbidity in patients with multiple myeloma. Our understanding of the pathophysiology of multiple myeloma has increased substantially during the past decade. However the underlying mechanisms of bone destruction and the treatments available have, until recently, received relatively little specific attention. In this review, we provide an overview of the RANK/RANKL/osteoprotegerin system; we describe its interaction with other cellular mechanisms, through which malignant plasma cells drive osteolysis, and explain how bisphosphonates can be used to block this action. We also review the supporting evidence for bisphosphonates as the treatment of choice for patients with bone complications related to multiple myeloma, and discuss possible developments for targeted therapy in the future.

Antineoplastic Agents↗
PubMed2003

Bisphosphonates in the management of metastatic prostate cancer.

Prostate cancer (PCA) frequently metastasizes to the bones, and skeletal metastases represent the most common cause of morbidity in advanced PCA. Besides the development of skeletal events due to metastases, patients with PCA are at higher risk for benign osseous complications, such as osteoporosis and fractures. Bisphosphonates (BPs) have emerged as an integral part of the management of skeletal disease related to PCA. Currently available data support their routine use to prevent androgen-deprivation-induced osteoporosis and its secondary complications. Dosing at 3-month intervals is appropriate; further studies will have to demonstrate the efficacy of annual dosing. In men with already established bone metastases, BPs might be helpful in preventing skeletal-related events in patients who do not respond to alternative therapies and are at high risk for bone fractures or spinal cord compression. In patients with hormone-refractory prostate cancer, BPs might be administered for analgesic purposes. Prospective randomized trials will have to explore the clinical role of BPs in the prevention of bone metastases following local therapy with curative intent in men at high risk for PCA recurrences.

Antineoplastic Agents↗
PubMed2005

Rapid prevention of vertebral fractures associated with osteoporosis.

Osteoporosis affects postmenopausal women and patients on glucocorticoid therapy. Fractures are the most devastating outcome. Patients who experience an osteoporotic vertebral fracture are at substantial risk of experiencing another within 1 year. Risk can be reduced rapidly with antiresorptives. Risedronate reduced the risk of vertebral fracture in patients with post-menopausal or glucocorticoid-induced osteoporosis after 1 year by up to 71% in prospective studies. In post hoc analyses, significant reductions in clinical vertebral fractures were demonstrated after 6 months with risedronate and 1 year with alendronate and raloxifene. Rapid reduction in fracture risk is achievable with the potent therapeutic agents available.

Aged↗
PubMed2005

Newer drug treatments: their effects on fracture prevention.

Drug treatment of osteoporosis is based on the knowledge of mechanisms of bone turnover and the manipulation of the cellular components of bone turnover in terms of recruitment, activation and apoptosis of the cells involved. Based on their mechanisms of action, drugs used in the treatment of osteoporosis can be divided into those that inhibit bone turnover (bisphosphonates, SERMs, calcitonin), those that stimulate bone turnover (parathyroid hormone), and those with mixed effects (strontium ranelate). In this chapter we discuss the anti-fracture effects of some newer drugs together with innovative aspects of intake (monthly oral intake for ibandronate) or mechanisms of action (parathyroid hormone and strontium ranelate). Some new drugs that are being studied for their potential anti-fracture effects are listed.

Antibodies, Monoclonal↗
PubMed2001

The effects of MMP inhibitors on human salivary MMP activity and caries progression in rats.

Previous studies suggest that salivary and pulp-derived host enzymes, matrix metalloproteinases (MMPs), may be involved in dentin caries pathogenesis. To study the inhibition of acid-activated human salivary MMPs by non-antimicrobial chemically modified tetracyclines (CMTs), we used a functional activity assay with 125I-labeled gelatin as a substrate. To address the role of MMPs in the progression of fissure caries in vivo, we administered the MMP inhibitors CMT-3 and zoledronate to young rats per os for 7 weeks, 5 days a week. Caries lesions were visualized by Schiff reagent in sagittally sectioned mandibular molars. Marked reduction in gelatinolytic activity of human salivary MMPs was observed with CMT-3. CMT-3 and zoledronate, both alone and in combination, also reduced dentin caries progression in the rats. These results suggest that MMPs have an important role in dentin caries pathogenesis, and that MMP inhibitors may prove to be useful in the prevention of caries progression.

Analysis of Variance↗
PubMed2005

[Multiple myeloma--recent advances in diagnosis and treatment].

Multiple myeloma (MM) is a systemic malignancy of pathologic plasma cells that is treatable with various chemotherapeutic agents and irradiation, but rarely curable. The mean age of affected patients is mid-60s. Recent clinical studies have confirmed that high-dose chemotherapy with stem cell transplantation is the standard therapy for MM. Furthermore, novel therapeutic agents, such as thalidomide and other immunomodulatory agents have been extensively investigated. Recent advances in the diagnosis and treatment were reviewed and summarized.

Angiogenesis Inhibitors↗