Bone Metastases In Cancer Patients Research Articles

Suppression of NADPH Oxidase Activity May Slow the Expansion of Osteolytic Bone Metastases.

Lysophosphatidic acid (LPA), generated in the microenvironment of cancer cells, can drive the proliferation, invasion, and migration of cancer cells by activating G protein-coupled LPA receptors. Moreover, in cancer cells that have metastasized to bone, LPA signaling can promote osteolysis by inducing cancer cell production of cytokines, such as IL-6 and IL-8, which can stimulate osteoblasts to secrete RANKL, a key promoter of osteoclastogenesis. Indeed, in cancers prone to metastasize to bone, LPA appears to be a major driver of the expansion of osteolytic bone metastases. Activation of NADPH oxidase has been shown to play a mediating role in the signaling pathways by which LPA, as well as RANKL, promote osteolysis. In addition, there is reason to suspect that Nox4 activation is a mediator of the feed-forward mechanism whereby release of TGF-beta from bone matrix by osteolysis promotes expression of PTHrP in cancer cells, and thereby induces further osteolysis. Hence, measures which can down-regulate NADPH oxidase activity may have potential for slowing the expansion of osteolytic bone metastases in cancer patients. Phycocyanin and high-dose statins may have utility in this regard, and could be contemplated as complements to bisphosphonates or denosumab for the prevention and control of osteolytic lesions. Ingestion of omega-3-rich flaxseed or fish oil may also have potential for controlling osteolysis in cancer patients.

The effect of resistance training during radiotherapy on spinal bone metastases in cancer patients – A randomized trial

PurposeTo compare the effects of resistance training versus passive physical therapy on bone density in the metastatic bone during radiation therapy (RT) as combined treatment in patients with spinal bone metastases. Secondly, to quantify pathological fractures after combined treatment. Material and methodsIn this randomized trial, 60 patients were allocated from September 2011 until March 2013 into one of the two groups: resistance training (group A) or passive physical therapy (group B) with thirty patients in each group during RT. Bone density in metastatic and non-metastatic vertebral bone was assessed at baseline, 3 and 6months after RT. ResultsBone density in all metastases increased significantly by 28.3% (IQR 11.4–139.0) and 80.3% (IQR 32.6–250.6) after 3 and 6months in group A (both p<0.01). The bone density in group A was significantly increased compared to control group after 3 and 6months (both p<0.01, median 59.7; IQR 21.1–98.3 and median 62.9; IQR −9.7 to 161.7). The bone density data in group B showed no significant increase over the course of time (p=0.289, median 5.5, IQR 0.0–62.2 and p=0.057, median 52.1, IQR 0.0–162.7). 23.3% of the patients in group A and 30.0% of the patients in group B had pathological fractures, no fracture was assigned to intervention, and no difference between groups after 3 and 6months was observed (p=0.592 and p=0.604). ConclusionsOur trial demonstrated that resistance training concomitant to RT can improve bone density in spinal bone metastases. This combined treatment is effective, practicable, and without side effects for patients. Importantly, the pathological fracture rate in the intervention group was not increased. The results offer a rationale for future large controlled investigations to confirm these findings.Trial registration: Clinical trial identifier NCT01409720.

Oral bisphosphonate use and colorectal cancer incidence in the Women's Health Initiative.

Bisphosphonates are widely prescribed to increase bone density in postmenopausal women with osteopenia or osteoporosis. Aminobisphosphonates have numerous anticancer properties and reduce bone metastases in cancer patients. Several studies, including the Women's Health Initiative (WHI), have found that use of oral bisphosphonates is associated with reduced risk of developing breast cancer, but less is known about associations with other common malignancies in women such as colorectal cancer (CRC). A few case-control and retrospective cohort studies have reported decreased risk of CRC among bisphosphonate users. In contrast, a prospective cohort study found no association. We evaluated the association between oral bisphosphonate use and CRC incidence in 156,826 postmenopausal women, ages 50 to 79 years, who participated in WHI clinical trials and observational study. A detailed health interview was conducted at baseline, and bisphosphonate use was ascertained from an inventory of regularly used medications at baseline and over follow-up. A total of 1931 women were diagnosed with incident invasive CRC during a median follow-up of 12 years. Alendronate was the most commonly used bisphosphonate, accounting for >90% of the total person-years of use. The association between oral bisphosphonate use and CRC risk did not reach statistical significance (hazard ratio [HR] from multivariable-adjusted models = 0.88; 95% confidence interval [CI] 0.72-1.07; p = 0.19). Furthermore, we did not observe greater risk reductions for women with longer duration of use. Uncontrolled confounding may explain why previous studies have observed an association.

A modified method for reducing renal injury in zoledronic Acid treatment of hypercalcemia and adverse skeletal events.

Aims:In this paper, we have reported a previously undescribed risk factor of deterioration of renal function in zoledronic acid treatment of skeletal metastasis – high serum calcium level. Based on this consideration, a modified method of treatment of hypercalcemia (HCM) with zoledronic acid is suggested in this paper.Material and Methods:Bone scan findings of 1090 cancer patients were analyzed, of which 26 had intense renal parenchymal uptake as a result of HCM or bone metastases. Subsequently, a total of 56 bone metastases patients with zoledronic acid treatment were divided into three groups: HCM group who were pre-treated to normal serum calcium level (13 patients), HCM group (19 patients), and normal serum calcium group (24 patients).Results:More patients with intense renal parenchymal uptake were hyperglycemic, statistically significantly (18/26 versus 19/1064, P = 2.1, E-78). No more patients with intense renal parenchymal uptake were associated with bone metastases (14/26 versus 438/1064, P = 0.20). Subsequently, more HCM patients receiving zoledronic acid treatment showed renal injury compared to patients with normal serum calcium level (5/15 versus 2/24, P < 0.05) and HCM patients with pre-treatment to normal serum calcium level (5/15 versus 1/17, P < 0.05).Conclusions:Intense renal parenchymal uptake of bisphosphonates is closely related to HCM rather than to bone metastases in cancer patients. The serum calcium should be measured and reduced to normal level before zoledronic acid is used in managements of adverse skeletal events in order to decrease the risk of renal injury.

Survival After Bone Metastases in Cancer Patients in Denmark

Survival After Bone Metastases in Cancer Patients in Denmark

Biphosphonate related osteonecrosis of the jaws: Promising early piezosurgical resection-case series

Background: Biphosphonates, in particular Zoledronic acid, are used intravenously in bone metastases in cancer patients.

Serum N-Terminal Propeptide of Collagen Type I is Associated with the Number of Bone Metastases in Breast and Prostate Cancer and Correlates to Other Bone Related Markers

BackgroundA number of biomarkers have been proven potentially useful for their ability to indicate bone metastases (BM) in cancer patients. The aim of this study was to investigate the relative utility of a newly developed N-terminal propeptide of collagen type I (PINP) human serum assay for the detection of BM in cancer patients. This assay has a corresponding rat PINP assay which in the future might help in translational science between rodent and human trials.MethodsParticipants were 161 prostate, lung and breast cancer patients stratified by number of BM (Soloway score). PINP was assessed and correlated to number of BM. Additionally, the PINP marker was correlated to bone resorption of young (ALPHA CTX-I)- and aged bone (BETA CTX-I); number of osteoclasts (Tartrate-resistant acid phosphatase 5b, TRACP5B) and osteoclast activity (CTX-I/ TRACP5B).ResultsPINP was significantly elevated in breast- and prostate cancer patients +BM, compared to −BM (P < 0.001), however not in lung cancer patients. A strong linear association was seen between PINP and the number of BMs. Significant elevation of PINP was observed at Soloway scores 1–4 (<0 BM) compared with score 0 (0 BM) (P < 0.001). The correlation between bone resorption of young bone or aged bone and bone formation was highly significant in patients +BM and −BM (P < 0.0001).ConclusionsData suggest that the present PINP potentially could determine skeletal involvement in patients with breast or prostate cancer. Correlations suggested that coupling between bone resorption and bone formation was maintained in breast- and prostate cancer patients.

Tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) as a serum maker for cancer with bone metastasis

The spread of cancer to bone is considered a terminal event. Two main types of bone metastasis can manifest, i.e. osteoblastic and osteolytic. Irrespective of metastatic type, uncoupled bone remodeling is always present and perpetuates a vicious cycle of excess bone resorption and destruction. Biochemical markers of bone metabolism are potentially useful to diagnose metastatic bone disease and to monitor treatment response in cancer patients. Tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) is a biochemical marker of osteoclast number and activity. Mounting evidence has demonstrated serum TRACP 5b as a useful marker of bone resorption and therefore bears clinical applicability in diagnosis and management of metabolic and pathologic bone diseases. Serum TRACP 5b is among one of the many bone resorption biochemical markers that have been studied to be a surrogate marker of bone metastasis in cancer patients. Its serum level may reflect the degree of lytic bone metastasis and, in turn, the tumor burden within the bone milieu. This review summarizes the development of specific immunoassays for serum TRACP 5b as well as current evidence for its exploitation as a biomarker for diagnosis, treatment response, and prognosis in various cancers with high incidence of bone metastasis including breast, prostate, lung, and multiple myeloma.

Comparison of 18F-FDG-PET/CT with 99mTc-MDP bone scintigraphy for the detection of bone metastases in cancer patients

We tried to assess the efficacy of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) ((18)F-FDG-PET/CT) scan in detecting bone metastases in cancer patients and to compare the results with bone scan (BS) findings. Seventy patients with a variety of neoplastic diseases, who had undergone both (18)F-FDG-PET/CT and BS and were eventually diagnosed as having metastatic bone disease, were enrolled in this study. The confirmation of the final diagnosis of bone metastasis was made by histopathological findings or clinical follow-up for 11 months, on average, including magnetic resonance imaging, (18)F-FDG-PET/CT or BS findings, showing progression of the lesions or their disappearance after therapy. (18)F-FDG-PET/CT imaging detected bone involvement in 68 out of 70 patients with a sensitivity of 97.1%. In contrast, BS showed the presence of metastases in 60 patients (85.7%). PET/CT detected 666 out of 721 metastatic lesions correctly (92.3%), whereas BS detected 506 lesions totally (70.1%). PET/CT revealed organ metastases in 24 patients and in seven patients with unknown primary; PET/CT also depicted primary tumor. (18)F-FDG-PET/CT is more sensitive than BS in detecting bone metastasis in patients with neoplastic diseases. (18)F-FDG-PET/CT has the advantage of detecting unknown primary cancers and visceral metastases besides bone metastases.

Denosumab-related osteonecrosis of the jaws

Dear Editors, Denosumab is a human monoclonal IgG2 antibody that binds selectively and with high affinity to the receptor activator of nuclear factor-κB ligand(RANK-L) and pharmacologically mimics the effect of osteoprotegerin on RANK-L [1, 2] thereby blocking the binding of RANK-L to the receptor activator of nuclear factor-κB(RANK) [1]. Denosumab rapidly decreases bone turnover markers resulting in a significant increase in bone mineral density and reduction in fracture risk [3]. Osteonecrosis of the jaws (ONJ) was initially erroneously ascribed to being a later chemotherapy effect [2, 4]. ONJ became one of the most discussed adverse events in advanced malignancy [5]. Importantly, ONJ has never been reported to be associated with other pharmaceutical agents, except bisphosphonates [2, 4]. The case of a cancer patient who developed ONJ without previous history of irradiation or bisphosphonate administration has been published [6]. In this patient, ONJ was reported to have healed completely following sequestration, 15 months after drug discontinuation [6]. Despite the fact that this is the only case published to date, additional evidence published in scientific meeting proceedings suggest that the condition of ONJ may not be solely associated to bisphosphonates [7, 8]. Results from two randomized clinical trials (RCTs; NCT00321464 [8], NCT00330759 [7]) of denosumab in cancer patients with bone metastases report that ONJ occurred infrequently [7, 8] (Table 1). Both studies have current or prior intravenous or oral bisphosphonate administration in their exclusion criteria [7, 8], thus bisphosphonates as an etiopathological factor for ONJ in those participants who received denosumab can be ruled out. Since ONJ has not been previously described to be associated with other drugs agents administered to cancer patients [2], it can be suggested that these cases of ONJ are related to denosumab administration. The role of dosing interval and cumulative dose appears to be important regarding development of denosumabrelated ONJ. All denosumab RCTs published to date include a dosing interval longer than 3 months and a cumulative dose of not more than 210 mg per 6 months [3]. None of these studies does report any cases of ONJ. On the contrary, preliminary results of both RCTs studying denosumab for the treatment of bone metastases in cancer patients include a monthly dosing interval and a dose of 120 mg per month [7, 8]. It is evident that denosumabrelated ONJ could be a dose-related adverse effect. This latter argument has also been reported to apply to bisphosphonate administration [4, 9]. ONJ has been reported to be a much more common event in those patients receiving bisphosphonates for the treatment and prevention of cancer-related skeletal events (mainly intravenously), rather than in those patients receiving bisphosphonates (mainly orally) for non-malignancy indications [10, 11]. Similar to bisphosphonate-related ONJ pharmacosurveillance and reporting history [4], one could anticipate that broad introduction of denosumab into clinical practice, would allow for the recognition of the denosumab-related ONJ adverse effect in a much wider spectrum of prescription indications, including those for non-malignancy [10]. A. Kyrgidis (*) Department of Oral and Maxillofacial Surgery, School of Dentistry, Aristotle University of Thessaloniki, 3 Papazoli St, Thessaloniki 546 30, Greece e-mail: akyrgidi@gmail.com

An efficient and aseptic preparation of “sodium fluoride (18F) injection” in a GMP compliant facility

"Sodium fluoride ((18)F) injection" is an isotonic NaCl solution containing [(18)F]NaF to be used as bone imaging agent. Although its NDA was approved by the US FDA in 1972, it has not been commercially available since 1975 due to mostly the popularity of (99m)Tc-MDP. Recently, advances in PET/CT technology and the often interrupted (99m)Tc supply have led to the renewed interest in the use of [(18)F]NaF to detect bone metastases in cancer patients. This report introduces an efficient, low-cost and aseptic preparation of "Sodium fluoride ((18)F) injection" for PET scan. (18)F-Fluoride in target water from cyclotron was adsorbed onto four different forms of anion-exchange resins then desorbed by isotonic NaCl solution into the product vial. One of the resins that yielded the product at the suitable pH was used for the aseptic preparation. The components for this setup, including stopcocks, extension tubes, etc., were all single-use, individually packed and sterile. The process was done in a lead-line isolator maintained in grade A (PIC/S) aseptic condition. The quality of the obtained "Sodium fluoride ((18)F) injection" was analyzed according to its monograph in the European Pharmacopoeia (EP). The resin in the chloride form yielded the product of pH 6.7 and was chosen for the subsequent preparation. The radiochemical yield was quantitative. The product met all criteria specified in EP, including biological, physical and chemical specifications. This method is an efficient, space-saving and extremely low-cost operation that easily performed in an aseptic environment meeting GMP standard. The quality of the "Sodium fluoride ((18)F) injection" so yielded meets EP specifications. This setup provides hospital with facility meeting GMP standard a cost effective and efficient method for "Sodium fluoride ((18)F) injection" production without the need for the expensive automatic module and extra QC instrument.

｀８９´Ｓｒ制動放射線の画像化における基礎的検討

The radiopharmaceutical strontium chloride ((89)Sr) has been released as a new means of pain relief for painful bone metastasis in cancer patients. Because (89)Sr is a pure beta-emitting nuclide, it was considered difficult to know its distribution in the body from outside. Imaging with a gamma camera using bremsstrahlung radiation has been reported as one method, but there has been little detailed basic examination. We examined the optimal energy window and collimator when imaging with a gamma camera using bremsstrahlung radiation produced from (89)Sr beta rays. The results showed that setting the energy window at 75 keV, which is the peak formed by the characteristic X-ray of lead that is produced by the interaction of bremsstrahlung radiation and lead, is optimal for imaging. Also important are the material of the collimator and the use of an MELP collimator.

Increased tartrate-resistant acid phosphatase (TRAP) expression in malignant breast, ovarian and melanoma tissue: an investigational study

BackgroundTartrate-resistant acid phosphatase (TRAP) is a metalloprotein enzyme that belongs to the acid phosphatases and is known to be expressed by osteoclasts. It has already been investigated as a marker of bone metastases in cancer patients. In this study, which examined the value of serum TRAP concentrations as a marker of bone disease in breast cancer patients, we observed high concentrations of TRAP even in patients without bone metastases. To elucidate this phenomenon, we examined the expression of TRAP in breast cancer cells and the cells of several other malignancies.MethodsTRAP concentrations in the serum of tumor patients were determined by ELISA. The expression of TRAP in breast, ovarian, and cervical cancer and malignant melanoma was analyzed by immunohistochemistry. RT-PCR and immunocytology were used to evaluate TRAP expression in cultured tumor cells.ResultsA marked increase in serum TRAP concentrations was observed in patients with breast and ovarian cancer, regardless of the presence or absence of bone disease. TRAP expression was found in breast and ovarian cancers and malignant melanoma, while cervical cancer showed only minimal expression of TRAP. Expression of TRAP was absent in benign tissue or was much less marked than in the corresponding malignant tissue. TRAP expression was also demonstrated in cultured primary cancer cells and in commercially available cell lines.ConclusionOverexpression of TRAP was detected in the cells of various different tumors. TRAP might be useful as a marker of progression of malignant disease. It could also be a potential target for future cancer therapies.

Zoledronic acid (Z) as palliative treatment in cancer patients with bone metastases: Interim results of a prospective, open-label trial

8140 Background: Bone metastases in cancer patients may lead to severe bone pain, pathological fractures, and hypercalcemia. The development of osteolytic destruction is due to activation of osteoclasts by release of tumor-derived stimulating factors. The bisphosphonate (BP) Z is known to inhibit osteoclast function and thus to alleviate the adverse effects of tumor-induced increase in osteoclastic bone resorption. We investigated the effects of Z in patients with bone metastases in a broad range of tumor types Methods: BP-naive patients with at least one detectable bone lesion irrespective of the primary tumor were eligible for enrolment in this prospective, multicenter study with a single treatment arm, in which patients receive Z at a dose of 4 mg every 3–4 weeks for a maximum of 12 infusions. Primary study endpoints are the treatment-emergent changes in pain sensation assessed by a 100 mm visual analog scale (VAS) for bone pain, and in the concomitant consumption of analgesics, assessed by a five-point scale ranging from 0–4 in according to the analgesic capacity (both documented by a patient diary). Here, we present the data of an interim analysis after 24 weeks. Results: 606 patients in 67 centers have been included. 408 of them were valid for the efficacy analysis (non-validity mostly due to missing data from patient diaries). The age of this subset (61% females) ranged from 31–90 years. Predominant types of primary cancer were breast (49%) and prostate cancer (18%). 319 patients regularly completed treatment up to Week 24. The mean VAS value for pain decreased by 13.8 ± 30.6 from 36.9 ± 28.2 to 23.1 ± 23.8 (p<0.0001, t-test, (“last observation carried forward” procedure for drop-outs). Accordingly, the mean analgesic score not only remained stable, but even decreased by 0.37 ± 1.30 from 1.65 ± 1.56 to 1.28 ± 1.61 (p<0.0001, t-test). Conclusions: Based on the presented results, we conclude that treatment of bone metastases in a broad range of tumor types with Z acid provides substantial benefit to cancer patients also in terms of pain relief and thus improves their quality of life. (supported by Novartis Pharma GmbH, Nürnberg, Germany) Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Pharma GmbH Germany

Zoledronic acid (Z) as palliative treatment in cancer patients with bone metastases: Interim results of a prospective, open-label trial

8140 Background: Bone metastases in cancer patients may lead to severe bone pain, pathological fractures, and hypercalcemia. The development of osteolytic destruction is due to activation of osteoclasts by release of tumor-derived stimulating factors. The bisphosphonate (BP) Z is known to inhibit osteoclast function and thus to alleviate the adverse effects of tumor-induced increase in osteoclastic bone resorption. We investigated the effects of Z in patients with bone metastases in a broad range of tumor types Methods: BP-naive patients with at least one detectable bone lesion irrespective of the primary tumor were eligible for enrolment in this prospective, multicenter study with a single treatment arm, in which patients receive Z at a dose of 4 mg every 3–4 weeks for a maximum of 12 infusions. Primary study endpoints are the treatment-emergent changes in pain sensation assessed by a 100 mm visual analog scale (VAS) for bone pain, and in the concomitant consumption of analgesics, assessed by a five-poin...

Bisphosphonate actions on bone and visceral metastases.

Bone abundantly stores a variety of growth factors and thus provides migrating cancer cells with fertile soil. Osteoclastic bone resorption releases these growth factors providing fertile environment, which allows colonizing cancer cells to proliferate and survive. Consequently, cancer cells produce a variety of factors that in turn influence bone metabolism. This intimate partnership between cancer cells and bone will be a driving force to develop and progress bone metastases. Accordingly, suppression of osteoclastic bone resorption should be a logic approach to inhibit bone metastases. Bisphosphonates (BPs), specific inhibitors of osteoclasts, have been widely used for the treatment of bone metastases in cancer patients. In addition, recent studies suggest the possibility that BPs can reduce visceral metastases by inhibiting cell growth and inducing apoptosis in cancer cells. In this chapter, the authors will review the recent experimental results regarding the effects of BPs on bone and visceral metastases and also show their own data obtained using animal models of breast cancer metastasis. Accumulating data suggest that there is no doubt that BPs are beneficial for the treatment of existing bone metastases, while the beneficial effects of BPs on visceral metastases are not warranted yet.

The effect of Neovastat (Æ-941) on an experimental metastatic bone tumor model

Bone metastases are generally associated with bone destruction which occurs in response to factors secreted by metastatic cells. Some of these factors secreted by the metastatic cells activate osteoclats while others are proteases that degrade bone collagen. To determine if Neovastat (AE-941), a naturally occurring multi-functional inhibitor of angiogenesis, is able to regulate properties that are thought to have relevance to their propensity to form bone metastases in vivo, we used the human breast cancer MDA-MB-231 cell line which can metastasize to bone. We showed that Neovastat prevented the degradation of osteoid-like radiolabeled extracellular matrices which was induced by incubation of human SaOS-2 osteoblast-like cells with MDA-MB-231 cells. Moreover, Neovastat was demonstrated to inhibit the gelatinolytic activity of matrix metalloproteinase (MMP)-9 expressed by MDA-MB-231 cells. The potential of Neovastat to retard the spread, growth, and osteolysis of MDA-MB-231 cells was then estimated in vivo. Histomorphometric analysis of the vertebral bodies indicated that MDA-MB-231 cells inoculated in nude mice (intracardiac) successfully generate osteolytic metastases with an 83% reduction of the volume of medullary bone (p< or =0.01). However, when tumor-bearing animals were treated orally with Neovastat, there was only a 19% decrease in medullary bone thus indicating that Neovastat can prevent bone metastasis in this model. Consistent with histological results, radiographic analysis indicated that Neovastat decreased the number of osteolytic lesions by 33% (p< or =0.3). Moreover, a decrease in the tumor volume in bone was observed in Neovastat-treated animals. These results indicate that Neovastat may be useful in preventing bone metastasis in cancer patients.

Studies in Paget's disease and their relevance to oncology

Paget's disease and bone metastases in cancer patients share many common properties. Both are characterized by a localized increase in osteoclast (OCL) formation leading to bone resorption. In both Paget's disease and bone metastases the increased OCL formation and the increased osteoclastogenic nature of the bone microenvironment are mediated by common factors, namely interleukin (IL)-6 and RANK ligand (RANKL). Available data suggest that in the case of Paget's disease there is increased RANKL and IL-6 production, and IL-6 enhances the responsivity of the OCL precursors to RANKL, contributing to the elevated numbers of OCLs. In patients with multiple myeloma, 95% to 100% of whom develop bone lesions, both IL-6 and RANKL levels are increased. Bisphosphonates bind locally to the surfaces of the bone undergoing osteoclastic resorption to inhibit this process. Paget's disease has in the past and will continue in the future to provide a model to test the efficacy of bisphosphonates in inhibiting bone resorption. Paget's disease provides an ideal model in which to investigate the efficacy of the new third-generation bisphosphonates in the treatment of bone metastases as well as nonmalignant bone disease.

Actions of bisphosphonate on bone metastasis in animal models of breast carcinoma.

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. 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. 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. 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.

Oral bisphosphonates

BACKGROUND This study was conducted to review the efficacy and safety of oral bisphosphonates for the treatment of bone metastases in cancer patients. METHODS Available published clinical studies of oral bisphosphonates in bone metastases from 1980 to the present were identified through a MEDLINE search and from literature references. Data were reviewed for efficacy and safety, with an emphasis on double blind, placebo-controlled studies; clinically relevant endpoints; and appropriate study methodology. RESULTS Etidronate, alendronate, pamidronate, risedronate, and tiludronate currently are available in the U.S. as either intravenous and/or oral formulations. Although newer bisphosphonates are more potent, oral bioavailability remains < 1%. Oral etidronate has been found to be ineffective in patients with multiple myeloma and prostate carcinoma bone metastases. Pamidronate has been found to be effective in reducing skeletal morbidity associated with bone metastases in both multiple myeloma and breast carcinoma patients when given intravenously, but is ineffective orally in multiple myeloma patients. To the authors' knowledge, there are no double blind, placebo-controlled trials of oral pamidronate in patients with breast carcinoma and bone metastases. Several clinical trials with clodronate, a bisphosphonate that is not available in the U.S., have shown mixed results in patients with myeloma and breast carcinoma bone metastases. To the authors' knowledge, there are no published trials evaluating oral alendronate, tiludronate, or risedronate in patients with metastases to bone. CONCLUSIONS Oral bisphosphonates do not appear to be as effective as intravenous administration in reducing skeletal complications in patients with metastases to bone lesions. Low oral bioavailability is the most likely reason for this difference. Oral dosing should not be substituted for intravenous administration in the treatment of malignant osteolysis. Cancer 2000;88:6–14. © 2000 American Cancer Society.