帕米膦酸二钠与唑来膦酸治疗肺癌骨转移性疼痛的近期疗效及成本效益分析

目的:比较帕米膦酸二钠与唑来膦酸治疗肺癌骨转移性疼痛的近期疗效、不良反应及其对于患者住院时间及住院费用的影响.方法:将40例确诊肺癌骨转移患者随机分为2组:帕米膦酸二钠组(20例)、唑来膦酸组(20例).帕米膦酸二钠注射液60mg,加入500ml生理盐水内,静脉滴注4h;唑来膦酸注射液4mg,加入100ml生理盐水内,静脉滴注20min.两组均每4周给药1次,共2次给药.比较2组患者的疼痛控制效果、血碱性膦酸酶(AKP)、血钙的变化、平均住院时间及总住院费用.结果:帕米膦酸二钠、唑来膦酸组的获益率分别为90％及85％,不良反应发生率无明显差异,均未发生下颌骨坏死.2组治疗后AKP及血钙均明显下降(P＜0.05).2组病人的住院时间(P＞0.05)及住院费用无明显差异(P＞0.05).结论:帕米膦酸二钠与唑来膦酸应用于本研究中的肺癌病人,在疗效、不良反应及成本效益方面均无明显差异.     

Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction

Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor‐specific replicating oncolytic adenovirus OBP‐301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid (ZOL) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with OBP‐301 and ZOL against osteosarcomas with bone destruction. The antitumor activity of OBP‐301 and ZOL in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B, MNNG/HOS, SaOS‐2). The cytotoxic effect of OBP‐301 and/or ZOL was measured by assay of cell apoptosis. The effect of OBP‐301 and ZOL on osteoclast activation was investigated. The potential of combination therapy against tumor growth and bone destruction was analyzed using an orthotopic 143B osteosarcoma xenograft tumor model. OBP‐301 and ZOL decreased the viability of human osteosarcoma cells. Combination therapy with OBP‐301 and ZOL displayed a synergistic antitumor effect, in which OBP‐301 promoted apoptosis through suppression of anti‐apoptotic myeloid cell leukemia 1 (MCL1). Combination therapy significantly inhibited tumor‐mediated osteoclast activation, tumor growth and bone destruction compared to monotherapy. These results suggest that combination therapy of OBP‐301 and ZOL suppresses osteosarcoma progression via suppression of MCL1 and osteoclast activation.     

Effects of oral UFT combined with or without zoledronic acid on bone metastasis in the 4T1/luc mouse breast cancer

Bone metastasis is one of the major causes of increased morbidity and eventual mortality in breast cancer patients. Therefore, intervention of bone metastases is one of the important targets in the management of breast cancer. In the present study, we examined the effects of the orally administrable chemotherapeutic agent UFT (a combination of tegafur and uracil at a molar ratio of 1:4) on bone metastases using an animal model of the 4T1/luc mouse breast cancer. The 4T1/luc cells developed spontaneous metastases to bone following orthotopic cell inoculation. Oral daily administration of UFT (20 mg/kg/day) significantly reduced the orthotopic tumor burden; however, the lower dose (15 mg/kg/day) did not. In contrast, histologic examination showed that both doses of UFT significantly suppressed bone metastases in a dose-dependent manner. Since clinical studies have demonstrated that bisphosphonates (BPs), specific inhibitors of osteoclastic bone resorption, are beneficial for breast cancer patients with bone metastases, we next examined the effects of UFT combined with the BP zoledronic acid (ZOL) on established bone metastases. The combination of UFT (20 mg/kg/day) with ZOL (250 microg/kg) caused an enhanced reduction of bone metastases compared with UFT alone. In vitro studies showed that 5-fluorouracil (5-FU), an active metabolite of UFT, and ZOL increased apoptosis in 4T1/luc cells and inhibited osteoclast-like cell formation in an additive fashion. Our results suggest that oral UFT is an effective chemotherapeutic agent for advanced breast cancer accompanying bone metastases and that the combination with BP increases its benefits for bone metastases.     

Increased expression and serum levels of the stromal cell‐secreted protein periostin in breast cancer bone metastases

Periostin, a matricellular protein, is overexpressed in the stroma of several cancers. The aim of our study was to investigate more specifically whether periostin expression is associated with bone metastases from breast cancer and to determine its source in the affected bone. Nude mice were inoculated with human MDA‐B02 breast cancer cells. Bone metastases‐bearing mice were treated with zoledronic acid—an antiresorptive drug—or vehicle. Bone metastases were examined for tumor‐ and stroma‐derived periostin expression by quantitative polymerase chain reaction with human‐ and mouse‐specific primers and immunohistochemistry. Serum periostin and conventional bone turnover markers were also measured. MDA‐B02 cells did not express periostin both in vitro and in vivo. However, mouse‐derived periostin was markedly overexpressed (eightfold) in metastatic legs compared to noninoculated mice. Serum periostin levels were also markedly increased in metastatic mice and correlated with in situ expression levels. Immunostaining showed that periostin derived from the environing stromal cells of bone metastasis. Bone turnover blockade by zoledronic acid markedly decreased osteolytic lesions but only slightly modulated serum periostin levels. Bone metastases from breast cancer induce overexpression of periostin by surrounding stromal cells. Periostin could be a biochemical marker of the early stromal response associated to breast cancer bone metastasis formation.     

Zoledronic acid and skeletal complications in patients with solid tumors and bone metastases: analysis of a national medical claims database

BACKGROUND.: Bone is among the most common sites of metastasis in patients with advanced cancer, and the development of bone metastases places patients at increased risk for skeletal complications. METHODS.: This retrospective claims analysis included only patients with a diagnosis of bone metastasis who had a single type of solid tumor of the breast (women), prostate, or lung and experienced >/=1 skeletal complication between January 2002 and October 2005. RESULTS.: The mean follow-up (+/-standard deviation) for zoledronic acid (ZA)-treated patients versus untreated patients was 12.2 +/- 9.05 months versus 8.7 +/- 9.28 months, respectively (P < .001). The monthly rate of skeletal complications in ZA-treated patients versus untreated patients was 0.29 +/- 0.3 per month versus 0.43 +/- 0.4 per month, respectively (P < .001). Persistent ZA use was associated with longer follow-up duration (P < .05) and a greater probability of continuing follow-up. Greater persistency was associated with lower monthly rates of skeletal complications (P < .05). The length of follow-up for ZA use according to the recommended dosing schedule was 17.11 months compared with 9.93 months for nonrecommended schedules and 8.68 months for no treatment (analysis of variance; P < .001). The rate of skeletal complications with ZA use on the recommended schedule was 0.16 events per month versus 0.31 events per month for nonrecommended schedules and 0.43 events per month for no treatment. In the subgroup analysis, the mean time to first complication was 185 +/- 210 days in the ZA-treated group versus 98 +/- 161 days in the untreated group (P < .0001). The mean time from the first complication to the second complication was 111 +/- 124 days in the ZA-treated group versus 86 +/- 114 days in the untreated group (P < .05). CONCLUSIONS.: Real-world evidence indicated that ZA reduced the skeletal morbidity rate and delayed the time to skeletal complications. Cancer 2008. (c) 2008 American Cancer Society.     

Combined effects of a third-generation bisphosphonate, zoledronic acid with other anticancer agents against murine osteosarcoma

Bisphosphonates (BPs) are widely used to treat bone diseases and also appear to possess direct antitumour activity. We have previously reported that third-generation BPs such as zoledronic acid (ZOL) and minodronic acid (YM529) synergistically augment the effects of anticancer agents in various cancer cells. Recently, we have also reported the antitumour effects of YM529 on murine osteosarcoma cells. As YM529 has not been clinically available, we herein focused on the anti-osteosarcoma effects of ZOL which is clinically available. In addition to ZOL alone, we evaluated the concurrent or sequential combined effects of ZOL with other anticancer agents against murine osteosarcoma cell lines. ZOL showed almost same anti-osteosarcoma activity compared with YM529 and more sensitive growth inhibitory effects against osteosarcoma cells than normal cells. Moreover, ZOL acted synergistically in vitro when administered concurrently with paclitaxel (PAC) or gemcitabine (GEM), not only in wild-type osteosarcoma cells but also in P-glycoprotein (P-gp)-overexpressing osteosarcoma cells, which were much less sensitive against each anticancer agent. Furthermore, 24 h of ZOL pretreatment significantly augmented the sensitivity of doxorubicin (DOX), PAC or GEM against osteosarcoma cells. These findings suggest that combined administration of ZOL with other anticancer agents may improve the osteosarcoma treatment.     

Local irradiation in combination with bevacizumab enhances radiation control of bone destruction and cancer-induced pain in a model of bone metastases

Skeletal metastases are a major source of morbidity for cancer patients. The purpose of this study was to evaluate the effects of megavoltage irradiation and antiangiogenic therapy on metastatic bone cancer. A tumor xenograft model was prepared in C3H/Scid mice using 4T1 murine breast carcinoma cells. Twenty-eight mice bearing tumors were treated with either bevacizumab (15 mg/kg), local megavoltage irradiation (30 Gy in 1 fraction), combination of bevacizumab and local megavoltage irradiation or physiologic saline solution (control group). Tumor area, bone destruction, tumor microvessel density, pain-associated behaviors and expression of substance P were assessed. Combined modality treatment reduced the frequency of pain-associated behaviors, decreased levels of nociceptive protein expression in the spinal cord, maintained cortical integrity and decreased the density of microvessels as compared to single modality treatments. We conclude that concurrent antiangiogenic therapy and localized radiotherapy for the treatment of bone metastases warrants further evaluation in human clinical trials.     

放疗联合唑来磷酸治疗转移性骨痛的临床研究

目的：评价放疗联合唑来磷酸治疗恶性肿瘤骨转移引起的骨痛及不适。方法：114例恶性肿瘤骨转移骨痛的患者，采用随机分组方法，分为联合治疗组（A组，n=38），采用放疗联合唑来磷酸；放疗组（B组，n=42），采用6MVX线30Gy／10次，唑来磷酸组（C组，n=34），采用唑来磷酸4mg＋生理盐水100mL静脉滴注大于15min，每3—4周重复。采用视觉模拟评分法（VAS）对疼痛进行评分，0—10数字疼痛强度分级法，测定疼痛强度。结果：A组VAS评分下降程度较B、C组明显（P〈0．01）。医师总体评价，组A疼痛控制有效率也高于其他两组（P〈0．05）。结论：放疗联合唑来磷酸治疗恶性肿瘤转移性骨痛疗效优于单独放疗或单用唑来磷酸。     

唑来膦酸或帕米膦酸二钠联合阿那曲唑治疗绝经后乳腺癌骨转移的疗效观察

目的 比较唑来膦酸和帕米膦酸二钠分别联合阿那曲唑治疗绝经后乳腺癌骨转移的临床疗效及不良反应。方法 收集2010年1月至2014年6月我院肿瘤科收治的绝经后乳腺癌骨转移患者51例,以随机数字表法分为对照组（n=27）和治疗组（n=24）。治疗组口服阿那曲唑（1 mg/d）联合唑来膦酸4 mg静滴;对照组口服阿那曲唑（1 mg/d）联合帕米膦酸二钠60 mg静滴,28 d为1个周期。观察两组骨痛缓解情况、骨转移灶清退情况、无骨相关事件（skeletal related evend,SRE）生存时间、总生存时间及不良反应。结果 治疗14　d后对照组和治疗组疼痛控制总有效率分别为66.7%和87.5%,差异有统计学意义（P＜0.05）;治疗56 d后对照组疼痛控制总有效率为77.8%,治疗组为91.7%,差异无统计学意义（P＞0.05）。治疗组的骨转移灶清退情况显著优于对照组,差异有统计学意义（P＜0.05）。对照组与治疗组中位无SRE生存时间为17.4个月和22.4个月,中位总生存时间为25.8个月和35.1个月,差异均有统计学意义（P＜0.05）。不良反应主要为发热、肌肉及骨酸痛等,给予对症治疗后缓解。结论 唑来膦酸联合阿那曲唑治疗绝经后乳腺癌骨转移疗效较好,不良反应可耐受,安全性良好,值得临床推广应用。     

Changes of bone turnover markers and serum PTH after night or morning administration of zoledronic acid in breast cancer patients with bone metastases

Persistent circadian rhythm of bone turnover in bone metastatic breast cancer suggests greater skeletal retention of bisphosphonates if administered in the night. We assessed differential effects of night vs morning administration of zoledronic acid (ZA) on bone turnover. Forty-four breast cancer patients with bone metastases were randomised to receive intravenous ZA (4 mg) at 1100 or 2300 hours every 28 days for four times. Urinary concentration N-telopeptide of type-I collagen (NTX) and deoxypyridinolines, and serum C-telopeptide of type-I collagen (CTX), bone alkaline phosphatase (ALP), osteocalcin and Parathyroid hormone (PTH) was measured in the morning at baseline and after 4, 7, 14, 28, 56 and 84 days. Urinary ZA concentration was also measured. Zoledronic acid caused significant decreases of NTX and CTX (P<0.001), without any difference in percent changes between night and morning arms. Bone ALP and osteocalcin were also significantly affected by ZA (P=0.001), without any difference between arms. Parathyroid hormone significantly increased in both the arms; PTH increase was lower in the night arm (P=0.001). From the second administration onwards, urinary ZA level was significantly higher in the night arm (P<0.01). Administration of ZA at two opposite phases of the circadian cycle causes similar changes of bone-turnover marker levels, but has differential effects on the level of serum PTH.     

Zoledronic acid down-regulates adhesion molecules of bone marrow stromal cells in multiple myeloma: a possible mechanism for its antitumor effect

BACKGROUND: Myeloma plasma cells interact with the bone marrow microenvironment which, in turn, supports their growth and protects them from apoptosis. In vitro studies have demonstrated the antitumor potential of zoledronic acid (ZOL) on myeloma cell lines, but few data are available on its effects on bone marrow stromal cells (BMSCs). The aim of the current study was to evaluate the antiproliferative and apoptotic effect of ZOL on BMSCs, as well as its effect on the expression of adhesion molecules. METHODS: BMSCs, obtained from bone marrow mononucleated cells of 8 patients with multiple myeloma, were treated with increasing concentrations of ZOL for 3 days. Cytotoxic effect was analyzed by 3-(4-5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide; thiazolyl blue (MTT) assay whereas the induction of apoptosis was evaluated by flow cytometric detection of fluorescein isothiocyanate-labeled annexin V, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, and nuclear changes. Moreover, expression of CD106, CD56, CD50, CD49d, CD44, and CD40 was analyzed by flow cytometry. Data were evaluated by the Friedman test. RESULTS: After 3 days of exposure at concentrations of 10(-4) to 10(-5) M, ZOL induced a decrease in proliferation (P < 0.0001) and an increase in apoptosis (P < 0.002). Analysis of culture supernatants showed that myeloma BMSCs expressed interleukin (IL)-6, negligible levels of tumor necrosis factor-alpha, and no IL-1beta. In vitro exposure to the lowest concentrations of ZOL decreased IL-6 production by BMSCs. Among the adhesion molecules, CD106, CD54, CD49d, and CD40, which were strongly expressed at baseline, showed a statistically significant reduction compared with controls after exposure to ZOL. CONCLUSIONS: ZOL interfered with myeloma BMSCs by reducing proliferation, increasing apoptosis, and modifying the pattern of expression of adhesion molecules, especially those involved in plasma cell binding. These effects on BMSCs might explain the antitumor activity of ZOL.     

Different tumors in bone each give rise to a distinct pattern of skeletal destruction,bone cancer-related pain behaviors and neurochemical changes in the central nervous system

Pain is the most common presenting symptom in patients with bone cancer and bone cancer pain can be both debilitating and difficult to control fully. To begin to understand the mechanisms involved in the generation and maintenance of bone cancer pain, we implanted 3 well-described murine tumor cell lines, 2472 sarcoma, B16 melanoma and C26 colon adenocarcinoma into the femur of immunocompromised C3H-SCID mice. Although each of the tumor cell lines proliferated and completely filled the intramedullary space of the femur within 3 weeks, the location and extent of bone destruction, the type and severity of the pain behaviors and the neurochemical reorganization of the spinal cord was unique to each tumor cell line injected. These data suggest that bone cancer pain is not caused by a single factor such as increased pressure induced by intramedullary tumor growth, but rather that multiple factors are involved in generating and maintaining bone cancer pain.     

Gene expression profiling of alpha‐radiation‐induced rat osteosarcomas: Identification of dysregulated genes involved in radiation‐induced tumorigenesis of bone

To better understand the molecular basis of radiation‐induced osteosarcoma (OS), we performed global gene expression profiling of rat OS tumors induced by the bone‐seeking alpha emitter ²³⁸Pu, and the expression profiles were compared with those of normal osteoblasts (OB). The expressions of 72 genes were significantly differentially expressed in the tumors related to OB. These included genes involved in the cell adhesion (e.g., Podxl, Col18a1, Cd93, Emcn and Vcl), differentiation, developmental processes (e.g., Hhex, Gata2, P2ry6, P2rx5, Cited2, Osmr and Igsf10), tumor‐suppressor function (e.g., Nme3, Blcap and Rrm1), Src tyrosine kinase signaling (e.g., Hck, Shf, Arhgap29, Cttn and Akap12), and Wnt/β‐catenin signaling (e.g., Fzd6, Lzic, Dkk3 and Ctnna1) pathways. Expression changes of several genes were validated by quantitative real‐time RT‐PCR analysis. Notably, all of the identified genes involved in the Wnt/β‐catenin signaling pathway were known or proposed to be negative regulators of this pathway and were downregulated in the tumors, suggesting the activation of β‐catenin in radiation‐induced OS. By using immunohistochemical and immunoblot analyses, constitutive activation of the Wnt/β‐catenin signaling pathway in the tumors was confirmed by observing nuclear and/or cytoplasmic localization of β‐catenin and a decrease in its inactive (phosphorylated) form. Furthermore, we found a significant reduction in the levels of glycogen synthase kinase 3β (GSK‐3β) protein in the tumors relative to OB. Taken together, these findings provide new insights into the molecular basis of radiation‐induced OS. © 2009 UICC     

Characterization of a rat model with site-specific bone metastasis induced by MDA-MB-231 breast cancer cells and its application to the effects of an antibody against bone sialoprotein

Metastasis into the skeleton is a serious complication of certain neoplastic diseases such as breast, prostate and lung cancer, but the reasons for this osteotropism are poorly understood. Our aim was to establish a physiologically relevant animal model that is characterized by osteolytic lesions confined to the hind leg of nude rats. For this purpose, we injected 1x10(5) MDA-MB-231 human breast cancer cells transfected with GFP into the superficial epigastric artery, which is an anastomosing vessel between the femoral and iliac arteries. As assessed with the aid of X-rays, computed tomography and immunohistochemisty, osteolytic lesions occurred exclusively in the femur, tibia and fibula of the animals. The tumor take rate was 93% in a series of 96 rats and the increase in lesion size was observed up to 110 days after tumor cell inoculation. When applying this animal model to the effects of an antibody against bone sialoprotein (BSP), a significantly reduced osteolytic lesion size was observed after preincubation of cells (2 hr, 600 microg/ml anti-BSP) prior to intra-arterial tumor cell injection resulting in 19 T/C% at day 60 after tumor implantation (p < 0.05). In addition, the osteolytic lesion size was also significantly reduced after s.c. treatment of the animals with the antibody (20 mg/kg anti-BSPx3 within 5 days after tumor implantation), resulting in 30 T/C% at day 60 after tumor cell implantation (p < 0.05). In conclusion, the novel rat model for site-specific osteolytic lesions provides in vivo evidence that preincubation of MDA-MB-231GFP cells and treatment of rats after tumor implantation with an antibody against BSP significantly reduces the size of lytic lesions in bone.     

Oral ibandronate is as active as intravenous zoledronic acid for reducing bone turnover markers in women with breast cancer and bone metastases.

BACKGROUND: Phase III study comparing the effect of oral ibandronate and intravenous zoledronic acid on bone markers. PATIENTS AND METHODS: Breast cancer patients with bone metastases received ibandronate 50 mg/day (n = 137) or zoledronic acid 4 mg every 4 weeks (n = 138) for 12 weeks. The primary end point was mean percentage change in serum levels of cross-linked C-terminal telopeptide of type I collagen (S-CTX) at week 12. Urinary CTX (U-CTX), bone alkaline phosphatase (ALP), amino-terminal procollagen propeptide of type I collagen (PINP) and osteocalcin (OC) were also measured and bone pain and safety assessed. RESULTS: Both bisphosphonates significantly reduced S-CTX (mean ibandronate 76% +/- 29 (SD) versus mean zoledronic acid 73% +/- 47; P < 0.001 for both versus baseline) and U-CTX (ibandronate 78% +/- 50 versus zoledronic acid 86% +/- 17; P < 0.001). The difference in S-CTX between treatments was 0.6% (confidence interval -1.7% to 3.0%), which was within the prespecified noninferiority margin. Bone ALP, PINP and OC decreased by 26%-47% compared with baseline with both bisphosphonates. Compared with zoledronic acid, ibandronate patients reported fewer adverse events overall (65.0% versus 75.9%), and on days 1-3 (8.0% versus 47.5%), including less pyrexia (overall incidence 0% versus 16.8%) and bone pain (5.8% versus 12.4%). CONCLUSIONS: Oral ibandronate was well tolerated and statistically noninferior to zoledronic acid for percentage change in the bone resorption marker, S-CTX.     

Long‐term safety of monthly zoledronic acid therapy beyond 1 year in patients with advanced cancer involving bone (LoTESS): A multicentre prospective phase 4 study

Malignant bone disease can cause significant morbidity. Monthly zoledronic acid (ZOL) reduces skeletal complications; however, limited data are available regarding long‐term safety. We aimed to assess efficacy and safety of ZOL beyond 1 year of treatment. We prospectively evaluated 73 patients; breast cancer (n = 29), castrate‐resistant prostate cancer (n = 13), multiple myeloma (n = 31) from 2006 to 2008 in 19 cancer centres. All patients were diagnosed with bone disease and had completed 1–2 years of monthly ZOL (4 mg) and received a further 1–2 years of therapy following contemporary guidelines for managing risks of osteonecrosis of the jaw (ONJ) and renal toxicity. Overall rates of skeletal‐related events (SREs), renal impairment and ONJ were assessed. Over the additional 1 year of treatment, only 5.5% (n = 4) of patients developed a new SRE. The overall Kaplan–Meier estimate for SRE incidence after 48 weeks on study was 6.75% (95 CI: 2.5–17.3). Although 51% of patients reported serious adverse events, only two cases were suspected as ZOL related. No patients had confirmed ONJ. The observed incidence of new renal impairment was 11% (none due to ZOL). Our study confirms the benefit over risk of continuing monthly ZOL for at least 2 years in patients with advanced cancer involving bone.     

Single infusion of zoledronic acid to prevent androgen deprivation therapy‐induced bone loss in men with hormone‐naive prostate carcinoma

BACKGROUND:

Androgen‐deprivation therapy (ADT) decreases bone mineral density (BMD) and increases fracture risk in patients with prostate carcinoma. The authors investigated the effectiveness of a single infusion of zoledronic acid initiated subsequent to ADT on BMD with hormone‐naive prostate carcinoma.

METHODS:

Forty men received either a single infusion of zoledronic acid (4 mg intravenously on Day 1) or no infusion during ADT. BMD of the proximal femur and posteroanterior lumbar spine was measured by dual‐energy x‐ray absorptiometry and urinary N‐telopeptide (u‐NTx) at 6 and 12 months.

RESULTS:

At baseline, the overall BMDs demonstrated no significant difference in lumbar spine and hip regions. At 6months, mean (±standard error) BMD of the posteroanterior lumbar spine decreased 4.6% ± 1.0% in control patients and increased 5.1% ± 1.2% in patients receiving zoledronic acid, a significant difference (P = .0002). At 12 months, the change in BMD between the 2 groups was statistically significantly different at the lumbar region (P = .0004), indicating that zoledronate preserved BMD. For u‐NTx, bone turnover was statistically significantly decreased in the zoledronate group compared with controls at 6 months (P < .0001), but returned to pretreatment levels at 12 months in the zoledronate group.

CONCLUSIONS:

Bone loss begins at 6 months with ADT. A single infusion of zoledronic acid in patients receiving ADT reduces bone mineral loss and maintains BMD at least at 12 months during ADT. Further study is needed to determine the best dosing schedule to prevent ADT‐induced bone loss in men with hormone‐naive prostate carcinoma. Cancer 2009. © 2009 American Cancer Society.     

Concurrent administration of zoledronic acid and irradiation leads to improved bone density, biomechanical strength, and microarchitecture in a mouse model of tumor-induced osteolysis

BACKGROUND AND OBJECTIVES: Bone metastases are typically treated with bisphosphonates as adjuncts to radiation therapy. The goal of this study was to determine whether radiotherapy combined with a bisphosphonate could restore bone density, microarchitecture, and biomechanical strength of a tumor-burdened bone to normal. MATERIALS AND METHODS: Breast cancer cells were injected into the right femur of 30 female nude mice. Mice were divided into three treatment groups (0 Gy, 20 Gy, and 20 Gy + ZA). Left limbs served as non-operated normal bones. Tumor-bearing femora were irradiated 3 weeks later. ZA (100 microg/kg SC) was administered once weekly for 6 weeks. Mice were euthanized at 9 weeks or earlier if severe lameness or pathology occurred. RESULTS: Mice treated with 20 Gy/ZA exhibited higher bone density, bone volume, fractional trabecular bone volume, and biomechanical strength compared to mice treated with 20 Gy only (P < 0.05). Statistical analysis revealed that mice treated with 20 Gy/ZA were not significantly different from normal bones with respect to bone density and strength. Micro-CT reconstructions showed improved microarchitecture in the 20 Gy/ZA group compared to 20 Gy. CONCLUSIONS: Treatment of an osteolytic bone with radiation therapy plus zoledronic acid restores normal bone qualities with respect to bone density, microarchitecture, and biomechanical strength.