Skeletal Morbidity In Patients Research Articles

Baseline N-Telopeptide Levels Correlate with Risk of Skeletal Morbidity in Patients with Multiple Myeloma during Zoledronic Acid Therapy.

BACKGROUND: Biochemical markers of bone metabolism provide valuable information about rates of bone turnover in patients with malignant bone disease. N-telopeptide of type I collagen (NTX) is released during osteolysis and is indicative of pathologic increases in bone resorption. Elevated NTX levels recently have been correlated with increased risks of skeletal-related events (SREs, defined as pathologic fracture, surgery to bone, spinal cord compression, hypercalcemia of malignancy, and the requirement for palliative radiotherapy), disease progression, and death in patients with bone metastases from solid tumors (Coleman RE, et al. J Clin Oncol. 2005; 23:4925–4935; Brown J, et al. J Natl Cancer Inst . 2005; 97:59–69).METHODS: The current univariate analysis investigated the correlation between NTX levels at baseline and SREs (including palliative radiotherapy to bone) in patients with multiple myeloma who were treated with 4 mg zoledronic acid in a phase III clinical trial (Rosen LS, et al. Cancer J. 2001; 7:377–387).RESULTS: Forty-three patients had low NTX (< 50 nmol/mmol creatinine), 45 had moderate NTX (50 to < 100 nmol/mmol creatinine), and 18 had high NTX (≥ 100 nmol/mmol creatinine) at baseline. Patients with either moderate or high NTX at baseline had significantly increased risks of on-study SREs and significantly increased risks of experiencing their first SRE while on-study compared with patients with low NTX (Table). A similar correlation was also observed for pathologic fractures alone. The risk of first events was especially high in the high NTX group. There were no significant correlations between NTX levels and the requirement for palliative radiotherapy alone.Hazard Ratios for Time to Onset and Occurrence of On-Study SRE Compared With Low (< 50 nmol/mmol creatinine) NTX (P Value)SREPathologic fracturePalliative radiotherapyBaseline NTX levelOnset of first SREAny eventOnset of first eventAny eventOnset of first eventAny eventModerate*2.76 (.012)2.26 (.003)3.78 (.001)2.98 (< .001)1.21 (.777)1.61 (.386)High†6.80 (< .001)4.01 (.001)8.87 (< .001)5.35 (< .001)3.23 (.095)3.44 (.124)*50 to < 100 nmol/mmol creatinine.; † ≥ 100 nmol/mmol creatinine.Conclusions: Multiple myeloma patients with elevated baseline NTX levels have a significantly increased risk of experiencing SREs.

MP55-16 SKELETAL-RELATED EVENTS IN PATIENTS WITH BONE-METASTATIC CARCINOMA OF THE BLADDER OR UPPER URINARY TRACT

You have accessJournal of UrologyBladder Cancer: Invasive II (MP55)1 Apr 2020MP55-16 SKELETAL-RELATED EVENTS IN PATIENTS WITH BONE-METASTATIC CARCINOMA OF THE BLADDER OR UPPER URINARY TRACT Nima Almassi*, Imaani Easthausen, Soleen Ghafoor, Paul Christos, Timothy Donahue, Jonathan Rosenberg, and Azeez Farooki Nima Almassi*Nima Almassi* More articles by this author , Imaani EasthausenImaani Easthausen More articles by this author , Soleen GhafoorSoleen Ghafoor More articles by this author , Paul ChristosPaul Christos More articles by this author , Timothy DonahueTimothy Donahue More articles by this author , Jonathan RosenbergJonathan Rosenberg More articles by this author , and Azeez FarookiAzeez Farooki More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000924.016AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Bone metastases are common in patients with advanced bladder or upper urinary tract cancer. The morbidity of bone metastasis can be quantified using the composite endpoint skeletal related event (SRE), however data are limited on the morbidity of bone metastases in this patient population. The objective of this study was to measure SRE-free survival in patients with bone-metastatic bladder cancer or UTUC, identify clinicopathologic characteristics associated with the development of SREs, and assess use of antiresorptive therapy in patients with bone metastases. METHODS: Under an institutional review board-approved protocol, we identified 328 patients with bone-metastatic bladder or upper urinary tract cancer managed at Memorial Sloan Kettering between 2000 and 2018. SREs were defined as presence of spinal cord compression from bone metastasis, pathologic fracture, treatment of bone metastasis with radiotherapy or surgery, or hypercalcemia of malignancy. SRE-free survival from the time of bone metastasis diagnosis was estimated using Kaplan-Meier analysis. Predictors of SRE were identified using competing-risks regression analysis. RESULTS: Of 328 patients with bone-metastatic disease, 198 (60%) developed ≥1 SRE, including 84 (26%) with multiple SREs. Two-hundred sixty four patients (80%) had non-metastatic disease at diagnosis. At the time of bone metastasis diagnosis, the most commonly involved sites were the vertebrae (n=216; 66%), pelvis (n=202; 62%), and nonvertebral thoracic bones (n=73; 22%). The most common SREs were bone radiotherapy (n=165; 83%), pathologic fracture (n=73; 37%), and orthopedic surgery (n=39; 20%). Median SRE-free survival from time of bone metastasis diagnosis was 7.4 months. One hundred eighteen patients (36%) received antiresorptive therapy. On competing-risks regression analysis, history of radical cystectomy (hazard ratio [HR], 1.40; 95% CI, 1.05-1.86; P=0.02) and hip involvement at the time of bone metastasis diagnosis (HR, 1.65; 95% CI, 1.12-2.42; P=0.01) were independently associated with risk of SRE. CONCLUSIONS: SREs are common among patients with bone-metastatic cancer of the bladder or upper urinary tract and typically occur soon after the development of bone metastasis. Patients with a history of radical cystectomy or with hip involvement at the time of bone metastasis diagnosis have a higher risk of SRE. Use of antiresorptive therapy in these patients should be considered. Additional studies are needed to identify interventions to further reduce skeletal morbidity in patients with bone metastasis. Source of Funding: This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers and by National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30 CA008748. N.A. was supported by National Institutes of Health T32 Ruth L. Kirschstein Institutional National Research Service Award. I.J.E. and P.J.C. were partially supported by National Institutes of Health 1-UL1-TR002384-01 from the Clinical and Translational Science Center at Weill Cornell Medicine. © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e844-e844 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nima Almassi* More articles by this author Imaani Easthausen More articles by this author Soleen Ghafoor More articles by this author Paul Christos More articles by this author Timothy Donahue More articles by this author Jonathan Rosenberg More articles by this author Azeez Farooki More articles by this author Expand All Advertisement PDF downloadLoading ...

Traitements anti-résorptifs pour le traitement et la prévention des métastases osseuses

Bone-targeted treatments play an important role in the management of malignant tumor osteolysis. Bisphosphonates and denosumab have demonstrated their efficacity for delaying the time to skeletal-related event (SRE) in patients with bone metastases. In large randomized trials, denosumab was more effective than zoledronic acid in preventing skeletal morbidity in patients with breast or prostate cancer with bone metastases, and non-inferiority was shown in the trial with other solid tumors. Questions concerning the duration of the treatment, the optimal dosing interval remain. The interest of these treatments as adjuvant therapy before the occurrence of bone metastases is currently being evaluated; recent data with adjuvant bisphosphonate treatment in breast cancer could change clinical practice, especially in postmenopausal women with breast cancer at high risk of recurrence.

Pathophysiology of Metastatic Bone Disease and the Role of the Second Generation of Bisphosphonates: From Basic Science to Medicine.

Bone metastasis is one of the most common causes of skeletal morbidity in patients with advanced cancer and is manifested as osteoblastic and osteolytic lesions. Bone metastasis occurs as an organized and multistep process involving tumor intravasation and the survived tumor cells in circulation. Extravasation into the secondary site, initiation of tumorgenesis and angiogenesis are also included in developing the bone metastasis. Several studies demonstrated that Zoledronic acid, which belongs to the second generation of BP (nitrogen-containing BPs) class agents, is an important and well-established drug in the treatment of wide range of cancer patients, such as breast cancer, prostate cancer, and multiple myeloma associated with bone metastases.

Traitements inhibiteurs de la résorption osseuse en situation métastatique : bilan actuel et perspectives

The current main use of inhibitors of bone resorption, bisphosphonates and denosumab, is the prevention of the complications of bone metastases. Monthly infusions of zoledronic acid, the most potent bisphosphonate, decrease the complication rate of tumor-induced osteolysis by about 40%. Recent controlled double-blind phase III trials have demonstrated the superiority of denosumab against zoledronic acid to decrease skeletal morbidity in patients with bone metastases from breast or prostate cancer, and its noninferiority in a third trial including patients with other solid tumors or myeloma. The overall toxicity was similar between both compounds. It is recommended to start an inhibitor of bone resorption as soon as bone metastases are diagnosed, at least in patients with breast cancer. However, the optimal duration of therapy is unknown and we lack validated criteria to better individualize therapy and to define the place of intermittent treatments or of larger intervals between infusions. Lastly, recent studies indicate that zoledronic acid, but also clodronate, are able to reduce the risk of bone metastases and to prolong survival, at least in postmenopausal patients with breast cancer after surgery. This use of inhibitors of bone resorption in the adjuvant setting is not admitted yet although clinical practice is likely to change in the near future.

Skeletal-related Events and Clinical Outcomes in Patients with Bone Metastases and Normal Levels of Osteolysis: Exploratory Analyses

AimsHigh levels of bone resorption markers (e.g. N-telopeptide of type I collagen; NTX) have been correlated with increased risks of skeletal-related events and death in patients with bone metastases from solid tumours. However, the disease course has not been well characterised in patients with bone metastases but normal NTX levels. Therefore, the aim of this study was to evaluate the patterns of skeletal morbidity in patients with normal NTX levels. Materials and methodsExploratory analyses were carried out on patients with bone metastases from breast cancer, castration-resistant prostate cancer, non-small cell lung cancer or other solid tumours treated with zoledronic acid (ZOL) in phase III trials. The effects of covariates on the relative risk of death were estimated using the Cox proportional hazard model. The prognostic values of covariates were compared between patients with normal (<64 nmol/mmol creatinine) versus elevated (≥64 nmol/mmol creatinine) NTX levels. ResultsAmong patients with normal baseline NTX (n = 501), less than 10% developed elevated NTX levels before a skeletal-related event or death during ZOL treatment over 12 months. The prognostic factors identified in these analyses were mostly similar across NTX groups. However, some indicators of aggressive disease (e.g. visceral/cerebral metastases from breast cancer) were associated with poor clinical outcomes only in the normal NTX group. ConclusionsSkeletal-related events were generally not preceded or followed by transition to elevated NTX in patients treated with ZOL. Elevated baseline NTX and aggressive extraskeletal disease were independently associated with reduced survival.

Preventing bone complications in prostate cancer

Bone metastases alone or in combination with androgen deprivation therapy-related bone loss places prostate cancer patients at greater risk for skeletal morbidities, including pain, pathologic fracture and spinal cord compression. These events significantly impair the patient's quality of life and place a significant burden on health-care resources. This review focuses on the management options for reducing skeletal morbidity in patients with prostate cancer, including life-style modifications, food supplementation, osteoclast-targeted therapy and selective estrogen-receptor modulators. The use of osteoclast-targeted therapy (denosumab and zoledronic acid) is supported by the strongest evidence and has been US Food and Drug Administration-approved for the treatment of patients with PCa at high risk of osteoporotic fractures and for the reduction of the risk of skeletal-related events in patients with castration-resistant prostate cancer. Ongoing trials are studying the potential role of osteoclast-targeted therapy in other settings throughout the course of the disease.

Bisphosphonate Anticancer Activity in Prostate Cancer and Other Genitourinary Cancers

Anticancer therapies have traditionally been targeted directly against cancer cell growth. However, newer treatment strategies also target the microenvironment that supports metastatic cancer cell growth. Bisphosphonates are the standard of care for maintaining bone health in patients with bone metastases from solid tumors and bone lesions from multiple myeloma, and emerging evidence supports potential anticancer activity of bisphosphonates. Zoledronic acid (ZOL), a third-generation nitrogen-containing bisphosphonate, is currently advised for reducing the risk of skeletal morbidity in patients with bone metastases from prostate cancer and other genitourinary cancers, such as renal cell carcinoma and bladder cancer. Clinical studies indicate that ZOL can normalize bone marker levels (a potential measure of skeletal disease burden), which may improve survival in patients with aggressive bone disease from prostate and other genitourinary cancers, supporting a broader therapeutic role for ZOL in genitourinary malignancies. This review examines the rationale and emerging evidence supporting the anticancer activity of bisphosphonates, especially ZOL, against prostate and other genitourinary cancers.

Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial

SummaryBackgroundBisphosphonates are the standard of care for reducing the risk of skeletal-related events in patients with bone lesions from multiple myeloma. The MRC Myeloma IX study was designed to compare the effects of zoledronic acid versus clodronic acid in newly diagnosed patients with multiple myeloma. Here, we report the secondary outcomes relating to skeletal events.MethodsPatients (≥18 years) with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK and received intensive or non-intensive antimyeloma treatment. A computer-generated randomisation sequence was used to allocate patients in a 1:1 ratio, through an automated telephone service to intravenous zoledronic acid (4 mg every 21–28 days) or oral clodronic acid (1600 mg/day), and the drugs were continued at least until disease progression. No investigators, staff, or patients were masked to treatment allocation. The primary endpoints—overall survival, progression-free survival, and overall response rate—and adverse events have been reported previously. We assessed between-group differences with Cox proportional hazards models for time to first skeletal-related event and incidence of skeletal-related events. These were defined as fractures, spinal cord compression, radiation or surgery to bone, and new osteolytic lesions. Data were analysed until disease progression. Analyses were by intention to treat. This trial is registered, number ISRCTN68454111.Findings1960 patients were randomly assigned and analysed—981 in the zoledronic acid group and 979 in the clodronic acid group. This trial is fully enrolled, and follow-up continues. At a median follow-up of 3·7 years (IQR 2·9–4·7), patients in the zoledronic acid group had a lower incidence of skeletal-related events than did those in the clodronic acid group (265 [27%] vs 346 [35%], respectively; hazard ratio 0·74, 95% CI 0·62–0·87; p=0·0004). Zoledronic acid was also associated with a lower risk of any skeletal-related event in the subsets of patients with (233 [35%] of 668 vs 292 [43%] of 682 with clodronic acid; 0·77, 0·65–0·92; p=0·0038) and without bone lesions at baseline (29 [10%] of 302 vs 48 [17%] of 276 with clodronic acid; 0·53, 0·33–0·84; p=0·0068). Fewer patients in the zoledronic acid group had vertebral fractures than did those in the clodronic acid group (50 [5%] in the zoledronic acid group vs 88 [9%] in the clodronic acid group; p=0·0008), other fractures (45 [5%] vs 66 [7%]; p=0·04), and new osteolytic lesions (46 [5%] vs 95 [10%]; p<0·0001).InterpretationThe results of this study support the early use of zoledronic acid rather than clodronic acid in patients with newly diagnosed multiple myeloma for the prevention of skeletal-related events, irrespective of bone disease status at baseline.FundingMedical Research Council (London, UK), Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.

Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial

Compared with placebo, prophylactic treatment with bisphosphonates reduces risk of skeletal events in patients with multiple myeloma. However, because of toxicity associated with long-term bisphosphonate treatment, establishing the lowest effective dose is important. This study compared the effect of two doses of pamidronate on health-related quality of life and skeletal morbidity in patients with newly diagnosed multiple myeloma. This double-blind, randomised, phase 3 trial was undertaken at 37 clinics in Denmark, Norway, and Sweden. Patients with multiple myeloma who were starting antimyeloma treatment were randomly assigned in a 1:1 ratio to receive one of two doses of pamidronate (30 mg or 90 mg) given by intravenous infusion once a month for at least 3 years. Randomisation was done by use of a central, computerised minimisation system. Primary outcome was physical function after 12 months estimated by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire (scale 0-100). All patients who returned questionnaires at 12 months and were still on study treatment were included in the analysis of the primary endpoint. This study is registered with ClinicalTrials.gov, number NCT00376883. From January, 2001, until August, 2005, 504 patients were randomly assigned to pamidronate 30 mg or 90 mg (252 in each group). 157 patients in the 90 mg group and 156 in the 30 mg group were included in the primary analysis. Mean physical function at 12 months was 66 points (95% CI 62·9-70·0) in the 90 mg group and 68 points (64·6-71·4) in the 30 mg group (95% CI of difference -6·6 to 3·3; p=0·52). Median time to first skeletal-related event in patients who had such an event was 9·2 months (8·1-10·7) in the 90 mg group and 10·2 months (7·3-14·0) in the 30 mg group (p=0·63). In a retrospective analysis, eight patients in the pamidronate 90 mg group developed osteonecrosis of the jaw compared with two patients in the 30 mg group. Monthly infusion of pamidronate 30 mg should be the recommended dose for prevention of bone disease in patients with multiple myeloma. Nordic Cancer Union and Novartis Healthcare.

Procollagen type I N-propeptide is a predictor of skeletal morbidity in patients with malignant osteolytic bone disease on bisphosphonates

There is an urgent need for individualized treatment of malignant bone disease (MBD), as the clinical benefit from bone-targeted therapies is moderate. We assessed the predictive value of the bone formation marker procollagen type I N-propeptide (PINP) for skeletal morbidity in patients with MBD receiving pamidronate. Seventy patients with advanced MBD were randomized to receive pamidronate 60 mg (n = 35) or 90 mg (n = 35) every 3 weeks for six cycles in a double-blind study. PINP was analyzed at baseline and before each administration of pamidronate, using a validated ELISA. Serum PINP concentrations were compared with pain response (visual analog scale VAS, composite pain score) and skeletal morbidity (skeletal-related events, SRE) using Student's T-test, Wilcoxon rank-sum and log-rank test, respectively. Patients with ≥20% pain reduction in the VAS had lower baseline PINP concentrations when compared to patients with <20% VAS response (P < 0.0001). A high baseline serum PINP concentration (highest tertile versus lower two tertiles) was significantly associated with a shorter duration of pain response (P < 0.0001) and a shorter time interval to first SRE (P < 0.008). Sensitivity of a low baseline PINP serum concentration for freedom from SRE at 1 year from randomization was 75% (15 out of 20 patients), while specificity was 82% (27 out of 33 patients). Serum PINP has been shown to be a significant predictor for skeletal morbidity in patients with MBD on pamidronate treatment. Prospective validation of PINP in patients with MBD to assess the prognosis or individualize bone-targeted treatment is justified.

Should bisphosphonates be utilized in the adjuvant setting for breast cancer?

Adjuvant therapies for early breast cancer are associated with substantial decreases in bone mineral density. Bisphosphonates are antiresorptive agents that have an established role in preventing skeletal morbidity in patients with bone metastases and in the treatment of osteoporosis. Recently, several trials have demonstrated the efficacy of bone-directed agents for prevention of cancer treatment-induced bone loss in both premenopausal and postmenopausal women with early stage breast cancer. Moreover, it is now becoming evident that bisphosphonates may also exert anticancer effects in the adjuvant setting. For example, long-term follow-up of a study in patients with bone marrow micrometastases from breast cancer revealed overall survival benefits for clodronate versus placebo, and an ongoing large trial may provide further insights. Addition of twice-yearly zoledronic acid to standard adjuvant endocrine therapy significantly improved disease-free survival and decreased disease recurrence compared with standard therapy alone in 3 clinical trials involving nearly 3,500 patients with stage I-IIIA breast cancer, and monthly zoledronic acid during neoadjuvant therapy decreased residual tumor volume and improved pathologic response in patients with stage II/III breast cancer. Overall, a large and growing body of evidence suggests the potential adjuvant benefits of bisphosphonates in early breast cancer.

Markers of bone remodeling and skeletal morbidity in patients with solid tumors metastatic to the skeleton receiving the biphosphonate zoledronic acid

The molecular triad, which includes the receptor activator of nuclear factor kappa-B ligand (RANKL), its receptor RANK, and the endogenous soluble RANKL decoy receptor osteoprotegerin (OPG), has emerged as an important determinant of bone metabolism. We aimed to evaluate the effect of treatment with the biphosphonate zoledronic acid (ZA) on biochemical markers of bone remodeling and to detect possible correlations of markerlevel changes with skeletal morbidity and clinical outcomes in patients with solid tumors and osseous metastases. The following serum markers were measured at the onset of skeletal metastases and after 6 months of treatment with ZA (4 mg intravenously monthly) in 70 patients with breast (n = 30), lung (n = 18), or prostate (n = 22) cancer: RANKL, OPG, C-terminal cross-linking telopeptide of type I collagen (CTX), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), bone-specific alkaline phosphatase (bALP), and osteopontin (OPN). Logistic regression models were applied to assess the correlation between marker-level changes and skeletal related events (SRE, primary endpoint), recurrence or progression, and death. Within a median follow-up of 32 months, 34 patients (48.6%) presented with at least 1 SRE and 48 patients (68.6%) relapsed. The RANKL/OPG ratio was upregulated in patients with breast and lung cancer, and it tended to decline after treatment with ZA, whereas prostate cancer patients presented with profound elevation of OPG only that persisted after treatment. CTX levels were significantly reduced after treatment in the whole study population (P = 0.003). None of the markers was able to predict skeletal morbidity or clinical outcomes independently of well-established prognostic clinical parameters.

Natural history of malignant bone disease in breast cancer and the use of cumulative mean functions to measure skeletal morbidity

BackgroundBone metastases are a common cause of skeletal morbidity in patients with advanced cancer. The pattern of skeletal morbidity is complex, and the number of skeletal complications is influenced by the duration of survival. Because many patients with cancer die before trial completion, there is a need for survival-adjusted methods to accurately assess the effects of treatment on skeletal morbidity.MethodsRecently, a survival-adjusted cumulative mean function model has been generated that can provide an intuitive graphic representation of skeletal morbidity throughout a study. This model was applied to the placebo-control arm of a pamidronate study in patients with malignant bone disease from breast cancer.ResultsAnalysis by bone lesion location showed that spinal metastases were associated with the highest cumulative mean incidence of skeletal-related events (SREs), followed by chest and pelvic metastases. Metastases located in the extremities were associated with an intermediate incidence of SREs, and those in the skull were associated with the lowest incidence of SREs.ConclusionApplication of this model to data from the placebo arm of this trial revealed important insight into the natural history of skeletal morbidity in patients with bone metastases. Based on these observations, treatment for the prevention of SREs is warranted regardless of lesion location except for metastases on the skull.

Advances in the Therapy of Prostate Cancer–Induced Bone Disease: Current Insights and Future Perspectives on the RANK/RANKL Pathways

Abstract Context Prostate cancer (PCa) cells are characterised by an exquisite tropism for the bone, which translates into one of the highest rates of bone metastases and skeletal morbidity. New, effective treatments have emerged from a better understanding of the physiopathology of bone metastases. Objective To summarise current insights and future perspectives in the therapy of PCa-induced bone disease. Evidence acquisition This manuscript is based on presentations given at a satellite symposium held at the 2nd World Congress on Controversies in Urology (CURy) in Lisbon, Portugal. Data were retrieved from original and recent review papers on PCa-induced bone disease. Evidence synthesis In normal, healthy bone, there is a balance between bone resorption and bone formation through the coordinated activity of osteoclasts and osteoblasts. The receptor activator of nuclear factor-κB ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. The RANKL pathway represents a therapeutic target for osteoclast-induced bone destruction in pathologic conditions, including treatment-induced bone loss and metastatic cancer. Based on a multicentre, randomised, open-label, active-controlled phase 2 trial, denosumab, a fully human monoclonal antibody against RANKL, reduced the incidence of skeletal morbidity in patients with bone metastases from PCa, breast cancer, or other neoplasms. Conclusions In a phase 2 clinical study, denosumab reduced skeletal-related events in patients with bone metastases from PCa. In addition, the potential role of denosumab in the management of treatment-induced bone loss and the prevention of bone metastases is currently under investigation.

A novel third generation bisphosphonate, minodronate (YM529), prevented proliferation and migration of hepatocellular carcinoma cells through inhibition of mevalonate pathway

Skeletal metastases and bone metasitasis are a common occurrence in patients with advanced hepatocellular carcinoma (HCC). Bisphosphonates (BPs), which are used for the treatment of osteoporosis and tumor-associated hypercalcemia, have recently been reported to decrease skeletal morbidity in patients with metastatic bone disease. Several studies revealed that nitrogen-containing BPs (N-BPs) could inhibit tumor growth and migration, indicating the possibility that N-BPs have direct inhibitory effects. We aimed to determine the effects of novel a N-BP (YM529) on human HCC cells in vitro. HCC cells were treated with various concentrations of YM529 and the growth inhibition rate was determined. Apoptosis was evaluated by caspase-3/7 assay and caspase-9 cleavage detection. The effects of YM529 on the migration of HCC cells induced by hepatocyte growth factor (HGF) were determined by cell migration assay. To evaluate the involvement of the mevalonate pathway, farnesol (FOH) and geranylgeraniol (GGOH) were added. YM529 inhibited the proliferation of HCC cells in a dose-dependent manner. The activation of caspase-3/7 and cleavage of caspase-9 demonstrated the involvement of apoptosis in cytotoxicity. GGOH reduced the growth inhibitory effect of YM529 and suppressed the induction of caspase-3/7 activities by YM529 on HCC cells. YM529 inhibited tumor cell migration induced by HGF and this effect was reduced by co-treatment with GGOH. YM529 inhibited the cell proliferation and migration of HCC cells, implicating the involvement of the mevalonate pathway. These results suggest that N-BPs are potential agents for the treatment of HCC skeletal metastases.

BMP7: A New Bone Metastases Prevention?

Prostate cancer is the most frequently diagnosed cancer in men and a leading cause of cancer death. More than 218,000 cases will occur in 2007, and prostate cancer will lead to more than 27,000 deaths.1 Although the 5-year survival rate is excellent for localized stages (100%), the relative survival rapidly decreases to 33% when prostate cancer metastasizes.1 Cancer cells from prostate primary tumors commonly colonize bones, and postmortem analyses show that 65 to 75% of patients with advanced disease have bone metastases.2 Scientific knowledge of bone metastasis pathophysiology has increased in recent years, but effective therapy for this devastating complication of cancer remains suboptimal. In this issue of The American Journal of Pathology, Buijs and colleagues3 shed more light into pathophysiology of bone metastases. More importantly, they apply this knowledge to develop novel therapy for bone metastases using bone morphogenetic protein 7 (BMP7).

Efficacy and Safety of Intravenous Bisphosphonates in Patients with Bone Metastases Caused by Metastatic Breast Cancer

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.

The role of bisphosphonates in the management of prostate cancer

Current therapies have extended the survival of patients with prostate cancer. However, these patients often develop skeletal morbidity from disease- and treatment-related effects that undermine skeletal integrity throughout the course of the disease. Low bone mineral density (BMD) is prevalent in patients with early-stage prostate cancer, and androgen-deprivation therapy by either pharmaceutical agent (including hormonal) or surgical castration causes significant decreases in BMD. Fractures can result in a loss of independence and have been associated with shorter survival in patients with prostate cancer. Zoledronic acid is the only bisphosphonate that has demonstrated objective and long-term benefits in reducing skeletal morbidity in patients with bone metastases due to prostate cancer, and it has produced long-term reductions in pain levels compared with placebo in this setting. Therefore, bisphosphonates, particularly zoledronic acid, may provide important benefits for preserving bone health during the course of prostate cancer progression.

The Treatment Continuum in the Management of Prostate Cancer Patients: What's New?

Objectives Symptom control is a priority in patients with hormone-refractory prostate cancer. However, since the approval of androgen deprivation therapy, there have been few meaningful therapeutic advances. Several current treatment options and novel agents are presented in this review. Methods Existing and novel therapies were identified and researched through PubMed and published guidelines. Results Treatment options include chemotherapy, second-line hormonal manipulations, radiation/radioisotope therapy, and bisphosphonates. Chemotherapy has demonstrated significant palliative benefits, and docetaxel has demonstrated a survival advantage. Hormonal manipulation lowers PSA levels, but has not significantly delayed the course of disease progression. Radiation/radioisotope therapy and bisphosphonates are palliative treatments for patients with bone metastases. Zoledronic acid significantly reduces skeletal morbidity in patients with bone metastases. Several novel treatments, including vaccines and vitamin D analogues, are currently being investigated. Conclusions Although improving survival is the optimal goal, it may not be feasible in elderly patients who may not tolerate some therapies. In addition, advanced HRPC is a multifaceted disease and needs a multidisciplinary approach. Urologists should be familiar with the new challenges that this disease presents and remain involved throughout the continuum of patient care.