Bisphosphonate therapy for bone metastases from Breast Cancer: Clinical results and a new therapeutic approach

BACKGROUND: We evaluated the usefulness of bisphosphonate (BIS) monotherapy, the safety of rapid infusion of BIS and the efficacy of BIS-sequential therapy for bone metastases from breast cancer. PATIENTS AND METHODS: Twenty-nine patients with bone metastasis or invasion were treated with BIS monotherapy. Each BIS (pamidronate 30 mg, alendronate 10 mg, or incadronate 10 mg) was infused over 30 minutes every two weeks a median of 12 times. RESULTS: With BIS therapy, five patients (17%) showed partial response of the bone lesions, and eighteen patients (64%) had pain relief. Of the nine patients treated with BIS-sequential therapy, one (11%) showed a partial response of the bone metastases, three (33%) had pain relief, and one (11%) showed a decrease in the serum tumor marker level. CONCLUSION: BIS therapy is effective against bone metastases from breast cancer, and rapid infusion of BIS is both safe and convenient for patients. BIS-sequential therapy can be a unique therapeutic option in some cases.     

A phase II trial evaluating the palliative benefit of second-line oral ibandronate in breast cancer patients with either a skeletal related event (SRE) or progressive bone metastases (BM) despite standard bisphosphonate (BP) therapy

Background Despite bisphosphonate treatment, most patients with metastatic breast cancer will have either progressive bone metastases or skeletal related events (SREs). We evaluated the impact of second-line ibandronate on pain control and markers of bone turnover in these patients. Methods Patients with either an SRE or bony progression while on clodronate or intravenous (IV) pamidronate were switched to oral ibandronate 50 mg daily for 12 weeks. Pain scores and urinary N-telopeptide were evaluated weekly for 4 weeks and at weeks 8 and 12. There was no change in systemic anti-cancer treatment in the month before or after commencing study treatment. Palliative response was defined as a ≥ two-unit reduction in the worst pain score. Patient preferences between IV and oral bisphosphonate therapy were assessed. Results Thirty women completed the study. By week 12, patients experienced a significant improvement in pain control (OR = 0.41; P = 0.028) with 12 of 26 (46.2%) evaluable patients achieving a palliative response. Of the 23 patients who had received first-line IV pamidronate, 20 of 23 (87.0%) preferred oral therapy. Conclusion Patients with either progressive bone metastases or SREs while on clodronate or pamidronate may experience significant pain palliation with a switch to a more potent bisphosphonate. If confirmed by randomized trials, clinicians can start moving away from the paradigm whereby patients remain on a single bisphosphonate regimen throughout the course of their disease.     

Study on the safety of rapid infusion and the efficacy of incadronate against bone metastasis of breast cancer]

To assess the safety of rapid infusion of incadronate and its efficacy against bone metastasis of breast cancer, we conducted a trial using incadronate therapy for breast cancer patients with bone metastasis. Of the 12 patients, 6 had undergone pamidronate or alendronate therapy. Rapid infusion of incadronate consisted of administration of 10 mg incadronate diluted in 100 ml saline in 30 minutes, and was repeated every two weeks. Each patient underwent 2 to 20 incadronate administrations. With the incadronate therapy, no patients showed hypocalcemia, but 3 patients showed asymptomatic hypophosphoremia. Of the 11 patients with bone pain, 5 patients (45%) experienced pain relief. A decrease in tumor marker levels in serum was found in 5 (56%) of the 9 patients with elevated marker levels. The side effects of incadronate administration were general fatigue (25%), pyrexia (17%) and transient pain increase (17%), but no renal dysfunction was found. In conclusion, rapid infusion of incadronate was a safe treatment and the incadronate therapy was effective against bone metastasis of breast cancer.     

Markers of bone turnover for the management of patients with bone metastases from prostate cancer

Although increased bone formation is a prominent feature of patients with osteosclerotic metastases from prostate cancer, there is also some evidence for increased bone resorption. The aim of this study was to compare the clinical utility of new bone resorption markers to that of bone formation in patients with bone metastases from prostate cancer before and after bisphosphonate treatment. Thirty-nine patients with prostate cancer and bone metastasis, nine patients with prostate cancer without bone metastases, nine patients with benign prostatic hyperplasia and 355 healthy age-matched men were included. Urinary non-isomerized (alpha CTX) and beta isomerized (beta CTX) type I collagen C-telopeptides (CTX) and a new assay for serum CTX were used to assess bone resorption. Bone formation was determined by serum osteocalcin, serum total (T-ALP) and bone (BAP) alkaline phosphatase and serum type I collagen C-terminal propeptide (PICP). Fourteen patients with bone metastases were also evaluated 15 days after a single injection of the bisphosphonate pamidronate (120 mg). Levels of all bone formation and bone resorption markers were significantly (P < 0.006-0.0001) higher in patients with prostate cancer and bone metastasis than in patients with benign prostatic hyperplasia, patients with prostate cancer without bone metastases and healthy controls. In patients with bone metastases the median was increased by 67% for serum osteocalcin, 128% for T-ALP, 138% for BAP, 79% for PICP, 220% for urinary alpha CTX, 149% for urinary beta CTX and 214% for serum CTX. After bisphosphonate treatment all three resorption markers significantly decreased by an average of 65% (P = 0.001), 71% (P = 0.0010) and 61% (P = 0.0015) for urinary alpha CTX, urinary beta CTX and serum CTX, respectively, whereas no significant change was observed for any bone formation markers. Patients with prostate cancer and bone metastases exhibit a marked increase in bone resorption, which decreases within a few days of treatment with pamidronate. These findings suggest that these new resorption markers may be useful for the management of these patients.     

Clinical efficacy of bisphosphonate therapy for bone metastasis from breast cancer

Bisphosphonates inhibit osteoclastic bone resorption and are being used as treatment for bone metastases from breast cancer. Intravenous bisphosphonate therapy can significantly reduce skeletal related events (SREs) when administered concurrently with chemotherapy or endocrine therapy. In addition, intravenous bisphosphonate monotherapy is also able to alleviate cancer induced bone pain, and to improve bone metastases in some patients. Oral bisphosphonates are not routinely used for the treatment of bone metastases due to their low bioavailability. However, minodronate, a bisphosphonate 100-fold more potent than pamidronate, is now in phase II clinical studies in Japan, and may alter the role of oral bisphosphonates in the treatment of bone metastasis from breast cancer. The ASCO guidelines recommend that patients with osteolytic bone metastases be treated not with bisphosphonate monotherapy, but with concurrent bisphosphonate and systemic therapy. In addition, it is also recommended that current standards of care for cancer pain, analgesics and radiotherapy, should not be replaced with bisphosphonate therapy.     

Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases

BACKGROUND: This study evaluated the dose-response relation for zoledronic acid, a new generation high potency bisphosphonate, given as a 5-minute infusion in patients with malignant osteolytic disease. METHODS: Two-hundred eighty patients with osteolytic lesions due to metastatic breast carcinoma or multiple myeloma were randomized to double-blind treatment with either 0.4, 2.0, or 4.0 mg of zoledronic acid or 90 mg pamidronate. The primary efficacy endpoint was the proportion of patients receiving radiation to bone. Other skeletal-related events, bone mineral density (BMD), bone markers, Eastern Cooperative Oncology Group performance status, pain and analgesic scores, and safety also were evaluated. RESULTS: Zoledronic acid at doses of 2.0 and 4.0 mg and pamidronate at a dose of 90 mg each significantly reduced the need for radiation therapy to bone (P < 0.05) in contrast with 0.4 mg zoledronic acid, which did not. Skeletal-related events of any kind, pathologic fractures, and hypercalcemia also occurred less frequently in patients treated with 2.0 or 4.0 mg zoledronic acid or pamidronate than with 0.4 mg zoledronic acid. Increases in lumbar spine BMD (6.2-9.6%) and decreases in the bone resorption marker N-telopeptide (range, -37.1 to -60.8%) were observed for all treatment groups. Skeletal pain, fatigue, nausea, vomiting, and headache were the most commonly reported adverse events. Adverse events were similar in nature and frequency with zoledronic acid and pamidronate. CONCLUSIONS: A 5-minute infusion of 2.0-4.0 mg zoledronic acid was at least as effective as a 2-hour 90-mg pamidronate infusion in treatment of osteolytic metastases. A 0.4-mg dose of zoledronic acid was significantly less effective. Both zoledronic acid and pamidronate were well tolerated.     

Prognostic significance of bone markers in patients with lung cancer metastatic to the skeleton: a review of published data

The presence of bone metastases significantly affects clinical outcome and quality of life parameters in patients with lung cancer. In this review, we aimed to evaluate the predictive value of markers of bone turnover in skeletal morbidity and clinical parameters, including disease-free survival (DFS) and overall survival (OS), in patients with lung cancer metastatic to the skeleton who were receiving bisphosphonate treatment. A comprehensive overview of all articles published from 1995 to date in 3 medical databases (PubMed, Scopus, and Cochrane) was performed using the keywords bone markers and lung cancer. Most bone formation markers (including bone alkaline phosphatase [bALP], osteocalcin [OC], and osteoprotegerin [OPG]), most bone absorption markers (including urinary calcium, osteopontin [OPN], receptor activator of nuclear factor κ-B ligand [RANKL], tartrate-resistant acid phosphatase isoform-5b [TRACP 5b]), and the metabolites of type I collagen had elevated concentrations in patients with lung cancer and bone metastases compared with patients without skeletal involvement. Two large studies showed that urinary N-terminal telopeptide (NTX) levels are a valid diagnostic method for early detection of bone metastases and a more consistent prognosticator than bALP. Treatment with zoledronic acid reduces NTX, TRACP-5b, RANKL, and OPG levels. Furthermore posttherapeutic reduction of urinary NTX levels seems to correlate with lower risk of skeletal-related events (SREs). Levels of markers of bone remodeling reflect the presence of bone metastases and may contribute to early detection of occult skeletal disease or monitor the effect of bisphosphonate treatment. However their ability to predict SREs, as well as DFS and OS, remains debatable.     

Bone metabolic markers in bone metastasis of breast cancer

Background. The efficacy and cost-performance benefit of radionuclide bone scintigraphy in monitoring metastatic bone activity remain controversial. Bone metabolic markers are now expected to play a role in the diagnosis and follow-up of bone metastasis. Methods. We investigated several bone metabolic markers in patients with breast cancer. We measured three metabolic markers of bone resorption: pyridinoline cross-linked carboxy terminal telopeptide (ICTP), C-telopeptides of type I collagen (CTx), and the free form of deoxypyridinoline (fDPD), and four metabolic markers of bone formation: procollagen I carboxy terminal peptide (PICP), total alkaline phosphatase (Al-p), bone-specific alkaline phosphatase (BAl-p), and osteocalcin (BGP) in 210 patients without and 268 patients with bone metastasis. Patients without bone metastasis were analyzed in terms of menstruation status. Patients with bone metastasis were analyzed in terms of bone metastatic burden and tumor lesion "condition" (ie, determination by X-ray and/or computed tomography and bone scan findings of new lesion, progression of disease, no change, improvement, and complete remission, according to the criteria of the International Unite Against Cancer). Results. In patients without bone metastasis, ICTP did not change with menopause. All markers other than ICTP were significantly elevated with menopause. In patients with bone metastasis, all markers, except for BGP, were significantly elevated according to metastatic bone tumor burden. Among the seven markers, ICTP showed the best receiver operating characteristic curves. ICTP also showed the best correlation to bone metastatic burden among the markers by Spearman's rank correlation coefficient. In patients stratified by "condition", ICTP, CTx, fDPD, Al-p, and BAl-p showed significant elevation in patients with progression, new lesion, and no change, while PICP and BGP showed only minimal elevation in those patients. Conclusion. Bone metabolic markers, particularly ICTP, appear to be valuable for the diagnosis of bone metastasis from breast cancer. Received: April 22, 1999 / Accepted: July 15, 1999     

Safety of intravenous and oral bisphosphonates and compliance with dosing regimens

Patients with advanced cancers--particularly breast and prostate cancers--are at high risk for bone metastasis, leading to accelerated bone resorption and clinically significant skeletal morbidity. Bisphosphonates are effective inhibitors of bone resorption and reduce the risk of skeletal complications in patients with bone metastases. The standard routes of administration for bisphosphonates used in clinical practice are either oral or i.v. infusion. Oral administration of bisphosphonates is complicated by poor bioavailability (generally <5%) and poor gastrointestinal tolerability. First-generation bisphosphonates, such as clodronate (Bonefos; Anthra Pharmaceuticals; Princeton, NJ), must be administered at high oral doses (1,600-3,200 mg/day) to achieve therapeutic effects, which leads to poor tolerability and compliance with oral dosing regimens. Infusion of bisphosphonates is associated with dose- and infusion-rate-dependent effects on renal function. In particular, high bisphosphonate doses (e.g., 1,500 mg clodronate) can cause severe renal toxicity unless infused slowly over many hours. In contrast, the newer, more potent bisphosphonates effectively inhibit bone resorption at micromolar concentrations, and the small doses required can be administered via relatively short i.v. infusions without adversely affecting renal function. Zoledronic acid (Zometa; Novartis Pharmaceuticals Corp.; East Hanover, NJ) is a new generation bisphosphonate, and the recommended dose of 4 mg can be safely infused over 15 minutes. The 90-mg dose of pamidronate (Aredia; Novartis Pharmaceuticals Corp.) and the 6-mg dose of ibandronate (Bondronat; Hoffmann-La Roche Inc.; Nutley, NJ) require 1- to 4-hour infusions. Intravenous bisphosphonates require less frequent dosing (once a month) and are generally well tolerated with long-term use in patients with bone metastases. Zoledronic acid has demonstrated the broadest clinical activity in patients with bone metastases.     

Comparative evaluation of markers of bone resorption in patients with breast cancer-induced osteolysis before and after bisphosphonate therapy.

The understanding of the pathophysiology and the monitoring of metastatic bone disease remains unsatisfactory. We compared several new markers of bone turnover in normocalcaemic patients with breast cancer-induced osteolysis before and after a single infusion of the bisphosphonate pamidronate. We studied 19 ambulatory patients with advanced breast cancer and extensive bone metastases who did not receive any systemic antineoplastic therapy. Pamidronate was administered at doses of 30, 60, 90 or 120 mg and the patients were followed weekly during a mean of 8 (range 4-10) weeks. Compared with healthy premenopausal women, the percentage of elevated values at baseline was 47% for fasting urinary calcium (uCa), 74% for hydroxyproline, 83% for CrossLaps (a new marker of type I collagen degradation) and 100% for the collagen cross-links (measured by high performance liquid chromatography), namely pyridinoline (Pyr) and deoxyPyr (D-Pyr). Pretreatment levels of uCa did not correlate significantly with any of the four markers of bone matrix resorption, whereas the correlations between these four markers were generally significant (r(s)=0.43-0.71). Alkaline phosphatase correlated significantly with markers of bone matrix resorption (r(s)=0.54-0.74). All parameters, except phosphaturia (uPi) and the bone formation markers (osteocalcin and alkaline phosphatase), fell significantly after pamidronate therapy, up to day 42 for hydroxyproline, D-Pyr and CrossLaps and day 56 for uCa. This longer lasting effect was probably due to the parathyroid hormone (PTH) surge following the decrease in serum calcium, implying that the decrease in uCa can overestimate the effects of bisphophonates on bone resorption. The decrease in bone turnover parameters was most marked for CrossLaps, indicating the potential of this new marker for monitoring therapy. Sequential determinations of markers of bone matrix resorption should be useful in delineating the optimal therapeutic schemes of bisphosphonates and for evaluating treatment effects on bone in cancer patients.     

Approval summary for zoledronic acid for treatment of multiple myeloma and cancer bone metastases.

PURPOSE: This article summarizes data submitted to the United States Food and Drug Administration for marketing approval of zoledronic acid (Zol; Novartis Pharmaceuticals, East Hanover, NJ), a bisphosphonate drug for treating patients with bone metastases. Experimental Design: We review the chemistry, toxicology, pharmacology, and clinical study results submitted to support the supplemental New Drug Application for Zol for treatment of patients with bone metastases. Four- and 8-mg Zol doses were selected for Phase III trials based on bone resorption markers and clinical efficacy parameters. Patients with bone metastases were randomized in three Phase III studies (prostate cancer, solid tumors, and multiple myeloma or breast cancer) to receive 4 or 8 mg of Zol or to a control arm. The control was a placebo in the prostate cancer study and the other solid tumor study and was 90 mg of pamidronate (Pam) in the study of breast cancer and multiple myeloma. Studies were amended twice because of renal toxicity, initially to increase Zol infusion time from 5 to 15 min and later to decrease the dose in the Zol 8-mg arm to 4 mg. The efficacy end point was skeletal-related events (SREs), a composite end point consisting of pathologic fracture, radiation therapy to bone, changes in antineoplastic therapy for bone pain (prostate cancer only), surgery to bone, or spinal cord compression. This end point was analyzed either as the proportion of patients with SRE or time to first SRE. The breast cancer and myeloma study used a noninferiority statistical analysis methods to determine efficacy. RESULTS: In prostate cancer, both the proportions analysis and time-to-SRE analysis showed significantly less bone morbidity on Zol (4 mg) than placebo, but no significant difference between Zol (8 mg) and placebo in either analysis. In the solid tumor study, the time to SRE analysis but not the proportions analysis showed significantly less skeletal morbidity on Zol (4 mg) than placebo, and Zol (8 mg) was significantly better than placebo in both analyses. The breast cancer and myeloma study demonstrated noninferiority of Zol compared with Pam, with Zol retaining at least 49.3% of the Pam treatment effect previously demonstrated in placebo-controlled trials. Zol was approved on February 22, 2002, by the United States Food and Drug Administration for the "treatment of patients with multiple myeloma and documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy." The recommended dose and schedule is 4 mg of Zol infused over 15 min every 3-4 weeks. Increased Zol doses and shorter infusions are not recommended because of potential renal toxicity.     

A Phase I, open label, dose ranging trial of intravenous bolus zoledronic acid, a novel bisphosphonate, in cancer patients with metastatic bone disease

BACKGROUND: Bone metastases typically are associated with osteolytic bone destruction, resulting in bone pain, pathologic fractures, spinal cord compression, and hypercalcemia. Bisphosphonates are potent inhibitors of normal and pathologic bone resorption and represent a significant therapeutic improvement in the management of patients with lytic bone metastases. Zoledronic acid is a new-generation, highly potent, nitrogen-containing bisphosphonate that to the authors knowledge is the most potent inhibitor of bone resorption currently in clinical trials. The objectives of the current study were to assess the safety and tolerability of increasing doses of zoledronic acid and to determine its activity with respect to reducing biochemical markers of bone resorption in cancer patients with bone metastases. METHODS: Forty-four cancer patients with bone metastases or primary bone lesions were enrolled sequentially into 1 of 5 fixed ascending-dose treatment groups. Each patient received a single intravenous bolus injection of 1, 2, 4, 8, or 16 mg of zoledronic acid over 30-60 seconds. Patients were monitored for 8 weeks for the evaluation of clinical findings, adverse events, vital signs, electrocardiograms, markers of bone resorption, and urinary N-acetyl-beta-D-glucosaminidase. RESULTS: Zoledronic acid was safe and well tolerated at all dose levels tested. Commonly reported adverse events included bone pain, fever, anorexia, constipation, and nausea, which were experienced by a similar proportion of patients in each treatment group. Seven patients reported serious adverse events, none of which appeared to be related to the study drug. Zoledronic acid effectively suppressed biochemical markers of bone resorption, including the highly specific markers N-telopeptide and deoxypyridinoline, for up to 8 weeks in the 2-16-mg dose groups and for a shorter duration in the 1-mg group. CONCLUSIONS: In the current study, zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption. The authors believe it may improve the treatment of metastatic bone disease.     

A phase 2 trial exploring the effects of high‐dose (10,000 IU/day) vitamin D3 in breast cancer patients with bone metastases

BACKGROUND:

Vitamin D deficiency has potential roles in breast cancer etiology and progression. Vitamin D deficiency has also been associated with increased toxicity from bisphosphonate therapy. The optimal dose of vitamin D supplementation is unknown, but daily sunlight exposure can generate the equivalent of a 10,000‐IU oral dose of vitamin D₃. This study therefore aimed to assess the effect of this dose of vitamin D₃ in patients with bone metastases from breast cancer.

METHODS:

Patients with bone metastases treated with bisphosphonates were enrolled into this single‐arm phase 2 study. Patients received 10,000 IU of vitamin D₃ and 1000 mg of calcium supplementation each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and toxicity were evaluated at baseline and monthly thereafter.

RESULTS:

Forty patients were enrolled. No significant changes in bone resorption markers were seen. Despite no change in global pain scales, there was a significant reduction in the number of sites of pain. A small but statistically significant increase in serum calcium was seen, as was a significant decrease in serum parathyroid hormone. Treatment unmasked 2 cases of primary hyperparathyroidism, but was not associated with direct toxicity.

CONCLUSIONS:

Daily doses of 10,000 IU vitamin D₃ for 4 months appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long‐term bisphosphonate use. There did not appear to be a significant palliative benefit nor any significant change in bone resorption. Cancer 2010. © 2010 American Cancer Society.     

A phase I dose-ranging trial of monthly infusions of zoledronic acid for the treatment of osteolytic bone metastases.

Bisphosphonates are potent inhibitors of bone resorption and provide a therapeutic benefit for patients with bone metastases. Zoledronic acid is a highly potent, nitrogen-containing bisphosphonate. In the present trial, we assessed the safety and tolerability of increasing doses of zoledronic acid and its effects on urinary markers of bone resorption in cancer patients with bone metastases. Fifty-nine cancer patients with bone metastases were enrolled sequentially into one of 8 treatment groups in the core protocol. Each patient received a 5-min i.v. infusion of 0.1, 0.2, 0.4, 0.8, 1.5, 2, 4, or 8 mg zoledronic acid monthly for 3 months. Patients were monitored for clinical findings, adverse events, electrocardiograms, markers of bone resorption, as well as routine hematology, blood chemistries, and urinalysis. Thirty patients who demonstrated a radiographic response to treatment or stable disease in the core protocol were enrolled in a humanitarian extension protocol and continued to receive monthly infusions. Zoledronic acid was well tolerated at all dose levels. Adverse events reported by >10% of patients included skeletal pain, nausea, fatigue, upper respiratory tract infection, constipation, headache, diarrhea, and fever. Three patients in the core protocol and one patient in the extension protocol experienced grade 3 skeletal pain, "flu-like" symptoms, or hypophosphatemia, which were possibly related to treatment; all recovered completely. Adverse events were reported with similar frequency across all of the dosage groups. Zoledronic acid resulted in sustained, dose-dependent decreases in urinary markers of bone resorption. Zoledronic acid was safe and well tolerated and demonstrated potent inhibition of bone resorption.     

Urinary N-telopeptide (uNTx) is an independent prognostic factor for overall survival in patients with bone metastases from castration-resistant prostate cancer

BackgroundIn patients with bone metastases from castration-resistant prostate cancer (CRPC) not pretreated with a bisphosphonate elevated N-telopeptide of type I collagen (uNTx), a marker of bone resorption, predicts skeletal-related events (SRE). The aim of this study was to assess the prognostic value of uNTx for overall survival (OS) and the incidence of SRE in patients with bone metastases from CRPC receiving zoledronic acid.MethodsFrom 2004 to 2007, 94 patients with bone metastases from CRPC receiving zoledronic acid for at least 2 months were screened for uNTx.ResultsMedian age was 66 years (range 46–88). Median serum prostate-specific antigen (PSA) was 66 ng/ml (0–3984) and median uNTx was 19 nmol/mM creatinine (3–489). During follow-up, 38 patients (40%) experienced an SRE. Median OS was 20 months [95% (CI) confidence interval 15–24). In the multivariate analysis, elevated uNTx [hazard ratio (HR) 2.2 (95% CI 1.2–4.0)], serum PSA [HR 2.8 (95% CI 1.6–5.1)], and ECOG performance status were the only independent prognostic factors for OS. Median OS was 12 months (10–16) and 25 months (21–34) in patients with uNTx ≥20 nmol/mM creatinine and in those with uNTx <20 nmol/mM creatinine, respectively.ConclusionAn elevated uNTx level is an independent prognostic factor for OS in patients with bone metastases from CRPC receiving a bisphosphonate.     

Failure to Suppress Markers of Bone Turnover on First-Line Hormone Therapy for Metastatic Prostate Cancer Is Associated With Shorter Time to Skeletal-Related Event

BackgroundElevated markers of bone turnover are prognostic for shorter survival in castration-resistant prostate cancer. We aimed to determine the prognostic value of bone turnover markers in metastatic hormone-sensitive prostate cancer.Patients and MethodsMarkers of bone turnover (urine deoxypyridinoline [DPD] and N-telopeptide, serum bone alkaline phosphatase (AP), and osteocalcin [OC]) from baseline and after 6 months of study were assessed in men enrolled in a prospective metastatic prostate cancer trial with androgen deprivation therapy (ADT) with or without risedronate (ClinicalTrials.gov, NCT00216060).ResultsSerum samples were collected from 63 patients with bone involvement and a median follow-up of 39.7 months. A multivariate model using Cox regression—which included prostate-specific antigen (PSA) nadir, bisphosphonate treatment, and extent of metastases—showed that suppression of bone turnover markers after 6 months of therapy compared with baseline was significantly associated with longer skeletal-related event (SRE)-free survival. ADT without bisphosphonate therapy was also associated with a decline in markers of bone turnover, presumably resulting from direct anticancer activity. Elevated baseline bone turnover markers were not prognostic.ConclusionFailure to suppress bone turnover while receiving ADT, even when otherwise responding to therapy, may identify patients with hormone-sensitive metastatic prostate cancer who are destined for a shorter time to SREs and progression.     

Breast cancer with osteoblastic bone metastasis treated successfully with bisphosphonate: a case report]

A 52-year-old woman with painful osteoblastic bone metastasis received pamidronate therapy which resulted in marked pain relief with a normalization of elevated tumor marker levels. However, the patient complained of increased pain after the 26th pamidronate infusion. Although a change from pamidronate to alendronate therapy did not relieve bone pain, a second change from alendronate to incadronate therapy resulted in pain relief with a decrease in re-elevated tumor marker levels. These findings suggest that bisphosphonate therapy is effective against osteoblastic bone metastasis in breast cancer, and that sequential therapy with bisphosphonates may be effective against bone metastasis in some cases.     

博宁对骨转移患者骨吸收标志的影响

目的：探讨博宁对骨转移患者骨吸收标志的影响。方法：临床确诊为骨转移患者２４例,一次性接受博宁９０ｇｍ静点,观察治疗前及后７天骨吸收标志的变化。结果：治疗前尿钙、尿吡啶酚和脱氧吡啶酚较正常值分别为２５％,７１％和１００％患者升高。治疗后第７水钙、尿吡啶酚和脱氧吡啶较治疗前均明显下降,三项指标较治疗前分别下降了５９％,６２％和６０％,血钙治疗后也有明显下降,而血磷治疗前后无明显变化。     

国产因卡膦酸二钠治疗骨转移癌疼痛的Ⅱ期临床试验

目的 :观察评价国产因卡膦酸二钠治疗恶性肿瘤骨转移疼痛的有效性和安全性。方法 :自 2 0 0 1年 1 2月至2 0 0 2年 1 0月 ,收治恶性肿瘤骨转移患者 4 3例 ,随机分配至试验组和对照组 ,分别给予国产因卡膦酸二钠 1 0mg与帕米膦酸二钠 90mg静滴 ,观察其疗效和毒副作用。结果 :试验组 2 3例止痛有效率 5 2 2 % ,生活质量改善有效率为 4 3 5 % ,与对照组 2 0例相比无显著性差异 (P >0 0 5 ) ,但毒副反应少见。结论 :国产因卡膦酸二钠治疗恶性肿瘤骨转移疼痛疗效显著 ,安全可靠 ,值得临床上推广使用     

Prevention of bone metastases from breast cancer by adjuvant bisphosphonate therapy

There is increasing evidence regarding the importance of osteoclast activation in the pathogenesis of bone metastases. Cancer cells produce osteoclast-activating factors which play an important role in the development of bone metastases. Bisphosphonates are drugs that inhibit bone turnover by decreasing bone resorption. In patients with bone metastases from breast cancer, the effectiveness of bisphosphonate is well established for reducing skeletal complications, such as bone pain, pathological fracture, bone surgery and hypercalcemia. Recent attention has focused on a possible preventive effect on bisphosphonates of bone metastases. Animal models have supported the prevention of bone metastasis by bishosphonate therapy, but three major adjuvant clinical trials of the oral bisphosphonate clodronate have yielded conflicting results. However, our preliminary trial of intravenous bisphosphonate with pamidronate showed effective inhibition of bone metastases. Use of bisphosphonates as adjuvant therapy is still investigational yet promising. Several more randomized trials are underway to further investigate adjuvant therapy with bisphosphonates.