Bone Protective Agents Research Articles

Systemic Therapy in Men with Metastatic Castration-resistant Prostate Cancer: A Systematic Review

AimsSince 2004, docetaxel-based chemotherapy has been the standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), but recently randomised controlled trials (RCTs) of novel agents have shown promise in extending overall survival. These trials have evaluated agents delivered before chemotherapy, to replace or supplement docetaxel, or addressed treatment options for men who have progressed on docetaxel therapy. This review was undertaken to determine which systemic therapies improve cancer- or patient-related outcomes in men with mCRPC. Materials and methodsSearches were carried out in MEDLINE, EMBASE, the Cochrane Library and relevant conference proceedings. Eligible articles included RCTs comparing systemic therapy or combination (excluding primary or secondary androgen deprivation therapy, bone protective agents or radionuclides) with placebo or other agents in men with mCRPC. ResultsTwenty-five RCTs met the selection criteria. In chemotherapy-naive patients, targeted therapy with tasquinimod conferred a benefit in progression-free survival. Immunotherapy with sipuleucel-T extended overall survival and was well tolerated, but had no effect on the time to disease progression. Hypercastration with abiraterone extended progression-free survival, whereas overall survival was improved but not statistically proven. In the chemotherapy setting, updated and new trials of docetaxel alone confirmed the survival benefit seen in previous studies. A survival benefit with the addition of estramustine to docetaxel shown in a previous study did not lead to an improvement in pain palliation or quality of life. Trials of combining targeted therapies with docetaxel generally did not extend survival. The addition of bevacizumab improved progression-free survival, but not overall survival. The addition of GVAX immunotherapy or calcitriol was harmful. In the post-chemotherapy setting, progression-free and overall survival benefits were detected with cabazitaxel, abiraterone and enzalutamide. Cabazitaxel was associated with greater toxicity, whereas abiraterone and enzalutamide had less severe adverse effects. Satraplatin and sunitinib both extended progression-free survival, but did not improve overall survival. ConclusionDocetaxel-based chemotherapy remains the standard of care in men with mCRPC who are candidates for palliative systemic therapy. Promising results are emerging with sipuleucel-T and abiraterone in the pre-docetaxel setting and cabazitaxel, abiraterone and enzalutamide in patients who progress on or after docetaxel. Further research to determine the optimal choice, sequence or even the combination of these agents is necessary.

PMO-260 Bone protection is under used in IBD patients: data from the 3rd round UK IBD audit

IntroductionBSG guidelines recommend that supplementation of calcium and vitamin D is given when systemic steroid use is necessary and that co-administration of bisphosphonates with steroids is given for patients aged...

Adrenomedullin22–52 combats inflammation and prevents systemic bone loss in murine collagen‐induced arthritis

Adrenomedullin(22-52) is a truncated peptide derived from adrenomedullin, a growth factor with antiapoptotic and immunoregulatory properties. It can act as an agonist or an antagonist depending on cell type. Its in vivo effects are unknown, but adrenomedullin(22-52) could possess immunomodulatory properties. This study was undertaken to evaluate the effect of adrenomedullin(22-52) in a mouse model of arthritis. DBA/1 mice with collagen-induced arthritis (CIA) were treated with 1.2 μg/gm adrenomedullin(22-52) , adrenomedullin, or saline at arthritis onset. Bone mineral density was measured at the beginning of the experiment and when mice were killed. Mouse joints were processed for histologic analysis and protein studies, and spleens were examined for Treg cell expression. Cytokine expression was studied in mouse joint tissue and serum. In mice with CIA, adrenomedullin and adrenomedullin(22-52) reduced clinical and histologic arthritis scores and shifted the pattern of articular and systemic cytokine expression from Th1 to Th2, as compared to untreated mice with CIA (controls). Tumor necrosis factor α, interleukin-6 (IL-6), and IL-17A levels were significantly decreased in the joints of mice with CIA treated with adrenomedullin or adrenomedullin(22-52) as compared to controls, whereas IL-4 and IL-10 levels were increased. Adrenomedullin(22-52) was more effective than adrenomedullin in modulating cytokine content and enhanced Treg cell function without changing Treg cell expression compared to controls. Adrenomedullin receptor binding and transcriptional adrenomedullin receptor expression were markedly increased in joints from controls, whereas adrenomedullin receptor binding was considerably decreased in treated animals. Mice with CIA treated with adrenomedullin or adrenomedullin(22-52) had considerably fewer apoptotic chondrocytes and diminished cartilage degradation. Adrenomedullin(22-52) completely prevented systemic bone loss by preserving osteoblastic activity, but without changes in osteoclastic activity. Our findings indicate that adrenomedullin(22-52) , which has no vasoactive or tumor-inducing effects, is a potent antiinflammatory and bone-protective agent in this arthritis model.

The Effects ofCosmos caudatuson Structural Bone Histomorphometry in Ovariectomized Rats

Osteoporosis is considered a serious debilitating disease. Cosmos caudatus (ulam raja), a plant containing antioxidant compounds and minerals, may be used to treat and prevent osteoporosis. This study determines the effectiveness of C. caudatus as bone protective agent in postmenopausal osteoporosis rat model. Thirty-two female rats, aged 3 months old, were divided into 4 groups. Group one was sham operated (sham) while group two was ovariectomized. These two groups were given ionized water by forced feeding. Groups three and four were ovariectomized and given calcium 1% ad libitum and force-fed with C. caudatus at the dose of 500 mg/kg, respectively. Treatments were given six days per week for a period of eight weeks. Body weight was monitored every week and structural bone histomorphometry analyses of the femur bones were performed. Ovariectomy decreased trabecular bone volume (BV/TV), decreased trabecular number (Tb.N), and increased trabecular separation (Tb.Sp). Both calcium 1% and 500 mg/kg C. caudatus reversed the above structural bone histomorphometric parameters to normal level. C. caudatus shows better effect compared to calcium 1% on trabecular number (Tb.N) and trabecular separation (Tb.Sp). Therefore, Cosmos caudatus 500 mg/kg has the potential to act as the therapeutic agent to restore bone damage in postmenopausal women.

Honokiol stimulates osteoblastogenesis by suppressing NF-κB activation

Magnolia officinalis, a component of Asian herbal teas, has long been employed in traditional Japanese and Chinese medicine to treat numerous maladies. Honokiol, a biphenolic compound, is now considered to be one of the major active ingredients of Magnolia extract, and is under intense investigation for its anti-angiogenic, anti-inflammatory, anti-tumor and neuroprotective properties. Biochemically, honokiol has been recognized to modulate the nuclear factor κ B (NF-κB) signal transduction pathway suggesting that it possesses anti-inflammatory properties. Inflammation is intimately associated with bone turnover and skeletal deterioration and consequently, anti-inflammatory drugs may hold significant promise as bone protective agents to stem bone loss in osteoporotic conditions. We and others have demonstrated that suppression of NF-κB blunts osteoclastic bone resorption, but promotes osteoblastic bone formation. Indeed previous studies have demonstrated the anti-osteoclastogenic effects of honokiol, however, activities on osteoblast differentiation and activity have yet to be investigated. In this study, we show that honokiol is a potent inducer of in vitro osteoblast differentiation by virtue of its capacity to suppress basal and tumor necrosis factor alpha (TNFα)-induced NF-κB activation and to alleviate the suppressive action of TNFα on bone morphogenetic protein (BMP)-2-induced Smad activation. Our data confirm that honokiol may have considerable promise as a dual anabolic/anti-catabolic agent for the amelioration of multiple osteoporotic diseases.

Abstract P1-13-08: A Cross-Sectional Study Evaluating Bone Quantity and Quality in Women with Bone Metastases from Breast Cancer

Abstract Background: Approximately 1/3 of patients with metastatic breast cancer (MBC) and bone disease will sustain a skeletal related event (SRE) despite use of a bisphosphonate; there is therefore an urgent unmet need in this large population to better assess individual SRE risk and develop more effective bone protective agents. Using novel tools to assess bone quality may help guide individual patient treatment choices as well as future trial design. Materials and Methods: Women with MBC and bone metastases were recruited. Baseline bone assessments were performed using dual-energy X-ray absorptiometry (DXA) [areal bone mineral density (BMD) and vertebral fracture assessment (VFA)], high-resolution peripheral quantitative computed tomography (HR-pQCT), and serum markers of bone turnover [serum CTX and bone-specific alkaline phosphatase (BAP)]. Risk factors for osteoporosis and fractures were then recorded. Results: 49 baseline assessments were completed. Mean age and body mass index were 53.6 (range 30-80) and 27 (range 17-45) respectively. One in four women had an ECOG 2-3, and 24% had a clinical fracture since the diagnosis of MBC. 94% had estrogen positive disease, 11% were HER2+. 53% had prior radiation therapy to bone; 90% received bisphosphonate therapy. Bone assessments are outlined in the Table. Vertebral compression deformity (VCD) using the novel technique of VFA was most strongly associated with clinical fracture (p = 0.003). Discussion: Prospective evaluation of individual SRE risk will enable improved patient-centred care and allow more rational use of bone targeted therapies. VFA is a novel tool that may better inform treatment decisions and choice of agents in women with MBC. Future follow-up of these patients will help determine the optimal assessment modality. Bone quantity and quality assessments Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-13-08.

Glucocorticoid‐induced osteoporosis: unawareness or negligence in India?

The burden of osteoporosis is on the rise and glucocorticoids are one of the leading causes of drug-induced osteoporosis. According to available guidelines, patients on long-term glucocorticoid therapy should receive adequate prophylaxis to prevent osteoporosis. To compare prescription patterns in relation to Royal College of Physicians (RCP) Guidelines 2002. To identify prescribing trends for prophylaxis and management of steroid-induced osteoporosis. We conducted a retrospective audit for patients in a tertiary care center to determine whether clinicians are evaluating and appropriately following prophylactic guidelines for corticoid-induced osteoporosis. Information regarding risk assessment for osteoporosis, instructions regarding its prevention, bone mineral density measurements, and prophylactic therapy were recorded. One hundred and five patients (38 men and 67 women), more then 18 years of age were included in this study. Of the 105 patients, 56% had at least one documented intervention for osteoporosis prevention (calcium, vitamin D, bisphosphonates or a bone mineral density study). Only three patients received bisphosphonates for osteoporosis prophylaxis. The study shows poor pre-therapeutic risk assessment, absence of instructions regarding preventive measures, inappropriate investigation for presence of osteoporosis, and unacceptable absence of bone protective agents.

Soy phytoestrogens: impact on postmenopausal bone loss and mechanisms of action

Due to their ability to mimic the actions of mammalian estrogens, soy phytoestrogens have been proposed as potential therapeutic agents to aid in preventing postmenopausal bone loss. In vitro, phytoestrogens promote osteoblastogenesis and inhibit osteoclastogenesis. Although a relatively large number of intervention studies have been undertaken in animals and humans, the efficacy of phytoestrogens as bone-protective agents in vivo remains unclear. Differences in the bioactivities of individual phytoestrogens, differences in phytoestrogen metabolism and bioavailability within different study populations, and imprecise reporting of the dose of phytoestrogens administered in intervention studies may have contributed to the disparity in study findings.

Bortezomib Inhibits Osteoclast Activity in Patients with Multiple Myeloma

BackgroundThe antimyeloma agent bortezomib functions as an inhibitor of nuclear factor (NF)–κB. Although NF-κB inhibition is predicted to affect osteoclast function, preclinical and clinical studies have primarily reported an effect on osteoblasts. Patients and MethodsWe examined parameters of bone turnover prospectively in patients with multiple myeloma treated with bortezomib before and after autologous transplantation. Thirty-nine patients received 2 cycles of bortezomib on days 1, 4, 8, and 11 of a 21-day cycle. After high-dose melphalan with autologous stem cell transplantation, bortezomib 1.3 mg/m2 on days 1, 8, 15, and 22 of a 5-week cycle was administered as maintenance therapy. ResultsDuring posttransplantation bortezomib, decreases in the urinary excretion of collagen N-telopeptide indicated that bortezomib suppresses osteoclast function. ConclusionThe effects on osteoclasts occurred in the absence of bisphosphonate treatment and independently of changes in monoclonal protein levels. Further studies exploring the role of bortezomib as a bone protective agent could be warranted.

160 INVITED Biopsy-driven biomarker development: pharmacodynamic studies in early clinical trials

Since 2004, docetaxel-based chemotherapy has been the standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), but recently randomised controlled trials (RCTs) of novel agents have shown promise in extending overall survival. These trials have evaluated agents delivered before chemotherapy, to replace or supplement docetaxel, or addressed treatment options for men who have progressed on docetaxel therapy. This review was undertaken to determine which systemic therapies improve cancer- or patient-related outcomes in men with mCRPC.Searches were carried out in MEDLINE, EMBASE, the Cochrane Library and relevant conference proceedings. Eligible articles included RCTs comparing systemic therapy or combination (excluding primary or secondary androgen deprivation therapy, bone protective agents or radionuclides) with placebo or other agents in men with mCRPC.Twenty-five RCTs met the selection criteria. In chemotherapy-naive patients, targeted therapy with tasquinimod conferred a benefit in progression-free survival. Immunotherapy with sipuleucel-T extended overall survival and was well tolerated, but had no effect on the time to disease progression. Hypercastration with abiraterone extended progression-free survival, whereas overall survival was improved but not statistically proven. In the chemotherapy setting, updated and new trials of docetaxel alone confirmed the survival benefit seen in previous studies. A survival benefit with the addition of estramustine to docetaxel shown in a previous study did not lead to an improvement in pain palliation or quality of life. Trials of combining targeted therapies with docetaxel generally did not extend survival. The addition of bevacizumab improved progression-free survival, but not overall survival. The addition of GVAX immunotherapy or calcitriol was harmful. In the post-chemotherapy setting, progression-free and overall survival benefits were detected with cabazitaxel, abiraterone and enzalutamide. Cabazitaxel was associated with greater toxicity, whereas abiraterone and enzalutamide had less severe adverse effects. Satraplatin and sunitinib both extended progression-free survival, but did not improve overall survival.Docetaxel-based chemotherapy remains the standard of care in men with mCRPC who are candidates for palliative systemic therapy. Promising results are emerging with sipuleucel-T and abiraterone in the pre-docetaxel setting and cabazitaxel, abiraterone and enzalutamide in patients who progress on or after docetaxel. Further research to determine the optimal choice, sequence or even the combination of these agents is necessary.

Alendronate PLGA microspheres with high loading efficiency for dental applications

Purpose: Alendronate sodium, used systemically as a bone protective agent, proved to also be effective locally in various dental bone applications. Development of alendronate-loaded microspheres with high loading efficiency for such applications would be greatly challenged by the hydrophilicity and low MW of the drug. The aim of this study was to incorporate alendronate sodium, into poly (lactide-co-glycolide) (PLGA) microspheres (MS) with high loading efficiency.Methods: Three multiple emulsion methods: water-in-oil-in-water (W/O/W), water-in-oil-in-oil (W/O1/O2) and solid-in-oil-in-oil (S/O1/O2) were tested. In addition to entrapment efficiency, MS were characterized for surface morphology, particle size, in vitro drug release and in vitro degradation of the polymer matrix. Alendronate microspheres with maximum drug loading and good overall in vitro performance were obtained using the W/O1/O2 emulsion technique.Results: Drug release from the microspheres exhibited a triphasic release pattern over a period of 13 days, the last fast release phase being associated with more rapid degradation of the PLGA matrix.Conclusions: Biocompatible, biodegradable PLGA microspheres incorporating alendronate sodium with high loading efficiency obtained in this study may offer promise as a delivery system for bisphosphonates in dental and probably other clinical applications.

The Effects of Thyrotropin-Suppressive Therapy on Bone Metabolism in Patients with Well-Differentiated Thyroid Carcinoma

Patients with differentiated thyroid carcinoma (DTC) are commonly treated long-term with thyrotropin (TSH)- suppressive thyroxine replacement therapy resolving in a state of subclinical hyperthyroidism. The relationship between subclinical hyperthyroidism and osteoporosis is not clear. In this review, we systematically selected and analyzed 21 studies addressing this issue. Although multiple methodological differences between studies prevented a structured meta-analysis, our data suggest that postmenopausal women with subclinical hyperthyroidism are most at risk, whereas no increased risk was observed in men and premenopausal women. Based on these findings we believe that measurement of bone mineral density is recommended in postmenopausal women with DTC starting TSH suppressive therapy. This should be subsequently regularly measured to enable timely intervention with bone protective agents.

Skeletal morbidity in inflammatory bowel disease

Patients with Crohn's disease are at increased risk of developing disturbances in bone and mineral metabolism because of several factors, including the cytokine-mediated nature of the inflammatory bowel disease, the intestinal malabsorption resulting from disease activity or from extensive intestinal resection and the use of glucucorticoids to control disease activity. Inability to achieve peak bone mass when the disease starts in childhood, malnutrition, immobilization, low BMI, smoking and hypogonadism may also play a contributing role in the pathogenesis of bone loss. The relationship between long-term use of glucocorticoids for any disease indication and increased risk for osteoporosis and fractures is well established. However, the relationship between Crohn's disease and ulcerative colitis and bone loss remains controversial. Depending on the population studied the prevalence of osteoporosis has thus been variably reported to range from 12 to 42% in patients with inflammatory bowel disease (IBD). In IBD most studies demonstrate a negative correlation between bone mineral density (BMD) and glucocorticoid use, but not all authors agree on the relationship between long-term glucocorticoid use and continuing bone loss. Whereas prospective studies do suggest sustained bone loss at both trabecular and cortical sites in long-term glucocorticoid users with inflammatory bowel disease, a decrease in bone mass is also observed in patients with active Crohn's disease not using glucocorticoids, and bone loss is not universally observed in patients with Crohn's disease using orally or rectally administered glucocorticoids. Data on vertebral fractures are scarce and there is no agreement about the risk of non-vertebral fractures in patients with Crohn's disease, although it has been suggested that non-vertebral fracture risk may be increased by up to 60% in patients with IBD. A recent publication reports an increased risk of hip fractures in Crohn's disease related to current and cumulative corticosteroid use and use of opiates, although these fractures could not be related to the severity of osteoporosis. The issue of the magnitude of the problem of osteoporosis has become particularly relevant in Crohn's disease, since the ability of therapeutic interventions to beneficially influence skeletal morbidity has been clearly established in patients with osteoporosis, whether post-menopausal women, men or glucocorticoid users. The main question that arises is whether all patients with Crohn's disease should be treated with bone protective agents on the assumption that they all have the potential to develop osteoporosis or whether the use of these agents should be restricted to patients clearly at risk of osteoporosis and fractures, providing these can be identified. We recommend, based on the available literature and our own experience, that all patients with Crohn's disease should be screened for osteoporosis by means of a bone mineral density measurement in addition to full correction of any potential calcium and vitamin D deficiency, to allow timely therapeutic intervention of the patient at risk while sparing the vast majority unnecessary medical treatment.

The prevention and treatment of glucocorticoid-induced osteoporosis in clinical practice

Glucocorticoids are associated with increased risk of bone loss and fracture. This study compared the prescribing of bone protective agents by rheumatologists in clinical practice with the standards recommended in the 1998 UK Consensus guidelines. All glucocorticoid users who attended rheumatology outpatients during a four-week period were eligible. Notes were audited according to a predefined proforma. Among the 1290 rheumatology outpatients seen in the study period, 189 (15%) were taking glucocorticoids. 63% of glucocorticoid patients were taking calcium and 46% vitamin D. In total, 124 (71%) of the 175 patients available for review were at high risk of osteoporotic fracture, of whom 76 (61%) were taking appropriate prophylaxis. In 26 (15%) patients, insufficient information was available to be able to quantify the risk of fracture. The study showed that the audit standard was not met in 39% of cases. A better strategy for the monitoring of clinical risk factors is therefore required.