Reduced Bone Turnover Markers Research Articles

Treatment of acromegaly increases BMD but reduces trabecular bone score: a longitudinal study.

Bone turnover is increased in acromegaly. Despite normalization of bone turnover after treatment, the risk for vertebral fractures remains increased. Gonadal status, but not BMD, is correlated with vertebral fractures. Trabecular bone score (TBS) is related to bone microarchitecture. The aim of this study is to assess the longitudinal change in TBS and BMD following treatment for acromegaly. DESIGN, SETTING, PATIENTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: This longitudinal study included 48 patients with acromegaly between 2005 and 2015. BMD, TBS, and markers for bone turnover (P1NP and CTX-1) were measured at baseline and following treatment. Following treatment, the mean TBS decreased by 3.0 (±7.0) %, whereas the BMD at the lumbar spine (LS) increased by 3.2 (±4.9) % (both P<0.01). The changes in BMD LS and TBS were not correlated (P=0.87). The TBS change was found to be -4.5 % (±6.7; P=0.003) in men and -0.3 % (±6.8; P=0.85) in women (P=0.063 for interaction men vs women). The mean BMD LS increased in men +4.2 g/cm(2) (±4.3; P<0.001), but not in women +1.5 g/cm(2) (±5.6; P=0.36); (P=0.073 for interaction). BMD increased in the ultradistal radius and total body (both P<0.01). The increase in BMD LS was associated with a decrease in P1NP and CTX-1 (P<0.001) and with lower P1NP and CTX-1 at the follow-up (P<0.02). Treatment of acromegaly affects TBS and BMD at LS in different manners. The reduction of bone turnover markers predicts the increase in BMD but not the decrease in TBS. The DXA changes were more pronounced in men. Alterations in trabecular bone architecture may explain the persistent fracture risk despite the increase in BMD after disease control.

Effects of Long-Term Odanacatib Treatment on Bone Gene Expression in Ovariectomized Adult Rhesus Monkeys: Differentiation From Alendronate.

Similar efficacy of the cathepsin K inhibitor odanacatib (ODN) and the bisphosphonate alendronate (ALN) in reducing bone turnover markers and increasing bone mineral density in spine and hip were previously demonstrated in ovariectomized (OVX)-monkeys treated for 20 months in prevention mode. Here, we profiled RNA from tibial metaphysis and diaphysis of the same study using Affymetrix microarrays, and selected 204 probe sets (p < 0.001, three-group ANOVA) that were differentially regulated by ODN or ALN versus vehicle. Both drugs produced strikingly different effects on known bone-related genes and pathways at the transcriptional level. Although ALN either reduced or had neutral effects on bone resorption-related genes, ODN significantly increased the expression of osteoclast genes (eg, APC5, TNFRSF11A, CTSK, ITGB3, and CALCR), consistent with previous findings on the effects of this agent in enhancing the number of nonresorbing osteoclasts. Conversely, ALN reduced the expression of known bone formation-related genes (eg, TGFBR1, SPP1, RUNX2, and PTH1R), whereas ODN either increased or had neutral effects on their expression. These differential effects of ODN versus ALN on bone resorption and formation were highly correlative to the changes in bone turnover markers, cathepsin K (Catk) target engagement marker serum C-terminal cross-linked telopeptide (1-CTP) and osteoclast marker tartrate resistant acid phosphatase isoform 5b (TRAP5b) in the same monkeys. Overall, the molecular profiling results are consistent with the known pharmacological actions of these agents on bone remodeling and clearly differentiate the molecular mechanisms of ODN from the bisphosphonates.

Denosumab versus zoledronic acid in patients previously treated with zoledronic acid.

Denosumab and zoledronic acid are potent antiresorptives. In this study in patients pre-treated with zoledronic acid, denosumab achieved similar increases with zoledronic acid in lumbar spine BMD despite the more prominent reduction of bone turnover markers. Denosumab reversibly reduced endogenous RANKL. We aimed to compare yearly changes in lumbar spine (LS) bone mineral density (BMD), bone turnover markers, free soluble receptor activator of nuclear factor kappaB ligand (sRANKL) and sclerostin levels between denosumab and zoledronic acid. Postmenopausal women with low bone mass previously treated with zoledronic acid for 1 year were assigned to denosumab injection (n = 32) or zoledronic acid infusion (n = 26). Procollagen type 1 N-terminal propeptide (P1NP), C-terminal cross-linking telopeptide of type 1 collagen (CTx), sRANKL, and sclerostin levels were measured in serum samples obtained at baseline and 3, 6, and 12 months after denosumab injection or zoledronic acid infusion. LS BMD was measured at baseline and 12 months. The mean LS increase was 4.5 and 4.4% with denosumab and zoledronic acid, respectively (p = 0.560). Denosumab caused a larger decrease in CTx at 3 months (p < 0.001) and P1NP at 3 (p < 0.001), 6 (p = 0.021), and 12 months (p = 0.042). Denosumab significantly decreased sRANKL by 87.4% at 3 months (p < 0.001). Sclerostin levels were not changed with either intervention (p = 0.162 and p = 0.214, respectively). In patients previously treated with zoledronic acid, denosumab reduces bone turnover more than zoledronic acid, but the increases in LS BMD are comparable. Furthermore, denosumab administration results in reversible inhibition of the metabolically significant endogenous free soluble RANKL levels. Serum sclerostin is not affected by either agent.

Sustained Modeling-Based Bone Formation During Adulthood in Cynomolgus Monkeys May Contribute to Continuous BMD Gains With Denosumab.

Denosumab (DMAb) administration to postmenopausal women with osteoporosis is associated with continued bone mineral density (BMD) increases and low fracture incidence through 8 years, despite persistently reduced bone turnover markers and limited fluorochrome labeling in iliac crest bone biopsies. BMD increases were hypothesized to result from additional accrual of bone matrix via modeling-based bone formation-a hypothesis that was tested by examining fluorochrome labeling patterns in sections from ovariectomized (OVX) cynomolgus monkeys (cynos) treated with DMAb for 16 months. Mature OVX or Sham cynos were treated monthly with vehicle for 16 months, whereas other OVX cynos received monthly 25 or 50 mg/kg DMAb. DMAb groups exhibited very low serum bone resorption and formation biomarkers and near-absent fluorochrome labeling in proximal femur cancellous bone. Despite these reductions, femoral neck dual-energy X-ray absorptiometry (DXA) BMD continued to rise in DMAb-treated cynos, from a 4.6% increase at month 6 to 9.8% above baseline at month 16. Further examination of cortical bone in the proximal femur demonstrated consistent and prominent labeling on the superior endocortex and the inferior periosteal surface, typically containing multiple superimposed labels from month 6 to 16 over smooth cement lines, consistent with continuous modeling-based bone formation. These findings were evident in all groups. Quantitative analysis at another modeling site, the ninth rib, demonstrated that DMAb did not alter the surface extent of modeling-based labels, or the cortical area bound by them, relative to OVX controls, while significantly reducing remodeling-based bone formation and eroded surface. This conservation of modeling-based formation occurred concomitantly with increased femoral neck strength and, when coupled with a reduction in remodeling-based bone loss, is likely to contribute to increases in bone mass with DMAb treatment. Thus, this study provides preclinical evidence for a potential mechanism that could contribute to the clinical observations of continued BMD increases and low fracture rates with long-term DMAb administration.

The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT).

While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p = 0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits.

Effect of risedronate in osteoporotic HIV males, according to gonadal status: a pilot study.

The aim of the study was to evaluate the effect of risedronate on bone mineral density (BMD) and bone turnover markers in HIV-infected osteoporotic males, according to their gonadal status. HIV patients were followed up for 24 months and divided into two groups: patients with osteoporosis or osteopenia with fractures (group A, n = 20) and those without (group B, n = 21). Group A and B were further divided according to the presence of reduced androgenizations. Both groups were treated with cholecalciferol 800 I.U. and calcium (Ca) 1,000 mg orally every day for the first 12 months. Risedronate 75 mg for two consecutive days a month orally was then added in group A, for another 12 months. Group B continued treatment with Ca and vitamin D. Every 6 months each patient underwent biochemical evaluation, and BMD measurement. A significant increase in lumbar BMD was observed in HIV males with adequate androgenization after 12 months of risedronate treatment in group A together with a reduction of bone turnover markers. BMD remained stable with a concomitant significant slight reduction of bone turnover markers in group B. Risedronate increased BMD and reduced bone turnover markers to a greater extent in patients with adequate androgenization compared to osteoporotic HIV males with symptomatic hypoandrogenization.

Clinical efficacy and treatment persistence of monthly minodronate for osteoporotic patients unsatisfied with, and shifted from, daily or weekly bisphosphonates: the BP-MUSASHI study.

SummaryThis multi-center, prospective, open-label, observational study evaluated the effects of once-monthly minodronate (50 mg) on treatment persistence, bone turnover markers, bone mineral density, low back pain, and upper gastrointestinal symptoms in outpatients with osteoporosis previously treated with daily or weekly bisphosphonate products.IntroductionThe purposes of this study were to investigate the effects of once-monthly oral minodronate (MIN 50 mg) on bone turnover markers and bone mineral density, low back pain, and upper gastrointestinal symptoms, as well as preference for and treatment persistence of MIN 50 mg among Japanese osteoporosis patients currently treated with daily or weekly bisphosphonates.MethodsStudy patients were allocated based on their preference to either the Switch group (patients willing to switch over to MIN 50 mg) or the Continue group (patients wanting to continue their current therapies). Patients’ treatment persistence and satisfaction levels with the therapies were assessed using a self-administered questionnaire. The study endpoints were serum TRACP-5b, serum P1NP, bone mineral density, upper gastrointestinal symptoms, and low back pain.ResultsIn total, 264 and 133 patients were allocated into the Switch and Continue groups, respectively. Approximately, 65 % of patients were willing to switch to MIN 50 mg, with the predominant reason being “less frequent dosing more convenient.” Treatment persistence was significantly higher in the Switch group (MIN 50 mg) than the Continue group. Almost all patients with abnormal bone metabolism markers demonstrated normalization after switchover. MIN 50 mg alleviated low back pain and upper gastrointestinal symptoms induced by prior bisphosphonate use.ConclusionsMIN 50 mg alleviates low back pain, reduces bone turnover markers and increases bone density, and induces fewer upper gastrointestinal symptoms after switchover from prior bisphosphonate products, and therefore, it may provide patients with a more convenient treatment option and enhance long-term treatment persistence.

Commentary on “Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial.” Smith DC, Smith MR, Sweeney C, Elfiky AA, Logothetis C, Corn PG, Vogelzang NJ, Small EJ, Harzstark AL, Gordon MS, Vaishampayan UN, Haas NB, Spira AI, Lara PN Jr, Lin CC, Srinivas S, Sella A, SchoffskiSchöffski P, Scheffold C, Weitzman AL, Hussain M,

PurposeCabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort. Patients and MethodsPatients received 100mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment. ResultsOne hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P<.001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by≥50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%). ConclusionCabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.

Calcium and Vitamin D Supplementation in Postmenopausal Women

Bone health is influenced by the intake of both calcium and vitamin D. Our objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover. SETTING, PATIENTS, AND DESIGN: At an ambulatory research center, 159 postmenopausal healthy white women participated in this double-blind, placebo-controlled parallel, longitudinal factorial study that was 6 months in duration. Subjects were randomly allocated to 4 groups: 1) double placebo, 2) calcium (1200 mg daily) plus placebo, 3) vitamin D3 (100 μg) plus placebo, and 4) vitamin D3 and calcium. Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months. Serum PTH, cross-linked C-telopeptide (CTX), and procollagen type I N-terminal propeptide (P1NP) were measured. Before study medication, a calcium load resulted in a decline in PTH and CTX and an increase in urinary calcium excretion. Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake. There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo. Suppression of PTH was greater after a calcium load in the vitamin D groups. A calcium load decreased PTH and CTX and raised urinary calcium. Fasting PTH declines with vitamin D supplementation. PTH declines after calcium intake. Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers, whereas supplementation with up to100 μg vitamin D3/d does not.

Intravenous Treatment With Ibandronate Normalizes Bone Matrix Mineralization and Reduces Cortical Porosity After Two Years in Male Osteoporosis: A Paired Biopsy Study

The spectrum of therapeutic options and the amount of clinical trials for male osteoporosis (mOP) is lower than those for postmenopausal osteoporosis. Therefore, we examined the effects of 24 months of ibandronate (IBN) treatment (3 mg/3 mL intravenously every 3 months) on bone material quality in 19 subjects with mOP within an open-label, single-center, prospective phase III study (Eudract number 2006-006692-20). Patients (median age [25th, 75th percentiles] 53.0 [44.5; 57.0] years) were included if they had low bone mineral density (BMD) and/or at least one low trauma fracture and no secondary cause of osteoporosis. The primary endpoint was to evaluate IBN effects on cancellous (Cn.) and cortical (Ct.) bone mineralization density distribution (BMDD) based on quantitative backscattered electron imaging (qBEI) of paired transiliacal bone biopsies (baseline, 24 months). Secondary endpoints included changes in areal bone mineral density (BMD by dual-energy X-ray absorptiometry [DXA]) and serum markers of bone turnover including type I collagen peptides CrossLaps (CTX), procollagen type 1 amino-terminal propeptide (P1NP), and osteocalcin (OC). At baseline, cancellous bone matrix mineralization from mOP was lower than published reference data (mean degree of mineralization Cn.CaMean -1.8%, p < 0.01). IBN treatment increased calcium concentrations versus baseline (Cn.CaMean +2.4%, Ct.CaMean, +3.0% both p < 0.01), and reduced heterogeneity of mineralization (Cn.CaWidth -14%, p = 0.044; Ct.CaWidth, -16%, p = 0.001), leading to cancellous BMDD within normal range. IBN treatment was associated with a decrease in porosity of mineralized cortical tissue (-25%, p = 0.01); increases in BMD at the lumbar spine, the femoral neck, and the total hip (+3.3%, +1.9%, and +5.6%, respectively, p ≤ 0.01); and reductions in CTX (-37.5%), P1NP (-44.4%), and OC (-36.3%, all p < 0.01). Our BMDD findings are in line with the reduction of bone turnover markers and the increase in BMD by IBN in our patients and suggest that the latter mainly reflects the increase in matrix mineralization and the reduction of cortical porosity in this cohort with mOP.

Osteoporosis in men

Osteoporosis in men contributes to significant morbidity and mortality, yet is underrecognised. Hip fractures in men are associated with greater mortality (up to 37.5% in the first year) compared with women. Timely diagnosis and treatment of osteoporosis in men are therefore critical. Secondary causes for osteoporosis are common and need to be excluded. Absolute fracture risk assessment guides selection of men for anti-osteoporotic therapy. Most studies of oral or intravenous (i.v.) bisphosphonate therapy in hypogonadal and eugonadal men with osteoporosis have reported effects on bone mineral density (BMD) and biochemical bone turnover markers, rather than fragility fractures. Intravenous zoledronic acid given to elderly men and women after hip fracture, reduced clinical, clinical vertebral and nonvertebral fractures, and mortality compared with placebo infusions. Recent studies in men with osteoporosis have reported reductions in vertebral fractures with oral or i.v. bisphosphonates. All studies have been underpowered to detect reductions of nonvertebral and hip fractures. Teriparatide treatment also reduces vertebral fractures. Denosumab increases BMD and reduces bone turnover markers, while strontium ranelate increases BMD in men with osteoporosis. As evidence-based anti-osteoporosis treatment is available, family physicians and patients should recognize that osteoporosis can affect men, so that early diagnosis and treatment can be initiated.

A phase II trial of cabozantinib (Cabo) in patients (pts) with castrate-resistant prostate cancer (CRPC) metastatic to bone (NCT01428219).

TPS5094 Background: MET overexpression predicts prostate cancer invasion and bone metastasis; inhibition of MET/VEGF pathways has synergistic activity in CRPC (Knudsen et al. Adv Cancer Res 2004; Aftab et al. Clin Transl Oncol 2011). Cabo is a small molecule that inhibits multiple receptor tyrosine kinases, including MET and VEGFR2. A phase II randomized discontinuation trial of Cabo showed clinical activity in CRPC, including reduction of soft tissue lesions, prolongation of progression-free survival (PFS), resolution of bone scans, and reductions in bone turnover markers, pain and narcotic use (Smith et al, JCO 2013). To further define the activity of Cabo in pts with CRPC and bone metastases, we launched a phase II trial to characterize the effects of Cabo on bone metabolism and tumor activity in prostate cancer bone lesions. We hypothesize that the clinical activity of Cabo correlates with measurable pharmacodynamic effects on bone micro-environment. Methods: After informed consent, chemotherapy-naive pts with progressive CRPC and bone metastases accessible to CT-guided biopsy, adequate performance status/organ function, are treated with Cabo 60 mg once daily. Primary endpoint: proportion of pts progression-free (PF) at 12 weeks. Secondary endpoints: safety, PFS, response proportion/duration, PSA response, PSA time-to-progression. A Simon's two-stage mini-max design permits early termination after the first 27 evaluable pts in case of unfavorable results. Alternatively, up to 46 evaluable pts will be accrued. Cabo would not be of interest if the 12-week PF proportion is &lt;0.45; it would be of definite clinical interest if the 12-week PF proportion is &gt;0.65 (5% type I error, 85% power). Perfusion/diffusion-weighted MRI (parametric response maps) and bone lesion biopsies are required at baseline and 6 weeks after starting Cabo. Doxycycline is administered prior to bone biopsy for bone labeling. Bone cores are sent for dynamic histomorphometry and immunohistochemistry (phospho-MET/MET, phospho-VEGFR2/VEGFR2, phospho-Akt/Akt). Serum is collected at several time-points to measure markers of bone metabolism. 13 of 27 first-stage pts have been enrolled and started Cabo. Clinical trial information: NCT01428219.

Clinical Efficacy on Fracture Risk and Safety of 0.5 mg or 1 mg/month Intravenous Ibandronate Versus 2.5 mg/day Oral Risedronate in Patients with Primary Osteoporosis

This randomized, double-blind study assessed the antifracture efficacy and safety of intermittent intravenous (IV) ibandronate versus oral daily risedronate in Japanese patients with primary osteoporosis. Ambulatory patients aged ≥60 years were randomized to receive 0.5 or 1 mg/month IV ibandronate plus oral daily placebo or 2.5 mg/day oral risedronate, the licensed dose in Japan, plus IV placebo. The primary end point was noninferiority of ibandronate versus risedronate for first new or worsening vertebral fracture over 3 years. A total of 1,265 patients were randomized. A total of 1,134 patients formed the per-protocol set. Both ibandronate doses were noninferior to risedronate: 0.5 mg, hazard ratio (HR) 1.09 [95 % confidence interval (CI) 0.77–1.54]; 1 mg, HR 0.88 (95 % CI 0.61–1.27). The rate of first new vertebral fracture over 3 years was 16.8 % (95 % CI 12.8–20.8) for 0.5 mg ibandronate, 11.6 % (95 % CI 8.2–15.0) for 1 mg ibandronate, and 13.2 % (95 % CI 9.6–16.9) for risedronate. Significant increases in bone mineral density relative to baseline were observed with all treatments after 6 months, with substantial reductions in bone turnover markers after 3 months. Greatest efficacy was obtained with 1 mg ibandronate. Analyses in women only showed similar results to the overall population. No new safety concerns were identified. This study demonstrated the noninferiority of IV ibandronate to the licensed Japanese dose of oral risedronate and suggested that 1 mg/month is an effective dose in Japanese patients with primary osteoporosis.

Prostate cancer: Interventions aimed at improving morbidity, mortality

In recent months, FDA approved Xtandi (enzalutamide—Astellas, Medivation), a new agent for metastatic castration-resistant prostate cancer, and expanded the approval of Zytiga (abiraterone—Janssen), an existing agent for the same patient population. In addition, recently published trials have shown the clinical activity of Cometriq (cabozantinib— Exelixis) for patients with advanced prostate cancer and bone metastases, as well as the benefi ts of aspirin therapy in reducing the risk of prostate cancer mortality in men treated with prostatectomy or radiotherapy.

Cabozantinib in Patients With Advanced Prostate Cancer: Results of a Phase II Randomized Discontinuation Trial

Cabozantinib (XL184) is an orally bioavailable tyrosine kinase inhibitor with activity against MET and vascular endothelial growth factor receptor 2. We evaluated the activity of cabozantinib in patients with castration-resistant prostate cancer (CRPC) in a phase II randomized discontinuation trial with an expansion cohort. Patients received 100 mg of cabozantinib daily. Those with stable disease per RECIST at 12 weeks were randomly assigned to cabozantinib or placebo. Primary end points were objective response rate at 12 weeks and progression-free survival (PFS) after random assignment. One hundred seventy-one men with CRPC were enrolled. Random assignment was halted early based on the observed activity of cabozantinib. Seventy-two percent of patients had regression in soft tissue lesions, whereas 68% of evaluable patients had improvement on bone scan, including complete resolution in 12%. The objective response rate at 12 weeks was 5%, with stable disease in 75% of patients. Thirty-one patients with stable disease at week 12 were randomly assigned. Median PFS was 23.9 weeks (95% CI, 10.7 to 62.4 weeks) with cabozantinib and 5.9 weeks (95% CI, 5.4 to 6.6 weeks) with placebo (hazard ratio, 0.12; P < .001). Serum total alkaline phosphatase and plasma cross-linked C-terminal telopeptide of type I collagen were reduced by ≥ 50% in 57% of evaluable patients. On retrospective review, bone pain improved in 67% of evaluable patients, with a decrease in narcotic use in 56%. The most common grade 3 adverse events were fatigue (16%), hypertension (12%), and hand-foot syndrome (8%). Cabozantinib has clinical activity in men with CRPC, including reduction of soft tissue lesions, improvement in PFS, resolution of bone scans, and reductions in bone turnover markers, pain, and narcotic use.

Denosumab for the treatment of osteoporosis: A systematic literature review

PurposeTo determine the efficacy and safety of denosumab in osteoporosis. MethodsA systematic search was performed in MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials (1950 to July 2010), meeting abstracts (2009–2010), trial registries, and reference lists. The selection criteria were as follows: (population) osteoporosis patients of any age; (intervention) treatment with denosumab; (outcome) efficacy and safety; (study design) randomized clinical trials (RCTs); no language restrictions. Two reviewers independently screened titles and abstracts and subsequently extracted data from the selected studies including quality items, and on outcomes of interest. A meta-analysis was performed for safety issues. ResultsA total of 25 studies were included. Denosumab reduces the risk of new radiographic vertebral fracture in a 68% compared with placebo (p<0.001) and increases bone mineral density (BMD) at lumbar spine, total hip, and one-third radius more than alendronate and placebo. A single subcutaneous dose of denosumab resulted in a dose-dependent, rapid, profound, and sustained decrease bone turnover markers (BTMs). Denosumab was in general well tolerated. A meta-analysis has shown an increase in the incidence of urinary infections (p=0.012) and eczema (p<0.001) in the patients treated with denosumab. Meta-analysis of efficacy was complicated due to the study features. ConclusionsDenosumab given subcutaneously twice yearly is associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. Denosumab is associated with greater and sustained increases in BMD and reductions in BTMs compared with placebo and/or alendronate and with a risk of urinary infections and eczema.

Use of bone turnover markers in clinical practice

To describe the modalities and interest of the use of bone turnover markers (BTMs) in clinical practice for osteoporosis management. Serum procollagen type I N-terminal propeptide and serum collagen type I crosslinked C-telopeptide are respectively the formation and resorption markers recommended to use as references for bone remodelling assessment in clinical studies. Biochemical BTMs reflect changes in bone metabolism. In clinical practice, many factors influencing BTMs, variability needs to be integrated during all of the dosage process. They include sample collection and storage conditions, patient's characteristics and lifestyle habits, recent fracture. The reference intervals are also affected by the type of automated assays used to assess BTMs. Appropriate references measured with the same assay method must be used for the optimum interpretation of results. BTMs have been extensively used as indicators in the diagnosis and monitoring of osteoporosis. However, their interest was mainly demonstrated to reflect changes in bone metabolism under antiosteoporotic treatments in clinical studies. Significant reductions in BTMs associated with fracture risk reduction needs to be determined in the management of osteoporosis. The standardization of BTMs, assays with international reference standards should provide conditions to state on the applications of BTMs in routine clinical practice.

Effects of Anti Rank Ligand Denusomab On Beta Thalassmia Major Induced Osteoporosis.

AbstractAbstract 2121 Introduction:Osteoporosis is defined as a metabolic bone disease characterized by low bone mass and microarchitectural deterioration of bony tissue leading to enhanced bone fragility and a consequent increase in fracture risk. It represents the second most common cause of endocrinopathy in patients with Beta thalassmia major (BTM). Some of the drugs proved effective to reduce vertebral and non-vertebral fracture risk. Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL), a member of the tumor necrosis factor receptor superfamily essential for osteoclastogenesis. However the efficacy and safety of Denosumab in BTM-induced osteoporosis has not been tested. This is the first study addressing this issue. Objective:To evaluate the efficacy and safety of anti RANK ligands on the biochemical and radiological parameters of bone mineralization in patients with BTM-induced osteoporosis. Radiological evaluation was done by DEXA scan (as per WHO criteria) and biochemical evaluation of bone turnover markers included bone specific alkaline phosphatase and type 1 collagen carboxy telopetide (T1CCT). Design:prospective study. Patients and methods:We studied 30 patients with BTM-induced osteoporosis as per WHO criteria (T score of less than −1.0 being defined as osteopenic and a T score of less than −2.5 being referred as osteoporotic). 19 males and 11 females aged between 17 and 32 years, with full pubertal development (Tanner’s stage 5) at the time of the study were studied. Their serum ferritin levels ranged from 500 to 5922 ng/ml (mean= 2686 ng/ml). Every patients underwent DEXA scan as baseline and after 12 months of Denosumab therpy. All patients were evaluated biochemically by checking their serum calcium, phosphorus, bone specific alkaline phosphatase and T1CCT with the use of enzyme-linked immunosorbent assay (ELISA) (Nordic Bioscience Diagnostics A/S) at baseline 1860+/− 430 and 12 months after starting Denosumab. Fasting serum samples were collected before the injection,1 month and 6 months after the injection. Follicle stimulating hormone(FSH) 4.4+/−2.27IU/L, Luteinizing hormone (LH) 3.8+/−1.87IU/L and testosterone (T) 20+/−8.8μmol/l in males were measured at baseline and repeated every 3months. Baseline urea and electrolytes were measured at baseline including calcium and phosphorus two months. Circulating parathyroid hormone (PTH) levels were checked at baseline and then every 3months. Patients with renal impairment, hypocalcaemia or hyperparathyroidism were excluded from the study. Denosumab was administered as 60 mg subcutaneously twice yearly for a year. The mean bone mineral density T scores were −2.7 at the lumbar spine, −1.8 at the total hip, and −2.1 at the femoral neck. Main Outcome Measures and Results:Denosumab therapy for a year was associated with a significant increase in bone mineral density of 9.2% (95% CI, 8.2 to 10.1) at the lumbar spine and 6.0% (95% CI, 5.2 to 6.7) at the total hip. Denosumab treatment decreased serum TICCT levels by 56% at 1 month and normalized them in all patients at 1 year. Significant correlation were found between bone mineral density T score before and 1year after Denosumab in vertebral (r = 0.752,p < 0.001) and both hips (r = 0.758 respectively p < 0.001). The most common side effects were pain in the extremities (12%) and nausea (10%) of patients. Hypocalcemia was not reported in any patient. Conclusion:Denosumab therapy for BTM induced osteoporosis significantly decrease bone resorption and increased bone mineral density through inhibition of RANKL and is associated with a rapid and sustained reduction in bone turnover markers, a continuous marked increase in bone mineral density at vertebral and hips of patients with BTM. However further studies are required to confirm long-term effects of this therapy. Disclosures:Yassin:Hamad medical corporation: Employment, Research Funding. Off Label Use: the study about effects of denosumab antirank ligands in patients with Beta thalassemia major induced osteoporosis which is off label indication. Soliman:Hamad medical corporation: Employment, Research Funding. Osman:Hamad Medical Corporation: Employment. Elawwa:Hamad medical corporation: Employment, Research Funding.

Denosumab for the treatment of osteoporosis: A systematic literature review

PurposeTo determine the efficacy and safety of denosumab in osteoporosis. MethodsA systematic search was performed in MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials (1950 to July 2010), meeting abstracts (2009–2010), trial registries, and reference lists. The selection criteria were as follows: (population) osteoporosis patients of any age; (intervention) treatment with denosumab; (outcome) efficacy and safety; (study design) randomized clinical trials (RCTs); no language restrictions. Two reviewers independently screened titles and abstracts and subsequently extracted data from the selected studies including quality items, and on outcomes of interest. A meta-analysis was performed for safety issues. ResultsA total of 25 studies were included. Denosumab reduces the risk of new radiographic vertebral fracture in a 68% compared with placebo (p<0.001) and increases bone mineral density (BMD) at lumbar spine, total hip, and one-third radius more than alendronate and placebo. A single subcutaneous dose of denosumab resulted in a dose-dependent, rapid, profound, and sustained decrease bone turnover markers (BTMs). Denosumab was in general well tolerated. A meta-analysis has shown an increase in the incidence of urinary infections (p=0.012) and eczema (p<0.001) in the patients treated with denosumab. Meta-analysis of efficacy was complicated due to the study features. ConclusionsDenosumab given subcutaneously twice yearly is associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. Denosumab is associated with greater and sustained increases in BMD and reductions in BTMs compared with placebo and/or alendronate and with a risk of urinary infections and eczema.

897O - Cabozantinib (XL184) At 40 Mg in Patients with Metastatic Castration Resistant Prostate Cancer (MCRPC): Results of a Phase 2 Non-Randomized Expansion Cohort (NRE)

ABSTRACT Background Cabozantinib (cabo) inhibits MET & VEGFR2. In a phase 2 NRE cohort of patients (pts) with mCRPC, cabo at 100 mg daily was associated with high rates of bone scan resolution, pain relief & overall disease control, independent of PSA changes. We now report the activity & safety of cabo 40 mg daily. Methods Docetaxel (D)-pretreated (≥225 mg/m) CRPC pts with bone metastasis were required to have progressed within 6 months of last dose of D. Tumor response was assessed q6 wks. Bone scan response used computer-aided assessment of bone scan lesion area (BSLA). Diffusion Weighted MRI was performed in some pts. Pain intensity (worst pain over the past 24 hrs; BPI scale 0-10) & interference with sleep & daily activity were prospectively assessed using an IVR system (7 day intervals). Analgesic use was collected by diary. Bone turnover markers & circulating tumor cells (CTCs) were assessed. Results 51 pts were enrolled. Among 30 pts who had ≥6 wks f/u, the median age was 66 yrs. 20% received cabazitaxel, 70% abiraterone, & 20% had visceral disease. 47% (14/30) had pain (BPI ≥4) at baseline (bsl) of which 86% (12/14) were using narcotics. Median bsl CTC count was 17 & 73% had ≥5. Median f/u was 84 days (range, 44-141). 55% (11/20 pts) with a f/u bone scan showed BSLA reduction (range, 1-70%). Increases in Apparent Diffusion Coefficient (suggestive of tumor necrosis) & enhancement reduction were observed in bone & soft tissue metastases. 10/14 pts (71%) evaluable for pain response had a ≥30% reduction from bsl; 7/12 (58%) pts decreased narcotics. Sleep & daily activity improved in pts with pain relief. Among pts with elevated bsl serum levels of CTx, NTx & bALP, 57%, 60% & 33% respectively, had declines ≥30%. In 22 pts with CTCs ≥5, 59% had a decrease of ≥30% at wks 6 or 12, & 23% converted to Conclusions Cabo 40 mg was well tolerated & demonstrated bone scan resolution, substantial pain relief with a narcotic sparing effect, & reductions in bone turnover markers & CTCs in heavily pretreated mCRPC pts. MRI results are consistent with an anti-tumor effect. Disclosure M.R. Smith: Consultant to Exelixis. O.A. Sartor: Consultant for Exelixis. All other authors have declared no conflicts of interest.