Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration.
ABSTRACT: Dickkopf-1 is an inhibitor of Wnt signaling, which is crucial for osteoblast differentiation. We evaluated serum levels of Dickkopf-1 in 66 patients with thalassemia-induced osteoporosis who received therapy with zoledronic acid in a placebo-controlled, randomized trial. At baseline, thalassemia patients had increased serum levels of Dickkopf-1 that correlated with reduced bone mineral density of the lumbar spine and the distal radius. High Dickkopf-1 also correlated with increased bone resorption and reduced bone formation markers. Zoledronic acid produced a reduction in serum Dickkopf-1, which was associated with bone mineral density increase after 12 months of therapy. On the contrary, placebo group showed a borderline increase of Dickkopf-1, which was higher in patients who showed deterioration in pain scores. These results suggest that Dickkopf-1 is implicated in the pathogenesis of osteoporosis in thalassemia and reveal Dickkopf-1 as a possible target for the development of novel agents for the management of thalassemia-induced osteoporosis.
Project description:Denosumab (DNM) is a fully human monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand (RANKL) that has been licensed for the treatment of different types of osteoporosis. However, the prospective data for the evaluation of DNM efficacy on transfusion-dependent thalassemia (TDT)-induced osteoporosis are rather limited. Thus, we conducted a randomized, placebo-controlled, double-blind, phase 2b clinical trial to evaluate DNM in TDT osteoporosis. Patients were assigned to receive either 60 mg DNM (n = 32) or placebo (n = 31) subcutaneously on day 0 and 180 during a total of 12 months of follow-up. The percentage increase of L1-L4 bone mineral density was higher in the DNM group than the placebo group (5.92% ± 5.25% vs 2.92% ± 5.56%, respectively; P = .043), whereas the advantage of DNM regarding wrist bone mineral density was much higher compared with placebo (-0.26% ± 5.31% vs -3.92% ± 8.71%, respectively; P = .035). No grade 3 or 4 toxicity was observed. DNM reduced pain scores that remained unaltered in the placebo group. DNM showed a significant reduction of soluble RANKL (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of collagen type I, tartrate-resistant acid phosphatase isoform-5b, and bone-specific alkaline phosphatase between baseline and the 12th month (P < .01 for all comparisons) without changes in dickkopf-1, sclerostin, and osteocalcin. On the contrary, placebo patients showed an increase in sRANKL, osteoprotegerin, dickkopf-1, sclerostin, C-telopeptide of collagen type I, tartrate-resistant acid phosphatase isoform-5b, and bone-specific alkaline phosphatase during the study period (P < .01 for all comparisons). In conclusion, DNM increased lumbar spine and wrist bone mineral density and reduced pain and bone remodeling markers, and thus it is another valuable option for the management of TDT-induced osteoporosis. This trial was registered at www.clinicaltrials.gov as #NCT02559648.
Project description:<h4>Abstract</h4>The main aim of this study is to compare the 2 medications denosumab and zoledronic acid for patients with beta-thalassemia major induced osteoporosis. Patients with B-thalassemia major induced osteoporosis will undergo baseline assessment of the bone densitometry by bone density(DEXA) scan as a standard of care by the radiology department, then a blood test for bone-specific alkaline phosphatase and type-1 collagen telopeptide will be measured by the chemistry laboratory.Patients with B-thalassemia major induced osteoporosis, who are 18 years of age or more and willing to participate in the study will be enrolled after consenting by the primary investigator in hematology outpatient clinics. Patients with osteoporosis will receive 1 of the 2 medications; at the end of the year, DEXA scan will be done to compare the response of the 2 medications. The potential risks include drug-related side effects.The outcome will be measured biochemically by measuring bone-specific alkaline phosphatase and type 1 collagen carboxy telopeptide and radiologically by DEXA scan at baseline and 1 year using Z score.
Project description:The prevention of fractures is the ultimate goal of osteoporosis treatments. To achieve this objective, developing a method to predict fracture risk in the early stage of osteoporosis treatment would be clinically useful. This study aimed to develop a mathematical model quantifying the long-term fracture risk after 2 annual doses of 5 mg of once-yearly administered zoledronic acid or placebo based on the short-term measurement of bone turnover markers or bone mineral density (BMD). The data used in this analysis were obtained from a randomized, placebo-controlled, double-blind, 2-year study of zoledronic acid that included 656 patients with primary osteoporosis. Two-year individual bone resorption marker (tartrate-resistant acid phosphatase 5b [TRACP-5b]) and lumbar spine (L2-L4) BMD profiles were simulated using baseline values and short-term measurements (at 3 months for TRACP-5b and 6 months for BMD) according to the pharmacodynamic model. A new parametric time-to-event model was developed to describe the risk of clinical fractures. Fracture risk was estimated using TRACP-5b or BMD and the number of baseline vertebral fractures. As a result, the fracture risk during the 2 years was successfully predicted using TRACP-5b or BMD. The 90% prediction intervals well covered the observed fracture profiles in both models. Therefore, TRACP-5b or BMD is useful to predict the fracture risk of patients with osteoporosis, and TRACP-5b would be more useful because it is an earlier marker. Importantly, the developed model allows clinicians to inform patients of their predicted response at the initial stage of zoledronic acid treatment.
Project description:Denosumab and zoledronic acid (ZOL) are parenteral treatments for patients with osteoporosis.The objective of the study was to compare the effect of transitioning from oral bisphosphonates to denosumab or ZOL on bone mineral density (BMD) and bone turnover.This was an international, multicenter, randomized, double-blind trial.A total of 643 postmenopausal women with osteoporosis previously treated with oral bisphosphonates participated in the study.Subjects were randomized 1:1 to sc denosumab 60 mg every 6 months plus iv placebo once or ZOL 5 mg iv once plus sc placebo every 6 months for 12 months.Changes in BMD and bone turnover markers were measured.BMD change from baseline at month 12 was significantly greater with denosumab compared with ZOL at the lumbar spine (primary end point; 3.2% vs 1.1%; P < .0001), total hip (1.9% vs 0.6%; P < .0001), femoral neck (1.2% vs -0.1%; P < .0001), and one-third radius (0.6% vs 0.0%; P < .05). The median decrease from baseline was greater with denosumab than ZOL for serum C-telopeptide of type 1 collagen at all time points after day 10 and for serum procollagen type 1 N-terminal propeptide at month 1 and at all time points after month 3 (all P < .05). Median percentage changes from baseline in serum intact PTH were significantly greater at months 3 and 9 with denosumab compared with ZOL (all P < .05). Adverse events were similar between groups. Three events consistent with the definition of atypical femoral fracture were observed (two denosumab and one ZOL).In postmenopausal women with osteoporosis previously treated with oral bisphosphonates, denosumab was associated with greater BMD increases at all measured skeletal sites and greater inhibition of bone remodeling compared with ZOL.
Project description:Annual intravenous administration of zoledronic acid is used in the treatment of osteoporosis. A mathematical model was developed to predict bone mineral density up to 2 years after two annual doses of zoledronic acid from the early values of a bone resorption marker in osteoporosis patients. INTRODUCTION:The measurement of bone mineral density (BMD) has been used as a surrogate marker instead of the observation of incident fractures to detect the efficacy of treatment. However, this method requires a long time to obtain significant changes. On the other hand, bone resorption markers respond to bone resorption inhibitors within a few weeks. Therefore, the aim of this study was to develop a mathematical model predicting long-term BMD after two annual doses of zoledronic acid (ZOL) using the early response of a bone resorption marker in osteoporosis patients. METHODS:The model was constructed using 3410 tartrate-resistant acid phosphatase 5b (TRACP-5b) serum concentrations and 1146 lumbar spine (L2-L4) BMD values from 306 patients with primary osteoporosis. A mathematical model was developed to describe the time-dependent profiles of TRACP-5b and BMD. RESULTS:The percentage changes from baseline of the BMD (%BMD) at up to 2 years were predicted from patients' baseline BMD and baseline and 12-week TRACP-5b values by the model obtained. The simulated 90% prediction interval almost covered the observed %BMD distribution at each time point, and the predictions were comparable to the observed %BMD. CONCLUSIONS:This is the first model to predict BMD for up to 2 years following two annual doses of ZOL using patients' background characteristics and the early response of TRACP-5b. This model allows us to inform patients at the initial stage of ZOL treatment of their predicted response to treatment.
Project description:Eighty-five percent of institutionalized elderly people have osteoporosis and bone fracture rates 8 to 9 times higher than rates observed among community-dwelling elderly people. Nevertheless, most of these persons are left untreated and are excluded from pivotal osteoporosis trials.To determine the efficacy and safety of zoledronic acid to treat osteoporosis in frail elderly women in long-term care facilities.We conducted a 2-year, randomized, placebo-controlled, double-blinded study from December 2007 through March 2012. Included were 181 women 65 or older with osteoporosis, including those with cognitive impairment, immobility, and multimorbidity, who were living in nursing homes and assisted-living facilities.One 5-mg dose of zoledronic acid or placebo intravenously and daily calcium and vitamin D supplementation.Hip and spine bone mineral density (BMD) at 12 and 24 months and adverse events.There were no baseline differences in mean (SE) age (85.4 [0.6] years), BMD, or functional or cognitive status, but the treatment group included more participants with frailty, falls history, diabetes, and anticonvulsant medication use. Values for BMD were available for 87% of participants at 12 months and 73% at 24 months. Mean (SE) BMD changes were greater in the treatment group: 3.2 (0.7) and 3.9 (0.7) percentage-point differences in the total hip at 12 and 24 months, respectively (P?<?.01 for both comparisons), and 1.8 (0.7) and 3.6 (0.7) percentage-point differences at the spine (P?<?.01); adjusted analyses were similar. The treatment and placebo groups' fracture rates were 20% and 16%, respectively (OR, 1.30; 95% CI, 0.61-2.78); mortality rates were 16% and 13% (OR, 1.24; 95% CI, 0.54-2.86). Groups did not differ in the proportion of single fallers (28% vs 24%; OR, 1.24; 95% CI, 0.64-2.42; P?=?.52), but more participants in the treatment group had multiple falls (49% vs 35%; OR, 1.83; 95% CI, 1.01-3.33; P?=?.047); however, this difference was no longer significant when adjusted for baseline frailty.In this group of frail elderly women with osteoporosis, 1 dose of zoledronic acid improved BMD over 2 years. The clinical importance of nonsignificant increases in fracture and mortality rates in the treatment group needs further study. Since it is not known whether such therapy reduces the risk of fracture in this cohort, any change in nursing home practice must await results of larger trials powered to assess fracture rates.clinicaltrials.gov Identifier: NCT00558012.
Project description:Zoledronic acid 5 mg (ZOL) annually for 3 years reduces fracture risk in postmenopausal women with osteoporosis. To investigate long-term effects of ZOL on bone mineral density (BMD) and fracture risk, the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT) was extended to 6 years. In this international, multicenter, double-blind, placebo-controlled extension trial, 1233 postmenopausal women who received ZOL for 3 years in the core study were randomized to 3 additional years of ZOL (Z6, n = 616) or placebo (Z3P3, n = 617). The primary endpoint was femoral neck (FN) BMD percentage change from year 3 to 6 in the intent-to-treat (ITT) population. Secondary endpoints included other BMD sites, fractures, biochemical bone turnover markers, and safety. In years 3 to 6, FN-BMD remained constant in Z6 and dropped slightly in Z3P3 (between-treatment difference = 1.04%; 95% confidence interval 0.4 to 1.7; p = 0.0009) but remained above pretreatment levels. Other BMD sites showed similar differences. Biochemical markers remained constant in Z6 but rose slightly in Z3P3, remaining well below pretreatment levels in both. New morphometric vertebral fractures were lower in the Z6 (n = 14) versus Z3P3 (n = 30) group (odds ratio = 0.51; p = 0.035), whereas other fractures were not different. Significantly more Z6 patients had a transient increase in serum creatinine >0.5 mg/dL (0.65% versus 2.94% in Z3P3). Nonsignificant increases in Z6 of atrial fibrillation serious adverse events (2.0% versus 1.1% in Z3P3; p = 0.26) and stroke (3.1% versus 1.5% in Z3P3; p = 0.06) were seen. Postdose symptoms were similar in both groups. Reports of hypertension were significantly lower in Z6 versus Z3P3 (7.8% versus 15.1%, p < 0.001). Small differences in bone density and markers in those who continued versus those who stopped treatment suggest residual effects, and therefore, after 3 years of annual ZOL, many patients may discontinue therapy up to 3 years. However, vertebral fracture reductions suggest that those at high fracture risk, particularly vertebral fracture, may benefit by continued treatment.
Project description:In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg significantly reduced fracture risk.The aim of the study was to identify factors associated with greater efficacy during ZOL 5 mg treatment.We conducted a subgroup analysis (preplanned and post hoc) of a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis.A single infusion of ZOL 5 mg or placebo was administered at baseline, 12, and 24 months.Primary endpoints were new vertebral fracture and hip fracture. Secondary endpoints were nonvertebral fracture and change in femoral neck bone mineral density (BMD). Baseline risk factor subgroups were age, BMD T-score and vertebral fracture status, total hip BMD, race, weight, geographical region, smoking, height loss, history of falls, physical activity, prior bisphosphonates, creatinine clearance, body mass index, and concomitant osteoporosis medications.Greater ZOL induced effects on vertebral fracture risk were seen with younger age (treatment-by-subgroup interaction, P = 0.05), normal creatinine clearance (P = 0.04), and body mass index >or= 25 kg/m(2) (P = 0.02). There were no significant treatment-factor interactions for hip or nonvertebral fracture or for change in BMD.ZOL appeared more effective in preventing vertebral fracture in younger women, overweight/obese women, and women with normal renal function. ZOL had similar effects irrespective of fracture risk factors or femoral neck BMD.
Project description:INTRODUCTION:Amino-bisphosphonates and statins inhibit the mevalonate pathway, and may exert anti-tumor effects. The Wnt inhibitor dickkopf-1 (DKK-1) promotes osteolytic bone lesions by inhibiting osteoblast functions and has been implicated as an adverse marker in multiple cancers. We assessed the effects of mevalonate pathway inhibition on DKK-1 expression in osteotropic breast cancer. METHODS:Regulation of DKK-1 by bisphosphonates and statins was assessed in human breast cancer cell lines, and the role of the mevalonate pathway and downstream targets was analyzed. Moreover, the potential of breast cancer cells to modulate osteoblastogenesis via DKK-1 was studied in mC2C12 cells. Clinical relevance was validated by analyzing DKK-1 expression in the tissue and serum of women with breast cancer exposed to bisphosphonates. RESULTS:DKK-1 was highly expressed in receptor-negative breast cancer cell lines. Patients with receptor-negative tumors displayed elevated levels of DKK-1 at the tissue and serum level compared to healthy controls. Zoledronic acid and atorvastatin potently suppressed DKK-1 in vitro by inhibiting geranylgeranylation of CDC42 and Rho. Regulation of DKK-1 was strongest in osteolytic breast cancer cell lines with abundant DKK-1 expression. Suppression of DKK-1 inhibited the ability of breast cancer cells to block WNT3A-induced production of alkaline phosphates and bone-protective osteoprotegerin in preosteoblastic C2C12 cells. In line with the in vitro data, treatment of breast cancer patients with zoledronic acid decreased DKK-1 levels by a mean of 60% after 12 months of treatment. CONCLUSION:DKK-1 is a novel target of the mevalonate pathway that is suppressed by zoledronic acid and atorvastatin in breast cancer.