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Higher response with bone mineral density increase with monthly injectable ibandronate 1 mg compared with oral risedronate in the MOVER study.
Nakano, T, Yamamoto, M, Hashimoto, J, Tobinai, M, Yoshida, S, Nakamura, T
Journal of bone and mineral metabolism. 2016;(6):678-684
Abstract
We examined response to bone mineral density (BMD) gains in the MOVER study following treatment with intravenous (IV) ibandronate 1 mg/month, and investigated the characteristics of a non-responder group. At 1 year, responder rates for patients with BMD increases >0 % were similar with IV ibandronate 0.5 or 1 mg/month and oral risedronate 2.5 mg/day. However, after 3 years, responder rates with BMD increases ≥3 % were highest with ibandronate 1 mg at all bone sites (>80 % at the lumbar spine [L2-L4] and >50 % at all femur sites, which was significantly higher than with risedronate). Non-responders were defined by BMD increases ≤3 % at L2-L4 or ≤0 % at total hip, and ≤50 % reduction in creatinine-corrected urinary collagen type 1 cross-linked C-telopeptide (uCTX) from baseline to 1 year. There were a small number of non-responders in the ibandronate 1 mg group: 3.3 % (10/299) with ≤0 % total hip BMD increase and ≤50 % uCTX reduction from baseline. These non-responders had lower 25-hydroxyvitamin D (25[OH]D) levels than responders, but no differences in kidney function, L2-L4 BMD or bone turnover marker baseline values. Throughout the study, non-responders failed to show any increases in BMD. Our analysis demonstrates significantly higher responder rates with IV ibandronate 1 mg/month than with risedronate at 3 years. A small number of non-responders in the ibandronate group had lower 25(OH)D baseline levels than responders, suggesting that 25(OH)D levels could be a useful indicator of BMD response to therapy.
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Comparison of two different strategies of treatment with zoledronate in HIV-infected patients with low bone mineral density: single dose versus two doses in 2 years.
Negredo, E, Bonjoch, A, Pérez-Álvarez, N, Ornelas, A, Puig, J, Herrero, C, Estany, C, del Río, L, di Gregorio, S, Echeverría, P, et al
HIV medicine. 2015;(7):441-8
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Abstract
OBJECTIVES Given the need for easily managed treatment of osteoporosis in HIV-infected patients, we evaluated the efficacy and tolerability of two doses of zoledronate, by comparing three groups of patients: those with annual administration, those with biennial administration (one dose in 2 years) and a control group with no administration of zoledronate. METHODS We randomized (2:1) 31 patients on antiretroviral therapy with low bone mineral density (BMD) to zoledronate (5 mg administered intravenously; 21 patients) plus diet counselling and to a control group (diet counselling; 10 patients). At week 48, patients treated with zoledronate were randomized again to receive a second dose (two-dose group; n = 12) or to continue with diet counselling only (single-dose group; n = 9). Changes in lumbar spine and hip BMD and bone turnover markers were compared. RESULTS The median percentage change from baseline to week 96 in L1-L4 BMD was -1.74% [interquartile range (IQR) -2.56, 3.60%], 7.90% (IQR 4.20, 16.57%) and 5.22% (IQR 2.02, 7.28%) in the control, two-dose and single-dose groups, respectively (P < 0.01, control vs. two doses; P = 0.02, control vs. single dose; P = 0.18, two doses vs. single dose). Hip BMD changed by a median of 2.12% (IQR -0.12, 3.08%), 5.16% (IQR 3.06, 6.74%) and 4.47% (IQR 1, 5.58%), respectively (P = 0.04, control vs. two doses; P = 0.34, two doses vs. single dose). No differences between the two-dose and single-dose groups were detected in bone markers at week 96. CONCLUSIONS The benefits for BMD of a single dose of zoledronate in 2 years may be comparable to those obtained with two doses of the drug after 96 weeks, although this study is insufficiently powered to exclude a real difference. Future studies should explore whether biennial administration of zoledronate is a useful alternative in the treatment of osteoporosis in HIV-infected patients.
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Bisphosphonate-induced osteonecrosis of the jaw: comparison of disease extent on contrast-enhanced MR imaging, [18F] fluoride PET/CT, and conebeam CT imaging.
Guggenberger, R, Fischer, DR, Metzler, P, Andreisek, G, Nanz, D, Jacobsen, C, Schmid, DT
AJNR. American journal of neuroradiology. 2013;(6):1242-7
Abstract
BACKGROUND AND PURPOSE Imaging of bisphosphonate-induced osteonecrosis of the jaw is essential for surgical planning. We compared the extent of BONJ on contrast-enhanced MR imaging, [(18)F] fluoride PET/CT, and panoramic views derived from standard conebeam CT with clinical pre- and intraoperative examinations. MATERIALS AND METHODS Between February 2011 and January 2012, ten subjects with written informed consent (9 women; mean, 69.6 years; range, 53-88 years) were included in this prospective ethics-board-approved study. Patients underwent CEMR imaging, [(18)F] fluoride PET/CT, and CBCT and were clinically examined pre- and intraoperatively. Surgery was performed, and BONJ was histologically confirmed in 9 patients. Location and extent of BONJ on different modalities/examinations were graphically compared (0 = no pathologic finding, 1 = smallest, 5 = largest extent of BONJ). Rank tests were used to assess overall and paired differences of ratings in 9 patients. A P value <.05 was considered statistically significant. RESULTS Significant differences in BONJ extent among different modalities and examinations were found (P < .001). The highest median rank was seen in PET/CT (4 ± 1.12) and CEMR imaging (4 ± 1.01), followed by intraoperative examinations (3 ± 0.71), CBCT (2 ± 0.33), and preoperative examinations (1 ± 0). No significant differences were found between PET/CT and CEMR imaging (P = .23), except when comparing PET/CT to either CBCT, pre- and intraoperative examinations (all P < .05). Preoperative examinations showed significantly less extensive disease than all other modalities/examinations (all P < .05). CONCLUSIONS [(18)F] fluoride PET/CT and CEMR imaging revealed more extensive involvement of BONJ compared with panoramic views from CBCT and clinical examinations.
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Comparison of non-vertebral fracture between minodronate and risedronate therapy in elderly female patients with Alzheimer disease.
Sato, Y, Honda, Y, Iwamoto, J, Amano, N
Journal of musculoskeletal & neuronal interactions. 2013;(3):346-52
Abstract
OBJECTIVES Minodronate is a nitrogen-containing bisphosphonate that is commercially available for the treatment of osteoporosis in Japan. Preclinical studies demonstrated that minodronate is at least 10 times more potent than alendronate in inhibiting bone resorption in vivo. A high incidence of fractures, particularly of the hip, represents an important problem in Alzheimer disease (AD) patients who are prone to falls and may have osteoporosis. METHODS A total of 256 elderly patients with AD were assigned to daily treatment with 1.0 mg of minodronate or a daily treatment with risedronate combined with daily 1000 IU ergocalciferol and 1200 mg elemental calcium, and followed up for 12 months. RESULTS At baseline, patients of both groups showed low 25-hydroxyvitamin D with compensatory hyperparathyroidism. Non-vertebral fractures occurred in 5 patients in the minodronate group and 7 patients in the risedronate group (5 hip fractures; one fracture each at the distal forearm and pelvis). There was no difference in risk of hip fracture between the two groups (p=.70; odds ratio=0.8). CONCLUSIONS The study medications were well tolerated with relatively few adverse events and were equivalent in reducing the risk of a fracture in elderly patients with AD.
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Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma.
Henry, DH, Costa, L, Goldwasser, F, Hirsh, V, Hungria, V, Prausova, J, Scagliotti, GV, Sleeboom, H, Spencer, A, Vadhan-Raj, S, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;(9):1125-32
Abstract
PURPOSE This study compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA) for delaying or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma. PATIENTS AND METHODS Eligible patients were randomly assigned in a double-blind, double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily supplemental calcium and vitamin D were strongly recommended. The primary end point was time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression). RESULTS Denosumab was noninferior to ZA in delaying time to first on-study SRE (hazard ratio, 0.84; 95% CI, 0.71 to 0.98; P = .0007). Although directionally favorable, denosumab was not statistically superior to ZA in delaying time to first on-study SRE (P = .03 unadjusted; P = .06 adjusted for multiplicity) or time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to 1.04; P = .14). Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred at similarly low rates in both groups. Acute-phase reactions after the first dose occurred more frequently with ZA, as did renal adverse events and elevations in serum creatinine based on National Cancer Institute Common Toxicity Criteria for Adverse Events grading. CONCLUSION Denosumab was noninferior (trending to superiority) to ZA in preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.
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[Doctor initiated clinical trial for obtaining evidences in treatment of osteoporosis: JOINT (Japanese Osteoporosis Intervention Trial) protocol].
Shiraki, M
Nihon rinsho. Japanese journal of clinical medicine. 2011;(7):1281-6
Abstract
Due to the recent advances in the treatment of osteoporosis, clinicians can utilize many kinds of drugs to prevent fractures. Evidence of drug supplied to clinicians was mainly obtained from the results of the developmental studies. However, the evidence is still lack for the treatment in an individual patient in the"real world". This is a reason why we build up A-TOP (Adequate Treatment of Osteoporosis) research group and why we perform JOINT (Japanese Osteoporosis Intervention Trial) protocol to obtain the evidences, which are required by the clinicians. The two protocols were aimed to investigate whether concurrent treatment with bisphosphonates and active vitamin D3 (JOINT02) or vitamin K2 (JOINT03) is effective or not comparing to the mono-therapy. The former project was finished the 2-year observation and the latter project is currently underwent. The present paper introduces the aims, rationale, and organization of JOINT studies.
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Impact of bisphosphonate wash-out prior to teriparatide therapy in clinical practice.
Keel, C, Kraenzlin, ME, Kraenzlin, CA, Müller, B, Meier, C
Journal of bone and mineral metabolism. 2010;(1):68-76
Abstract
Concurrent use of bisphosphonate therapy reduces the anabolic effect of teriparatide. Consequently, in clinical practice bisphosphonates are discontinued and teriparatide therapy held for a few months to allow bone turnover to increase. We aimed to evaluate the effect of prior bisphosphonate exposure and the effect of bisphosphonate wash-out on the treatment response to teriparatide. Thirty-nine patients with primary osteoporosis (mean age 63.6 +/- 14.0 years), including 26 patients previously treated with oral bisphosphonates (median duration 53 months) and 13 bisphosphonate-naïve patients were started on teriparatide (20 mug daily) and followed prospectively over 12 months. The primary study outcome was change in bone formation markers (PINP, bone ALP, osteocalcin). Secondary outcomes included changes in bone resorption (betaCTX) and 12-month changes in BMD. Markers of bone formation increased early during teriparatide therapy and were followed by an increase in betaCTX (p < 0.001). The magnitude of the increase in bone markers was comparable in both patient groups irrespective of prior bisphosphonate exposure; similarly, increases in BMD after 12 months were not significantly different between bisphosphonate-pretreated and bisphosphonate-naïve patients (lumbar spine 7.1 vs. 8.9%, p = 0.58; total hip 4.1 vs. 1.1%, p = 0.48). The response of teriparatide was not related to the duration of bisphosphonate wash-out (median duration 4.2 months). This study confirms that beneficial effects of teriparatide on intermediate bone endpoints can be translated into clinical practice with less constringent methodological circumstances than in RCTs. Furthermore, as bisphosphonate wash-out does not appear to influence the treatment effect, teriparatide therapy can be started immediately after ceasing bisphosphonate therapy and wash-out.
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Bisphosphonate Use and Prevalence of Valvular and Vascular Calcification in Women MESA (The Multi-Ethnic Study of Atherosclerosis).
Elmariah, S, Delaney, JA, O'Brien, KD, Budoff, MJ, Vogel-Claussen, J, Fuster, V, Kronmal, RA, Halperin, JL
Journal of the American College of Cardiology. 2010;(21):1752-9
Abstract
OBJECTIVES the aim of this study was to determine whether nitrogen-containing bisphosphonate (NCBP) therapy is associated with the prevalence of cardiovascular calcification. BACKGROUND cardiovascular calcification correlates with atherosclerotic disease burden. Experimental data suggest that NCBP might limit cardiovascular calcification, which has implications for disease prevention. METHODS the relationship of NCBP use to the prevalence of aortic valve, aortic valve ring, mitral annulus, thoracic aorta, and coronary artery calcification (AVC, AVRC, MAC, TAC, and CAC, respectively) detected by computed tomography was assessed in 3,710 women within the MESA (Multi-Ethnic Study of Atherosclerosis) with regression modeling. RESULTS Analyses were age-stratified, because of a significant interaction between age and NCBP use (interaction p values: AVC p < 0.0001; AVRC p < 0.0001; MAC p = 0.002; TAC p < 0.0001; CAC p = 0.046). After adjusting for age; body mass index; demographic data; diabetes; smoking; blood pressure; cholesterol levels; and statin, hormone replacement, and renin-angiotensin inhibitor therapy, NCBP use was associated with a lower prevalence of cardiovascular calcification in women ≥ 65 years of age (prevalence ratio: AVC 0.68 [95% confidence interval (CI): 0.41 to 1.13]; AVRC 0.65 [95% CI: 0.51 to 0.84]; MAC 0.54 [95% CI: 0.33 to 0.93]; TAC 0.69 [95% CI: 0.54 to 0.88]; CAC 0.89 [95% CI: 0.78 to 1.02]), whereas calcification was more prevalent in NCBP users among the 2,181 women <65 years of age (AVC 4.00 [95% CI: 2.33 to 6.89]; AVRC 1.92 [95% CI: 1.42 to 2.61]; MAC 2.35 [95% CI: 1.12 to 4.84]; TAC 2.17 [95% CI: 1.49 to 3.15]; CAC 1.23 [95% CI: 0.97 to 1.57]). CONCLUSIONS among women in the diverse MESA cohort, NCBPs were associated with decreased prevalence of cardiovascular calcification in older subjects but more prevalent cardiovascular calcification in younger ones. Further study is warranted to clarify these age-dependent NCBP effects.
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A single dose zoledronic acid enhances pin fixation in high tibial osteotomy using the hemicallotasis technique. A double-blind placebo controlled randomized study in 46 patients.
Harding, AK, Toksvig-Larsen, S, Tägil, M, W-Dahl, A
Bone. 2010;(3):649-54
Abstract
INTRODUCTION Bisphosphonates have been shown to reduce osteoclastic activity and enhance pin fixation in both experimental and clinical studies. In this prospective, randomized study of high tibial osteotomy using the hemicallotasis (HCO) technique, we evaluate whether treatment by one single infusion of zoledronic acid can enhance the pin fixation. MATERIALS AND METHODS 46 consecutive patients (35-65 years) were operated on for knee osteoarthritis by the HCO technique. After the osteotomy, two hydroxyapatite-coated pins were inserted in the metaphyseal bone and two non-coated pins in the diaphyseal bone. The insertion torque was measured by a torque force screw driver. Four weeks postoperatively, the patients were randomized to either one infusion of zoledronic acid or sodium chloride intravenously. At time for removal of the pins, the extraction torque forces of the pins were measured. RESULTS All osteotomies healed and no difference was found in time to healing. The mean extraction torque force in the non-coated pins in the diaphyseal bone was doubled in the zoledronic treated group (4.5 Nm, SD 2.1) compared to the placebo group (2.4 (SD 1.0, p<0.0001). The mean extraction torque forces of the hydroxyapatite-coated pins in the metaphyseal bone were similar in the zoledronic acid group (4.7 Nm, SD 1.3) and in the placebo group (4.0 Nm, SD 1.3). DISCUSSION A single infusion of zoledronic acid improved twofold the fixation of non-coated pins in diaphyseal bone. Bisphosphonates might be an alternative to hydroxyapatite-coated pins in nonosteoporotic bone.
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Solid-state forms of zoledronic acid: polymorphism in hydrates.
Ruscica, R, Bianchi, M, Quintero, M, Martinez, A, Vega, DR
Journal of pharmaceutical sciences. 2010;(12):4962-72
Abstract
Solid-state forms of zoledronic acid, a nitrogen-containing bisphosphonate used for treatment of bone diseases are studied using different experimental techniques (DSC, TG, and XRD). Two degrees of hydration have been obtained, containing one and three water molecules per zoledronic acid molecule. The crystal structure of the trihydrated form is reported. Two different anhydrated forms have been obtained when the hydrated ones were heated. Besides, during the dehydration process, an amount of metastable amorphous phase appears, as a function of the dehydration rate. The stability of the obtained crystalline forms is examined under high humidity and a different trihydrated form was obtained, setting clear that the same degree of hydration (trihydrated) can be obtained in two different crystalline forms, and then very different thermal behaviors have been observed.