Infusion Of Zoledronic Acid Research Articles

THU0373 Retrospective Analysis of the Safety of Zoledronic Acid in Patients with Osteoporosis in the Course of Connective Tissue Diseases Compared to Patients with Postmenopausal Osteoporosis.

BackgroundCauses of osteoporosis in patients with connective tissue diseases (CTD) are more complex than in patients with postmenopausal osteoporosis (PO). None of the studies published so far examined the safety...

THU0415 An Audit of Acute Side Effect Profile of Zolendronic Acid, Innovator Versus Generic Preparation

BackgroundZolendronic acid infusion is indicated in treatment and prevention of glucocorticoid induced osteoporosis, post-menopausal and male osteoporosis. The infusion is considered safe and well tolerated an even for domiciliary treatment.ObjectivesTo...

AB1049 Characterization and incidence on acute phase reaction in paget’s disease after zoledronic acid infusion

BackgroundZoledronic acid (AZ), characterized by its high antiresorptive activity, has restored the excessive pagetic bone remodeling, reduce or suppress the biological activity, influence on clinical features, and prevent the onset...

SAT0361 Comparison of the efficacy of annual zoledronic acid or weekly alendronate. A 3-yr analysis of postmenopausal women with low bone mineral density

BackgroundOsteoporosis remains as one of the leading cause of morbidity among postmenopausal women closely linked with higher risk of vertebral, hip and other fragility fractures. Treatment with bisphosphonates has been...

Comparison of ready-to-use and vial infusions of zoledronic acid

Comparison of ready-to-use and vial infusions of zoledronic acid

Arrhythmias during and after zoledronic acid infusion patients with bone metastasis

Zoledronic acid (ZA) is one of the important bisphosphonates which is widely used in bone metastatic cancer and osteoporotic patients. In a few studies, it has been reported that treatment with bisphosphonates was associated with an increased risk of atrial fibrillation. We aimed to evaluate the arrhythmias that developed during and immediately after infusion of the ZA. Fifty-two bone metastatic patients were included in the study group. All patients had 24-h Holter monitorization during the first dose ZA infusion day. All of the patients had 4-h basal cardiac rhythm records before ZA infusion and about 19 h after infusion. A short survey including demographic data and past medical history has been completed. None of patients had clinically important arrhythmias before ZA infusion. We divided arrhythmias into two groups as supraventricular and ventricular. We evaluated arrhythmias in pre-infusion, during infusion, and post-infusion periods. ZA was administered 4 mg intravenously (IV) in 15 min. Thirty-three of patients (63.5 %) were male and 19 (36.5 %) patients were female. Mean age of the patients was 53.9 ± 11.8 years. Most frequent cancers were breast (25 %) and lung cancer (15.3 %). Twelve (23 %) patients had history of mediastinal radiotherapy. In basal records, we detected that twenty-four (46 %) of patients had supraventricular premature complexes (SVPC) or ventricular premature complexes (VPC). Fifteen (28.8 %) of patients had SVPC and fourteen (26.9 %) had VPC during infusion period. After infusion period, 48 (92.3 %) of patients had SVPC and 41 (78.8 %) had VPC. Only 3 patients had no arrhythmia after infusion. Three patients had sinus arrhythmia and two had Mobitz type 2 atrioventricular blocks after infusion. One patient, who had no history of comorbidities and had SVPC in the basal records, developed atrial fibrillation that was refractory to medical cardioversion after 10 days of seventh dose of ZA infusion. In this study, we found that both SVPC and VPC increased in cancer patients treated with ZA. Furthermore, ZA may induce clinically important arrhythmias.

Markers of inflammation after zoledronic acid redosing

The symptoms of acute phase response (APR) following the first infusion of zoledronic acid (ZA) are attenuated after re-administration. We investigated the reasons for this attenuation, focusing on the changes in several hormones, bone markers and markers of inflammation occurring after the second ZA injection in patients who had experienced a severe APR after their first ZA infusion. Twenty-two postmenopausal women with osteoporosis and severe symptoms of APR following the first ZA infusion were included in the study (group A1). A year later, the same women (possibly with a residual activity of ZA) were subjected to ZA re-administration (group A2). Urine NTx (uNTx), white blood cells, parathyroid hormone, serum calcium, phosphorus and several serum markers of inflammation were measured before (0) and at 1 and 2 days following the first as well as the second infusion. In group A1, the APR was associated with a significant increase in serum C-reactive protein (CRP), high-sensitive interleukin 6 (hsIL-6), high-sensitive tumor necrosis factor alpha (hsTNF-α) and cortisol within 24 h after the infusion. The majority of the patients in group A2 did not experience an APR and serum calcium, phosphorus, CRP, hsIL-6, hsTNF-α, and cortisol remained essentially unchanged throughout the study. In group A2, on day 0, the uNTx were significantly lower than in group A1. In group A1 the uNTx decreased by 69 and 78% from baseline on days 1 and 2, whereas in group A2, they decreased by 48 and 53% (p < 0.01), respectively. A positive correlation was found between the degree of uNTx decline from the baseline levels (Δ-uNTx) and hsTNF-α and between Δ-uNTx and CRP. The Δ-uNTx, reflecting the osteoclast-mediated bone resorption, may play some role in the APR appearance, although it must be excluded if the relationships of the changes between uNTx and hsTNF-α/CRP are coincidental effects and not causal.

Arrhythmias during and after zoledronic acid infusion patients with bone metastasis.

e20614 Background: Zoledronic acid (ZA) is one of the important biphosphanate which is widely used in bone metastatic cancer patients and osteoporotic patients. In a few studies it has been reported that treatment with biphosphonate was associated with an increased risk for atrial fibrillation. We aim to evaluate the arrhythmias that developed during infusion and immediately after infusion of the ZA. Methods: Bone metastatic 52 patients were included in study group. All of patients had totally 24 hour holter motorization during the first dose ZA infusion day. All of patients had 4 hours basal cardiac rhythm records before ZA infusion and about 19 hours after infusion. A short survey including demographic data and past medical history was completed. None of patients had clinically important arrhythmias before ZA infusion. We divided arrhythmias as supraventricular and ventricular. We evaluated arrhythmias pre, during and after ZA infusion. ZA were administered 4 mg IV in 15 minutes. Results: Thirty three of patients (63,5%) were male and 19 (36,5%) female. Median age of the patients was 52 (27-73). Most frequent cancers were breast (25%) and lung cancer (15,3%).Twelve (23%) patients had history of mediastinal radiotherapy. Three patients had history of myocardial infarction. In basal records we detected that twenty four of patients had supraventricular tachycardia (SVT) or ventricular premature systole (VPS). Fifteen of patients had SVT and fourteen had VPS during infusion period. After infusion period 48 of patients had SVT and 41 had VPS. Only 3 patients had none of arrhythmia after infusion. Three of the patients had sinusoidal arrhythmia and two had Mobitz type 2 bloc after infusion and also one of our patient who had no history of co morbidities and had SVT basal records, developed atrial fibrillation that refractory to medical cardioversion after 10 days of seventh dose ZA infusion. Conclusions: In this study we found that both SVT and VPS increased in cancer patients treated with ZA. Furthermore ZA may induce clinically important arrhythmias.

Atypical femoral fractures associated with long-term bisphosphonate use

A 75-year-old woman with osteoporosis presented with a 2-year history of anterior thigh pain that was worse when standing and walking. She had taken alendronate for more than 20 years, which was replaced with annual zoledronic acid infusions for the last 3 years. On examination, she had an antalgic

Characterization and incidence on acute phase reaction in Paget's disease after zoledronic acid infusion

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

25-OH vitamin D and [gamma]-[delta] TCR lymphocyte interplay in the pathogenesis of acute phase reaction after zoledronic acid infusion for osteoporosis treatment

25-OH vitamin D and [gamma]-[delta] TCR lymphocyte interplay in the pathogenesis of acute phase reaction after zoledronic acid infusion for osteoporosis treatment

Effect on bone turnover markers of once-yearly intravenous infusion of zoledronic acid versus daily oral risedronate in patients treated with glucocorticoids

Long-term glucocorticoid use is accompanied by rapid bone loss; however, early treatment with bisphosphonates prevents bone loss and reduces fracture risk. The aim of this study was to examine the effects of two bisphosphonates, i.v. zoledronic acid (ZOL) versus oral risedronate (RIS), on bone turnover markers (BTMs) in subjects with glucocorticoid-induced osteoporosis (GIO). Patients were randomly stratified according to the duration of pre-study glucocorticoid therapy [prevention subpopulation (ZOL, n = 144; RIS, n = 144) ≤3 months, treatment subpopulation (ZOL, n = 272; RIS, n = 273) >3 months]. Changes in β-C-terminal telopeptides of type 1 collagen (β-CTx), N-terminal telopeptide of type I collagen (NTx), procollagen type 1 N-terminal propeptide (P1NP) and bone-specific alkaline phosphatase (BSAP) from baseline were measured on day 10 and months 3, 6 and 12. At most time points, there were significantly greater reductions (P < 0.05) in the concentrations of serum β-CTx, P1NP and BSAP and urine NTx in subjects on ZOL compared with RIS in both males and females of the treatment and prevention subpopulations. In pre- and post-menopausal women, there were significantly greater reductions in the concentrations of BTMs with ZOL compared with RIS. At 12 months, ZOL had significantly greater reductions compared with RIS (P < 0.05) for β-CTx, P1NP, BSAP and NTx levels, independent of glucocorticoid dose. Once-yearly i.v. infusion of ZOL 5 mg was well tolerated in different subgroups of GIO patients. ZOL was non-inferior to RIS and even superior to RIS in the response of BTMs in GIO patients. ClinicalTrials.gov, http://clinicaltrials.gov, NCT00100620.

Home-based zoledronic acid infusion therapy in patients with solid tumours: compliance and patient–nurse satisfaction

This study aimed to explore patient and nurse satisfaction, compliance with best practice, technical feasibility and safety of home infusion of the bisphosphonate zoledronic acid (ZOL). This was a prospective 1-year survey of home ZOL therapy (4 mg Zometa, 15-min i.v., every 3-4 weeks) in patients with bone metastases secondary to a solid malignancy. A physician questionnaire, nurse satisfaction/feasibility questionnaire and patient satisfaction questionnaire were administered at several time-points. Physician participation rate was 56.5% (87/154). Physicians enrolled 818 patients visited by 381 predominantly community nurses. Of the 788 case report forms received, 763 met inclusion criteria. Patient characteristics were as follows: median age, 68 years (30-95); M/F, 40/60; ECOG-PS 0 or 1, 78.6%; and primary tumour site, breast (55.2%), prostate (28.4%), lung (7.2%) or other (9.4%). Nurse satisfaction rates were high: organisation of home ZOL therapy, 90.9%; ease of infusion, 96.7%; patient-nurse relationship, 97.5%; and relationship with hospital staff, 73%. Patient satisfaction was also very high (95.3%). The main reasons were quality of the nurse-patient relationship (57.6%), less travel/waiting (68.8%), home environment (52.9%) and less disruption to daily routine (36.6%). ZOL therapy was well tolerated, the discontinuation rate due to adverse events (including deaths whether related to diseases progression or not) was 33.6%. The incidence of osteonecrosis of the jaw was 0.6% and of fractures, 0.2%. Practitioner compliance with best practice was 76.7-83.7% for recommended and/or tolerated dosage, 73% for dental hygiene checks at inclusion and 48-56% thereafter, 66% for pre-infusion hydration, and often undocumented for calcium/vitamin D supplementation. Home ZOL therapy was well tolerated. Both patient and nurse satisfaction were very high. However, better compliance with best practice should be encouraged.

Reduction in the Risk of Clinical Fractures After a Single Dose of Zoledronic Acid 5 Milligrams

Annual infusions of zoledronic acid 5 mg over 3 years have been shown to reduce fracture incidence. There is now evidence that the effects of a single dose of zoledronic acid on bone mineral density and bone turnover last for much more than a year. Whether this is associated with sustained fracture prevention is not known. The objective of the study was to assess fracture incidence after only 1 infusion of zoledronic acid. The design of the study included post hoc analysis of subgroups of subjects from 2 trials, who received only 1 study infusion. The study included multicenter, randomized controlled trials. A total of 1367 subjects from HORIZON-PFT and HORIZON-RFT studies who received only 1 of the planned annual infusions participated in the study. The intervention of the study consisted of 1 infusion of zoledronic acid or placebo. Clinical fracture was the main outcome measure of the study. Mean follow-up period was 1.5 years. In patients who received only a single infusion, there was a 32% reduction in clinical fracture comparing zoledronic acid with placebo over 3 years of follow-up (95% confidence interval 2-53%, P = .04), comparable with the fracture reduction seen in those who had 3 or more annual infusions (34%; 95% confidence interval, 23-43%, P < .0001). New morphometric vertebral fractures were reduced by 68% in the single-infusion group (P = .004). The between-group differences in total hip bone mineral density at 3 years were 3.8% in those receiving 1 infusion and 6.2% in those receiving 3 infusions. In this post hoc analysis based on postrandomization subgroups, fracture risk appears to be reduced for more than 1 year after a single infusion of zoledronic acid. Prospective studies designed to assess this possibility are now warranted.

Recalcitrant Hyperkalaemia Associated with a Single Dose Administration of Zoledronic Acid for Treatment of Post-Menopausal Osteoporosis

Hyperkalaemia is a very rare complication associated with zoledronic acid. We report the case of a patient with hyperkalaemia recalcitrant to treatment. A 72 year-old woman who was diagnosed with post-menopausal severe osteoporosis following a bone mineral density scan was treated with a single dose of zoledronic acid infusion. After 3 weeks, the patient’s serum potassium level increased from a baseline of 3.8 mmol/L to 5.9 mmol/L. Renal function was normal and all other possible causes of hyperkalaemia were excluded. She was started on oral sodium polystyrene sulfonate 15 g twice daily. Her serum potassium level remained persistently elevated over the next 9 weeks before it finally returned to a normal level on the 13th week after zoledronic acid infusion. We recommend close monitoring and prompt treatment of hyperkalaemia should it occur.

Osteonecrosis of the jaw in a patient taking once-yearly infusion of zoledronic acid for osteopenia

Osteonecrosis of the jaw (ONJ) is an adverse effect of nitrogen-containing bisphosphonates. Advancing age, intravenous administration of zoledronic acid (ZOL), history of dento-alveolar surgery, and concomitant systemic diseases such as diabetes are known as risk factors for developing ONJ. However, despite numerous studies, the exact pathophysiology remains unclear and management strategies are largely anecdotal. Once-yearly intravenously administered 5 mg ZOL was approved by the US Food and Drug Administration in 2007 for the treatment of osteoporosis and its efficacy with 3 year-regimen had been recently proven in preventing new clinical fracture. Although occurrences of ONJ have been reported to be rare with this drug administration, available data is very limited and long-term outcomes are lacking. We present a case of ONJ identified in an osteopenic patient with an intermittent but long standing sore mouth related to exposed mandibular bone. Once-yearly infusion of zoledronic acid used in the treatment of osteopenia may contribute to the spontaneous development of ONJ, especially in those presenting with multiple comorbidity factors. This report suggests the importance of health care professionals keeping abreast of new developments in this area and providing appropriate information to their patients.

Intravenous Bisphosphonates for Postmenopausal Osteoporosis: Safety Profiles of Zoledronic Acid and Ibandronate in Clinical Practice

Intravenous bisphosphonates are widely used for treatment of postmenopausal osteoporosis. They are associated with transient influenza-like symptoms, predominantly after the first zoledronic acid (up to 32 %) or ibandronate (up to 5 %) administration. The experience in clinical practice suggests that the incidence of post-dose symptoms is higher than has been reported in clinical trials. We assessed the safety of annual infusions of zoledronic acid and 3-monthly injections of ibandronate in women with postmenopausal osteoporosis. In this retrospective study we analysed safety data from 272 postmenopausal women treated with zoledronic acid (n = 127; mean age 68.6 ± 9.4 years) or intravenous (IV) ibandronate (n = 145; mean age 69.1 ± 9.0 years). Safety data (including occurrence of acute-phase reactions and osteonecrosis of the jaw) were gathered in phone call interviews by using a standardized questionnaire. The number of patients with adverse events was significantly higher in zoledronic acid as compared to ibandronate-treated patients, primarily because of a larger number of post-dose symptoms after bisphosphonate administrations (54.3 % vs. 33.1 %, p < 0.001). Except for occurrence of fever (more common after zoledronic acid infusion), other influenza-like symptoms (myalgia, arthralgia, headache) appeared in a similar proportion of patients after IV treatment (within 24-36 h). Symptoms lasted for >3 days in approximately 50 % of patients. The incidence of symptoms decreased after subsequent infusions. The rate of influenza-like symptoms was more frequent after zoledronic acid than after IV ibandronate in bisphosphonate-naïve patients but comparable in patients pretreated with oral bisphosphonates. There were no spontaneous reports of osteonecrosis of the jaw, arrhythmia or delayed fracture healing. Although IV bisphosphonates are generally safe, the occurrence of transient influenza-like symptoms after IV bisphosphonates seems to be more frequent in clinical practice than has been reported in clinical trials.

Prospective Observational Study of 110 Multiple Myeloma (MM) Patients On Monthly Versus 3 Monthly Infusion of Zoledronic Acid

AbstractAbstract 4245 Introduction:Osteonecrosis of the jaw (ONJ) is a recognized risk of bisphosphonate infusion; the incidence, etiology, risk factors and pathophysiology remains largely undefined. In this prospective study we evaluated patients on long-term zoledronic acid infusions; the aims of the study were to provide a comprehensive clinical, oral/dental assessment of patients prospectively and sequentially measure changes in zoledronic acid PKs, cytokines, microbial signatures and bone turnover markers in saliva and serum in correlation with 2 major clinical end points development of ONJ and myeloma relapse. Methods and patients:Over 6 months 110 patients were enrolled and followed for 18 months. Patients were on zoledronic acid infusions: monthly (n=75) for patients with significant bone disease (relapsed or newly diagnosed) or every 3 months (n=35) for those in stable remission > 3years. During the study follow up therapy was changed to pamidronate (n=4) due to renal insufficiency or denosumab (n=1). Patients had clinical and oral evaluations and saliva and blood samples collected at baseline and every 3 months up to 18 months; saliva samples were obtained before and after (5 and 15 minutes) zoledronic acid infusions. Results:Median time from MM diagnosis was 3.7 years (range: 1.5–13) for 100 patients; 10 newly diagnosed patients were enrolled as control with a median of 7 months (range: 1–9). Median age was 60 yrs (range: 32–82); 60 were Caucasians, 49 African American, one Asian; 68 were males. At study entry 79% of the patients were in remission: CR (n=35, 32%) of them 15 were in CR for > 7 years, PR (n=52, 47%) and PD (n=23, 21%). Twenty-four patients were not receiving any MM therapy; most were on maintenance with lenalidomide (n=52) or thalidomide (n=11) and the rest on other regimens (n=23). Fifty patients progressed during the 18 month study period; they continued the study with various salvage therapies that included: bortezomib (n=14), carfilzomib (n=14), lenalidomide (n=6) and clinical trails (n=16). Thirteen patients had died: 9 from complications of relapsed MM and 4 from other causes. Eighteen patients withdrew consent for sample collection and dental evaluations but were followed clinically. Most patients had prior-to-study entry dental procedures (extractions, n=80). The prevalent oral pathology detected on dental evaluations included: gingivitis (n=41), moderate/severe periodontal disease (n=35) and gross dental caries (n=15). During the 18 months of observation; 13 patients developed ONJ. Median time from MM diagnosis to ONJ was 5.7 years (range: 1.9–12 years). Risk factors for ONJ were relapsed disease (n=11), monthly zoledronic acid (n=8), dental extractions (n=8), severe periodontal disease (n=9), older age [median age was 62 yrs] and prior ONJ (n=3). ONJ treatment was conservative with antibiotics and holding BP therapy: 9 patients had complete healing of the site of ONJ and 4 had persistent non-healing ONJ lesions. Sequential saliva and serum samples were assessed for various cytokines involved in immune/inflammatory process (IL-1β, IL-6, IL-17, TNF-α, IFN-α, TGF-β, MIP-1 α β, MMP-9); bone turnover (Osteopontin, ostiocalcin, RANKL, Osteoprotregerin) and angiogenesis factors (VEGF and EGF) in 42 patients with ONJ (n=13), severe periodontal disease (n=10) and normal control (n=19), the later included 10 patients in remission and 9 with relapsed MM. In conclusion:In this longitudinal observational study, the ONJ incidence was 11%, 70% eventually healed. Our cytokine analysis suggest that saliva may accurately detect changes reflective of mucosal inflammation as well as bone turnover markers; data correlating these changes with ONJ and MM status will be presented. Disclosures:No relevant conflicts of interest to declare.

Effects of 3 years treatment with once-yearly zoledronic acid on the kinetics of bone matrix maturation in osteoporotic patients

Once-yearly administration of intravenous zoledronic acid for 3years in humans affects the kinetics of matrix filling in by mineral, independent of bone turnover. Yearly 5-mg infusions of zoledronic acid (ZOL) for 3years have shown pronounced antifracture efficacy. The purpose of the present study was to test whether ZOL affects the kinetics of forming bone material properties maturation. Iliac crest biopsies from the HORIZON-PFT clinical trial were analyzed by Raman microspectroscopy in actively bone-forming surfaces as a function of tissue age in trabecular and osteonal bone, to determine ZOL's effect on bone material quality indices maturation kinetics. Mineral/matrix ratio increased in both groups as a function of tissue age, at both osteonal- and trabecular-forming surfaces; ZOL exhibiting the greatest increase in the trabecular surfaces only. The proteoglycan content showed a dependency on tissue age in both trabecular and osteonal surfaces, with ZOL exhibiting lower values in the tissue age 8-22days in the trabecular surfaces. Mineral crystallinity (crystallite length and thickness) showed a dependence on tissue age, with ZOL exhibiting lower crystallite length compared with placebo only in the 8- to 22-day-old tissue at trabecular surfaces, while crystal thickness was lower in the 1- to 5-day-old tissue at both osteonal and trabecular surfaces. The results of the present study suggest that once-yearly administration of intravenous ZOL for 3years in humans does not exert any adverse effects on the evolution of bone material properties at actively forming osteonal and trabecular surfaces, while it may have a beneficial effect on the progression of the mineral-to-matrix ratio and mineral maturity bone quality indices.

Circulating activin-A is elevated in postmenopausal women with low bone mass: the three-month effect of zoledronic acid treatment

Activin-A is expressed in bone and seems to regulate osteoclastogenesis. In this study, serum activin-A was increased in postmenopausal women with low bone mass and was positively correlated to age and negatively to lumbar spinal bone mineral density (BMD). Serum activin-A levels did not change 3 months after zoledronic acid infusion. The aims of the study were to evaluate prospectively the circulating activin-A levels in postmenopausal women with low bone mass and explore possible correlations with clinical and laboratory data, as well as the 3-month effect of zoledronic acid infusion. Postmenopausal women with low bone mass assigned to receive zoledronic acid infusion (Patients, n = 47) and age-matched, postmenopausal women with normal bone mass (Controls, n = 27) were recruited on an outpatient basis. Main outcome measurement was serum activin-A levels. Serum activin-A was higher in patients at baseline compared to controls (p < 0.001) and activin-A in the serum of patients and controls was positively correlated with age (Spearman's coefficient of correlation [rs] = 0.325; p = 0.005) and negatively with lumbar spinal (LS) BMD (rs = -0.425; p < 0.001). In multiple linear regression analysis, only age (B = 8.93; 95 % CI = 4.39-13.46; p < 0.001) was associated with serum activin-A levels at baseline, independent from group (patients or controls), previous anti-osteoporotic treatment, LS BMD and follicle-stimulating hormone. Circulating activin-A levels were not affected 3 months after zoledronic acid infusion. Serum activin-A is increased in postmenopausal women with low bone mass compared with postmenopausal women with normal bone mass and is positively correlated to age and negatively to LS BMD.