The impact of acute-phase reaction on mortality and re-fracture after zoledronic acid in hospitalized elderly osteoporotic fracture patients.

This study involving 674 elderly osteoporotic fracture (OPF) patients undergoing orthopedic surgery investigated the long-term outcomes of acute phase reaction (APR) after initial zoledronic acid (ZOL). Those who had an APR had a 97% higher risk of mortality and a 73% lower rate of re-fracture than patients who did not. INTRODUCTION: Annual infusion of ZOL efficiently decreases the risk of fracture. A temporary APR, consisting of flu-like symptoms, myalgia, and fever, is frequently observed within 3 days after the first dose. This work aimed to identify whether the occurrence of APR after initial ZOL infusion is a reliable indicator of drug efficacy for mortality and re-fracture in elderly OPF patients undergoing orthopedic surgery. METHODS: This retrospectively observed work was constructed on a database prospectively collected from the Osteoporotic Fracture Registry System of a tertiary level A hospital in China. Six hundred seventy-four patients 50 years old or older with newly identified hip/morphological vertebral OPF who received ZOL for the first time after orthopedic surgery were included in the final analysis. APR was identified as a maximum axillary body temperature greater than 37.3 °C for the first 3 days after ZOL infusion. We utilized models of multivariate Cox proportional hazards to compare the risk of all-cause mortality in OPF patients with APR (APR+) and without APR (APR-). Competing risks regression analysis was used to examine the association between the occurrence of APR and re-fracture when mortality was taken into account. RESULTS: In a fully adjusted Cox proportional hazards model, APR+ patients had a significantly higher risk of death than APR- patients with a hazard ratio [HR] 1.97 (95% CI, 1.09-3.56; P-value = 0.02). Furthermore, in an adjusted competing risk regression analysis, APR+ patients had a significantly reduced risk of re-fracture compared with APR- patients with a sub-distribution HR, 0.27 (95% CI, 0.11-0.70; P-value = 0.007). CONCLUSIONS: Our findings suggested a potential association between the occurrence of APR and increased mortality risk. An initial dose of ZOL following orthopedic surgery was found to be protective against re-fracture in older patients with OPFs.

Zoledronic acid-induced severe lymphopenia.

Although anemia, thrombocytopenia, and mild lymphopenia have been reported in the acute phase response after zoledronic acid, severe lymphopenia has not been reported. This article describes a case of severe lymphopenia following a 5 mg zoledronic acid infusion administered to treat osteoporosis. Zoledronic acid is used to treat osteoporosis, hypercalcemia, Paget's disease, and solid malignancies, including multiple myeloma, breast cancer, and prostate cancer. An acute phase response can be seen in 42% of patients after zoledronic acid treatment. Acute phase response may be accompanied by short-term spontaneously recovered anemia, thrombocytopenia, and severe lymphopenia.

Acute phase response following pulmonary exposure to soluble and insoluble metal oxide nanomaterials in mice.

BACKGROUND: Acute phase response (APR) is characterized by a change in concentration of different proteins, including C-reactive protein and serum amyloid A (SAA) that can be linked to both exposure to metal oxide nanomaterials and risk of cardiovascular diseases. In this study, we intratracheally exposed mice to ZnO, CuO, Al2O3, SnO2 and TiO2 and carbon black (Printex 90) nanomaterials with a wide range in phagolysosomal solubility. We subsequently assessed neutrophil numbers, protein and lactate dehydrogenase activity in bronchoalveolar lavage fluid, Saa3 and Saa1 mRNA levels in lung and liver tissue, respectively, and SAA3 and SAA1/2 in plasma. Endpoints were analyzed 1 and 28 days after exposure, including histopathology of lung and liver tissues. RESULTS: All nanomaterials induced pulmonary inflammation after 1 day, and exposure to ZnO, CuO, SnO2, TiO2 and Printex 90 increased Saa3 mRNA levels in lungs and Saa1 mRNA levels in liver. Additionally, CuO, SnO2, TiO2 and Printex 90 increased plasma levels of SAA3 and SAA1/2. Acute phase response was predicted by deposited surface area for insoluble metal oxides, 1 and 28 days post-exposure. CONCLUSION: Soluble and insoluble metal oxides induced dose-dependent APR with different time dependency. Neutrophil influx, Saa3 mRNA levels in lung tissue and plasma SAA3 levels correlated across all studied nanomaterials, suggesting that these endpoints can be used as biomarkers of acute phase response and cardiovascular disease risk following exposure to soluble and insoluble particles.

Predicting the acute-phase response fever risk in bisphosphonate-naive osteoporotic patients receiving their first dose of zoledronate.

INTRODUCTION: To devise a precise and efficient tool for predicting the individualized risk of acute-phase response (APR) in bisphosphonate (BP)-naive osteoporotic (OP) patients, receiving their first intravenous dose of zoledronate (ZOL). METHODS: The baseline clinical and laboratory data of 475 consecutive BP-naive OP patients, who received their first intravenous dose of ZOL between March 2016 and March 2021 in the Affiliated Kunshan Hospital of Jiangsu University, were chosen for analysis. Univariate and multivariable logistic regression models were generated to establish candidate predictors of APR fever risk, using three distinct fever thresholds, namely, 37.3 °C (model A), 38.0 °C (model B), and 38.5 °C (model C). Next, using predictor regression coefficients, three fever-threshold nomograms were developed. Discrimination, calibration, and clinical usefulness of each predicting models were then assessed using the area under the curve (AUC), calibration curve (CC), and decision curve analysis (DCA). The internal and external model validations were then performed. RESULTS: The stable predictors were age, serum 25-hydroxy vitamin D, serum total calcium, and peripheral blood erythrocytes count. These were negatively associated with the APR fever risk. The AUCs of models A, B, and C were 0.828 (95% confidence intervals [CI], 0.782 to 0.874), 0.825 (95% CI, 0.767 to 0.883), and 0.879 (95% CI, 0.824 to 0.934), respectively. Good agreement was observed between the predictions and observations in the CCs of all three nomograms. CONCLUSIONS: This study developed and validated nomogram prediction models that can predict APR fever risk in BP-naive OP patients receiving their first infusion of ZOL.

A New Role of Acute Phase Proteins: Local Production Is an Ancient, General Stress-Response System of Mammalian Cells.

The prevailing general view of acute-phase proteins (APPs) is that they are produced by the liver in response to the stress of the body as part of a systemic acute-phase response. We demonstrated a coordinated, local production of these proteins upon cell stress by the stressed cells. The local, stress-induced APP production has been demonstrated in different tissues (kidney, breast cancer) and with different stressors (hypoxia, fibrosis and electromagnetic heat). Thus, this local acute-phase response (APR) seems to be a universal mechanism. APP production is an ancient defense mechanism observed in nematodes and fruit flies as well. Local APP production at the tissue level is also supported by sporadic literature data for single proteins; however, the complex, coordinated, local appearance of this stress response has been first demonstrated only recently. Although a number of literature data are available for the local production of single acute-phase proteins, their interpretation as a local, coordinated stress response is new. A better understanding of the role of APPs in cellular stress response may also be of diagnostic/prognostic and therapeutic significance.

Zoledronate promotes inflammatory cytokine expression in human CD14-positive monocytes among peripheral mononuclear cells in the presence of γδ T cells.

Bisphosphonates distributed to bone exert toxic effects specifically towards osteoclasts. On the other hand, intravenous administration of a nitrogen-containing bisphosphonate (N-BP) such as zoledronate induces acute-phase reactions (APRs), including influenza-like fever 1 day later, indicating an interaction with immunocompetent cells circulating blood. Although it has been reported that activation of γδ T cells is pivotal to induce an APR following treatment with zoledronate, downstream events, including the production of inflammatory cytokines after activation of γδ T cells, remain obscure. We investigated the effects of zoledronate on inflammatory cytokine expression in human peripheral blood mononuclear cells (PBMCs) in vitro. While zoledronate induced mRNA expressions of tumour necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6 and interferon-γ (IFN-γ) in PBMC, depletion of γδ T cells abolished that zoledronate-induced expression of those cytokines, indicating the necessity of γδ T cells for expression induction by zoledronate. However, which types of cells were responsible for the production of those cytokines in blood remained unclear. As it is generally accepted that monocytes and macrophages are primary sources of inflammatory cytokines, CD14+ cells from PBMC were exposed to zoledronate in the presence of PBMC, which resulted in induced expression of mRNAs for IL-1ß, IL-6 and IFN-γ, but not for TNF-α. These results indicate that CD14+ cells are responsible, at least in part, for the production of IL-1ß, IL-6 and IFN-γ in blood exposed to zoledronate. This suggests that CD14+ cells play an essential role in the occurrence of APRs following N-BP administration.

Fracture Prevention with Zoledronate in Older Women with Osteopenia.

BACKGROUND: Bisphosphonates prevent fractures in patients with osteoporosis, but their efficacy in women with osteopenia is unknown. Most fractures in postmenopausal women occur in those with osteopenia, so therapies that are effective in women with osteopenia are needed. METHODS: We conducted a 6-year, double-blind trial involving 2000 women with osteopenia (defined by a T score of -1.0 to -2.5 at either the total hip or the femoral neck on either side) who were 65 years of age or older. Participants were randomly assigned to receive four infusions of either zoledronate at a dose of 5 mg (zoledronate group) or normal saline (placebo group) at 18-month intervals. A dietary calcium intake of 1 g per day was advised, but calcium supplements were not provided. Participants who were not already taking vitamin D supplements received cholecalciferol before the trial began (a single dose of 2.5 mg) and during the trial (1.25 mg per month). The primary end point was the time to first occurrence of a nonvertebral or vertebral fragility fracture. RESULTS: At baseline, the mean (±SD) age was 71±5 years, the T score at the femoral neck was -1.6±0.5, and the median 10-year risk of hip fracture was 2.3%. A fragility fracture occurred in 190 women in the placebo group and in 122 women in the zoledronate group (hazard ratio with zoledronate, 0.63; 95% confidence interval, 0.50 to 0.79; P<0.001). The number of women that would need to be treated to prevent the occurrence of a fracture in 1 woman was 15. As compared with the placebo group, women who received zoledronate had a lower risk of nonvertebral fragility fractures (hazard ratio, 0.66; P=0.001), symptomatic fractures (hazard ratio, 0.73; P=0.003), vertebral fractures (odds ratio, 0.45; P=0.002), and height loss (P<0.001). CONCLUSIONS: The risk of nonvertebral or vertebral fragility fractures was significantly lower in women with osteopenia who received zoledronate than in women who received placebo. (Funded by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12609000593235 .).

Addition of dexamethasone to manage acute phase responses following initial zoledronic acid infusion.

Acute phase response (APR), including myalgia, influenza-like symptoms, headache, arthralgia, and pyrexia, is the most common adverse reaction to initial zoledronic acid infusion. Dexamethasone plus acetaminophen is effective in significantly reducing the incidence and severity of APR. INTRODUCTION: Acute phase response (APR), including myalgia, influenza-like symptoms, headache, arthralgia, and pyrexia, is due to immunomodulatory actions and is the most common adverse reaction to zoledronic acid (ZOL). The aims of our study were to compare the differences between acetaminophen and dexamethasone plus acetaminophen on the incidence and severity of APRs and to clarify the clinical factors related to APR with initial ZOL infusion. METHODS: Patients with osteoporosis receiving their first ZOL infusion (N = 96) were assigned into two groups and given either acetaminophen (58 patients, control group) or acetaminophen plus dexamethasone (38 patients, study group). APRs were assessed through telephone interviews 2 weeks later post-infusion. Clinical, demographic, and serologic data were recorded. RESULTS: There was a significant increase in the incidence and severity of any APR in the control group than the study group (67% vs. 34%, p = 0.003; 0.69 ± 0.50 vs. 0.34 ± 0.48, p = 0.001). Among the APRs, only myalgia incidence and score were significantly higher in the control group than in the study group. Multivariate analysis demonstrated that previous use of osteoporosis medication and participation in the study group was negatively related to the occurrence of any APR or myalgia. Advanced age was shown to significantly increase myalgia. Study group participants had significantly reduced severity of myalgia. The adherence for redosing ZOL was significantly higher in the study group. CONCLUSION: Dexamethasone plus acetaminophen is effective in significantly reducing the incidence and severity of APR, especially myalgia, and increasing adherence following initial ZOL infusion.

Acute Phase Reactions After Intravenous Infusion of Zoledronic Acid in Japanese Patients with Osteoporosis: Sub-analyses of the Phase III ZONE Study.

In a clinical trial involving Japanese patients with osteoporosis, post hoc analyses were performed to evaluate the incidence of acute phase reactions (APRs) after infusion of zoledronic acid (ZOL). The results highlighted differences in baseline factors between patients with vs without APRs. Changes in efficacy indicators such as bone turnover markers (BTMs) also showed significant differences. We, therefore, investigated the factors involved in the development of APRs in Japanese patients treated with a once-yearly intravenous infusion of ZOL 5 mg for 2 years by assessing the relation between APRs and efficacy. APRs reported in patients with primary osteoporosis from the ZONE study were analyzed post hoc. Baseline factors were compared in patients with vs without APRs, and changes in BTMs and bone mineral density (BMD) were also investigated. In the ZOL group, 51.2% (169/330) of patients developed APRs after the first infusion and 12.3% (33/268) after the second infusion. Comparison of baseline factors showed that patients without APRs in the ZOL group had a significantly higher neutrophil/lymphocyte ratio, lower serum levels of procollagen type I N-terminal propeptide, older age, and higher likelihood of prior bisphosphonate use vs patients with APRs. Patients with APRs showed significantly higher increases in total hip BMD at 6 and 12 months and larger reductions in BTMs vs patients without APRs. Patient profiles differed significantly between patients with vs without APRs, with APRs after the first infusion of ZOL being related to increases in total hip BMD and suppression of BTMs.This study is registered with ClinicalTrials.gov (identifier: NCT01522521; January 31, 2012).

Ozone-induced acute phase response in lung versus liver: the role of adrenal-derived stress hormones.

Acute-phase response (APR) is an innate stress reaction to tissue trauma or injury, infection, and environmental insults like ozone (O3). Regardless of the location of stress, the liver has been considered the primary contributor to circulating acute-phase proteins (APPs); however, the mechanisms underlying APR induction are unknown. Male Wistar-Kyoto rats were exposed to air or O3 (1 ppm, 6-hr/day, 1 or 2 days) and examined immediately after each exposure and after 18-hr recovery for APR proteins and gene expression. To assess the contribution of adrenal-derived stress hormones, lung and liver global gene expression data from sham and adrenalectomized rats exposed to air or O3 were compared for APR transcriptional changes. Data demonstrated serum protein alterations for selected circulating positive and negative APPs following 2 days of O3 exposure and during recovery. At baseline, APP gene expression was several folds higher in the liver relative to the lung. O3-induced increases were significant for lung but not liver for some genes including orosomucoid-1. Further, comparative assessment of mRNA seq data for known APPs in sham rats exhibited marked elevation in the lung but not liver, and a near-complete abolishment of APP mRNA levels in lung tissue of adrenalectomized rats. Thus, the lung appears to play a critical role in O3-induced APP synthesis and requires the presence of circulating adrenal-derived stress hormones. The relative contribution of lung versus liver and the role of neuroendocrine stress hormones need to be considered in future APR studies involving inhaled pollutants.

Exposure to different fractions of diesel exhaust PM2.5 induces different levels of pulmonary inflammation and acute phase response.

AIM: Ambient fine particulate matter (PM2.5) consists of various components, and their respective contributions to the toxicity of PM2.5 remains to be determined. To provide specific recommendations for preventing adverse effects due to PM2.5 pollution, we determined whether the induction of pulmonary inflammation, the putative pathogenesis for the morbidity and mortality due to PM2.5 exposure, was fractioned through solubility-dependent fractioning. METHODS: In the present study, the water and heptane solubilities-dependent serial fractioning of diesel exhaust particulate matter (DEP), a prominent source of urban PM2.5 pollution, was performed. The pro-inflammatory actions of these resultant fractions were then determined using both an intratracheal instillation mouse model and cultured BEAS-2B cells, a human bronchial epithelial cell line. RESULTS: Instillation of the water-insoluble, but not -soluble fraction elicited significant pulmonary inflammatory and acute phase responses, comparable to those induced by instillation of DEP. The water-insoluble fraction was further fractioned using heptane, a polar organic solvent, and instillation of heptane-insoluble, but not -soluble fraction elicited significant pulmonary inflammation and acute phase responses. Furthermore, we showed that DEP and water-insoluble DEP, but not water-soluble DEP, activated pro-inflammatory signaling in cultured BEAS-2B cells, ruling out the possibility that the solubility impacts the in vivo distribution and thus the pulmonary inflammatory response.

Acute Phase Response as a Biological Mechanism-of-Action of (Nano)particle-Induced Cardiovascular Disease.

Inhaled nanoparticles constitute a potential health hazard due to their size-dependent lung deposition and large surface to mass ratio. Exposure to high levels contributes to the risk of developing respiratory and cardiovascular diseases, as well as of lung cancer. Particle-induced acute phase response may be an important mechanism of action of particle-induced cardiovascular disease. Here, the authors review new important scientific evidence showing causal relationships between inhalation of particle and nanomaterials, induction of acute phase response, and risk of cardiovascular disease. Particle-induced acute phase response provides a means for risk assessment of particle-induced cardiovascular disease and underscores cardiovascular disease as an occupational disease.

Osteoporosis in the age of COVID-19.

As the world grapples with the crisis of COVID-19, established economies and healthcare systems have been brought to their knees. Tough decisions regarding redirection of resources away from the management of conditions deemed "nonessential" are being made. How can we balance urgent resourcing of our acute crisis while not abandoning the real need of patients with osteoporosis? This article offers a few practical solutions.

Effects of physicochemical properties of TiO2 nanomaterials for pulmonary inflammation, acute phase response and alveolar proteinosis in intratracheally exposed mice.

Nanomaterial (NM) characteristics may affect the pulmonary toxicity and inflammatory response, including specific surface area, size, shape, crystal phase or other surface characteristics. Grouping of TiO2 in hazard assessment might be challenging because of variation in physicochemical properties. We exposed C57BL/6 J mice to a single dose of four anatase TiO2 NMs with various sizes and shapes by intratracheal instillation and assessed the pulmonary toxicity 1, 3, 28, 90 or 180 days post-exposure. The quartz DQ12 was included as benchmark particle. Pulmonary responses were evaluated by histopathology, electron microscopy, bronchoalveolar lavage (BAL) fluid cell composition and acute phase response. Genotoxicity was evaluated by DNA strand break levels in BAL cells, lung and liver in the comet assay. Multiple regression analyses were applied to identify specific TiO2 NMs properties important for the pulmonary inflammation and acute phase response. The TiO2 NMs induced similar inflammatory responses when surface area was used as dose metrics, although inflammatory and acute phase response was greatest and more persistent for the TiO2 tube. Similar histopathological changes were observed for the TiO2 tube and DQ12 including pulmonary alveolar proteinosis indicating profound effects related to the tube shape. Comparison with previously published data on rutile TiO2 NMs indicated that rutile TiO2 NMs were more inflammogenic in terms of neutrophil influx than anatase TiO2 NMs when normalized to total deposited surface area. Overall, the results suggest that specific surface area, crystal phase and shape of TiO2 NMs are important predictors for the observed pulmonary effects of TiO2 NMs.

Efficacy of non-steroidal anti-inflammatory drugs on zoledronic acid-induced acute-phase reactions: randomized, open-label, Japanese OZ study.

INTRODUCTION: Zoledronic acid infusion is used to treat osteoporosis but patients, especially Japanese patients, often experience acute-phase reactions (APRs). In this multicenter, randomized, open-label, parallel-group study, we examined the efficacy of the most commonly used non-steroidal anti-inflammatory drug loxoprofen in Japan in reducing the incidence rate of zoledronic acid-induced APRs and body temperature, and investigated risk/protective factors for APRs in this population. MATERIALS AND METHODS: Patients aged ≥ 60 years with primary osteoporosis (n = 368) were allocated randomly to zoledronic acid plus loxoprofen (ZOL + LOX) or zoledronic acid alone (ZOL). All patients received 5-mg zoledronic acid infusion on day 1, and patients in the ZOL + LOX group also received 120 mg and 180 mg of oral loxoprofen on days 1 and 2, respectively. Adverse events and body temperature were recorded during the 7-day observation period. RESULTS: The incidence rates of APRs were 34.4% (64/186 patients) and 47.8% (87/182 patients) in the ZOL + LOX and ZOL groups, respectively (P = 0.0109). The proportions of patients with increased body temperature (≥ 1 °C and ≥ 37.5 °C) were similar in both groups (P = 0.1186). Past bisphosphonate users had a significantly lower incidence rate of APRs than treatment-naïve patients (odds ratio 0.444, 95% confidence interval 0.285-0.692, P = 0.0003). CONCLUSIONS: Zoledronic acid-induced APRs appeared to be suppressed by loxoprofen. Known risk/protective factors, including prior osteoporosis treatment, were applicable to Japanese patients.

The Acute Phase Response Is a Prominent Renal Proteome Change in Sepsis in Mice.

(1) Background: Sepsis-induced acute kidney injury (AKI) is the most common form of acute kidney injury (AKI). We studied the temporal profile of the sepsis-induced renal proteome changes. (2) Methods: Male mice were injected intraperitoneally with bacterial lipopolysaccharide (LPS) or saline (control). Renal proteome was studied by LC-MS/MS (ProteomeXchange: PXD014664) at the early phase (EP, 1.5 and 6 h after 40 mg/kg LPS) and the late phase (LP, 24 and 48 h after 10 mg/kg LPS) of LPS-induced AKI. Renal mRNA expression of acute phase proteins (APP) was assessed by qPCR. (3) Results: Renal proteome change was milder in EP vs. LP. APPs dominated the proteome in LP (proteins upregulated at least 4-fold (APPs/all): EP, 1.5 h: 0/10, 6 h: 1/10; LP, 24 h: 22/47, 48 h: 17/44). Lipocalin-2, complement C3, fibrinogen, haptoglobin and hemopexin were the most upregulated APPs. Renal mRNA expression preceded the APP changes with peak effects at 24 h, and indicated renal production of the majority of APPs. (4) Conclusions: Gene expression analysis revealed local production of APPs that commenced a few hours post injection and peaked at 24 h. This is the first demonstration of a massive, complex and coordinated acute phase response of the kidney involving several proteins not identified previously.

Adrenal crisis after first infusion of zoledronic acid: a case report.

Patients with Addison's disease are at greater risk of having reduced bone mineral density and hip fractures and are thus more likely to receive a bisphosphonate than their peers. Potent intravenous bisphosphonates could provoke an acute phase reaction. An 80-year-old female with Addison's disease received her first infusion of zoledronic acid for osteoporosis at our outpatient clinic around noon. Despite doubling her usual afternoon hydrocortisone dose, she became feverish, nauseous, extremely weak, and hypotensive over the night. When transported to the nearest general hospital the next morning, the patient was found to have signs of hypovolemic shock and she was admitted to the ICU. Crystalloid infusion, followed by dobutamine and norepinephrine drip, had no effect. Only after her European emergency card for glucocorticoid cover was found, adrenal crisis was recognized, and she was immediately given an intravenous bolus of hydrocortisone followed by continuous hydrocortisone infusion. The patient rapidly improved and was transferred to a regular ward the next day, where hydrocortisone dose was gradually tapered. Our experience might suggest that patients with Addison's disease should probably start their treatment with zoledronic acid in a hospital setting. Their usual oral dose of hydrocortisone should be doubled or even tripled. Careful monitoring of these patients seems to be warranted, and intravenous hydrocortisone should be given if any symptoms or signs of the imminent adrenal crisis are noted.

Editorial: dose-dependent ZnO particle-induced acute phase response in humans warrants re-evaluation of occupational exposure limits for metal oxides.

Epidemiological studies link inhalation of particles to increased risk of cardiovascular disease. Inhaled particles may induce cardiovascular disease by several different mechanisms including translocation of particles to systemic circulation, activation of airway sensory nerves resulting in autonomic imbalance and particle-induced pulmonary inflammation and acute phase response.The acute phase response is the systemic response to acute and chronic inflammatory states caused by for example bacterial infection, virus infection, trauma and infarction. It is characterized by differential expression of ca. 50 different acute phase proteins including C-reactive protein and Serum amyloid A, which are the most differentially up-regulated acute phase response proteins. Blood levels of these two acute phase proteins are closely associated with risk of cardiovascular disease in epidemiological studies and SAA has been causally related to the formation of plaques in the aorta in animal studies.In a recent paper in Particle and Fibre Toxicology, Christian Monsé et al. provide evidence that inhalation of ZnO nanoparticles induces dose-dependent acute phase response in humans at dose levels well below the current mass-based occupational exposure limits in a number of countries including Germany, The Netherlands, UK, Sweden, Denmark and the US.Given the evidence suggesting a causal relationship between increased levels of serum amyloid A and atherosclerosis, the current results call for a re-evaluation of occupational exposure limits for a number of particle exposures including ZnO taking induction of acute phase response into account. Furthermore, it underscores cardiovascular disease as an occupational disease.

Concentration-dependent systemic response after inhalation of nano-sized zinc oxide particles in human volunteers.

BACKGROUND: Inhalation of high concentrations of zinc oxide particles (ZnO) may cause metal fume fever. In an earlier human inhalation study, no effects were observed after exposure to ZnO concentrations of 0.5 mg/m3. Further data from experimental studies with pure ZnO in the concentration range between 0.5 and 2.5 mg/m3 are not available. It was the aim of this experimental study to establish the concentration-response relationship of pure nano-sized ZnO particles. METHODS: Sixteen healthy subjects were exposed to filtered air and ZnO particles (0.5, 1.0 and 2.0 mg/m3) for 4 h on 4 different days, including 2 h of cycling with a low workload. The effects were assessed before, immediately after, and about 24 h after each exposure. Effect parameters were symptoms, body temperature, inflammatory markers and clotting factors in blood, and lung function. RESULTS: Concentration-dependent increases in symptoms, body temperature, acute phase proteins and neutrophils in blood were detected after ZnO inhalation. Significant effects were detected with ZnO concentrations of 1.0 mg/m3 or higher, with the most sensitive parameters being inflammatory markers in blood. CONCLUSION: A concentration-response relationship with nano-sized ZnO particles in a low concentration range was demonstrated. Systemic inflammatory effects of inhaled nano-sized ZnO particles were observed at concentrations well below the occpational exposure limit for ZnO in many countries. It is recommended to reassess the exposure limit for ZnO at workplaces.

ACUTE PHASE REACTIONS AFTER ZOLEDRONIC ACID INFUSION: PROTECTIVE ROLE OF 25-HYDROXYVITAMIN D AND PREVIOUS ORAL BISPHOSPHONATE THERAPY.

OBJECTIVE: The most common adverse reaction to zoledronic acid (ZOL) infusion is the acute phase reaction (APR), characterized by transient, usually mild, flu-like symptoms. Previous treatment with oral amino-bisphosphonates (BPs) was reported as an independent protective factor for APR, and an association between APR and 25-hydroxyvitamin D (25(OH)D) levels in BP-naïve patients treated with ZOL was identified. The aims of our study were to confirm this association and to see if it was different in patients previously treated with oral BPs compared with BP-naïve patients and to investigate the role of 25(OH)D for the time of APR onset. METHODS: We included 153 consecutive patients with postmenopausal osteoporosis undergoing their first ZOL infusion. Sixty-eight had been previously treated with oral BPs. Clinical, demographic, and serologic data were recorded. RESULTS: 25(OH)D levels were significantly lower in patients experiencing APR compared to patients without APR (26.3 ± 12.7 vs. 37.0 ± 13.5 ng/mL, respectively; P<.0001). Patients with 25(OH)D <30 ng/mL had a significantly higher risk of APR (odds ratio [OR] 4.2 [95% confidence interval [CI] 2.1-8.2]) occurring in 65%. APR was significantly less frequent in patients previously treated with oral BPs than in BP-naïve subjects (33.8% [23/68] vs 52.9% [45/85], P = .018), but only a weak association remained after correction for 25(OH)D (OR 0.5, 95% CI 0.3-1.1, P = .08). CONCLUSION: Higher baseline 25(OH)D levels appear to be protective for APR post-ZOL infusion. The role of previous treatment with oral BPs as an independent protective factor for APR should be evaluated in a larger cohort. ABBREVIATIONS: APR = acute phase reaction; BPs = amino-bisphosphonates; CI = confidence interval; 25(OH)D = 25-hydroxyvitamin D; OP = osteoporosis; OR = odds ratio; PTH = parathyroid hormone; ROC = receiver operating characteristic; ZOL = zoledronic acid.