Multicenter Study on Observation of Acute‐phase Responses After Infusion of Zoledronic Acid 5 mg in Chinese Women with Postmenopausal Osteoporosis

Abstract

Objective

It has been reported that acute‐phase reactions (APR) after infusion of 5 mg zoledronic acid for the first time is common. This study surveyed the incidence and characteristics of APR in Chinese postmenopausal women receiving 5 mg zoledronic acid intravenously for osteoporosis and to evaluate the efficacy of non‐steroidal anti‐inflammatory drugs (NSAID) in preventing or alleviating APR following the first 5 mg zoledronic acid infusion.

Methods

A total of 2601 patients with an average age of 68.14 ± 9.89 years and a mean body mass index of 22.90 ± 3.24 kg/m² from 62 centers in China were treated with 5 mg zoledronic acid intravenously for the first time. The incidence of fever and pain were observed in these patients, and the time of fever or pain onset and duration, and the intensity of fever and grade of pain were also recorded. The dosage, duration, and efficacy of NSAID and safety outcomes were also documented.

Results

At the end of the study, 18 patients are eliminated due to incomplete records of temperature. The incidence of fever was 28.65% (740/2583) within 7 days following zoledronic acid infusion; 98.34% (727/740) occurred at 1.03 ± 0.66 days after infusion and lasted 1.72 ± 0.93 days. A total of 456 (17.53%) patients had newly onset pain (312 of 1187, 26.28%) or experienced pain aggravation (144 of 1414, 10.18%), which mostly occurred within 3 days after zoledronic acid infusion. A total of 1246 (47.6%) patients had received NSAID for a median time of 2.63 ± 2.45 days. Using NSAID for at least 2 days could decrease body temperature by 0.54 ± 0.86°C, increase the percentage of pain‐free patients by 6.17%, and reduce the percentage of patients with moderate to severe pain by 8.7%.

Conclusions

Compared with Western populations, Chinese patients had a higher rate of fever and pain after their first zoledronic acid infusion. These symptoms were often mild to moderate in intensity and transient in duration. NSAID could effectively reduce the incidence and severity of such APR.

Introduction

The first generation of bisphosphonates, such as etidronic acid used to curing pediatric fibrous dysplasia (reported on in Lancet in 1969), have been associated with severe side‐effects. After dozens of years of development, the third generation of bisphosphonates, including alendronic acid, sodium ibandronate, risedronate sodium, and zoledronic, are more safe and stable. In 2010, bisphosphonates comprised nearly 50% of the treatments for osteoporosis in the UK1. Bisphosphonates are now the most widely used medications for the treatment of osteoporosis, and are classified into two groups based on their structures. First generation bisphosphonates do not contain nitrogen, while new generation biphosphonates have a nitrogen‐containing side chain and, therefore, are named aminobisphosphonates. The structure has a high affinity for the hydroxyapatite at the bone surface, so the biphosphonates can remain at the bone surface for months or even years. Biphosphonates inhibit the activity of osteoclast, inducing osteoclast apoptosis; eventually, they inhibit the absorption of bone. They have been proved to successfully improve bone mineral density, and reduce the risk of fractures2.

Zoledronic acid is a new generation biphosphonate that contains nitrogen. Zoledronic acid is used to prevent or treat osteoporosis in women who have undergone menopause and is also used to treat osteoporosis in men, and to prevent or treat osteoporosis in men and women who are taking glucocorticoids. It can be administered intravenously once yearly for the treatment of osteoporosis. After intravenous injection, zoledronic acid gathers quickly into the active bone transformation regions. In the first 24 h, 39% ± 16% of the first dose appeared in the urine and was excreted. The rest of the drugs mainly combined with bone tissue. Afterwards, the drug was slowly released from bone tissue into the systemic circulation system, and to the kidneys for elimination.

Gastro‐esophageal irritation3 and nephrotoxicity4 have been recognized as potential long‐term side effects of bisphosphonates. In addition, bisphosphonate use may be associated with clinically serious problems, including osteonecrosis of the jaw5 and atypical femoral fractures. Based on a huge number of evidence‐based medical studies, a “bisphosphonates holiday” has been suggested to avoid those long‐term side effects. However, determining the benefits of such a break requires further study6.

Intravenous infusion with zoledronic acid may result in transient post‐infusion symptoms similar to those associated with mild‐to‐moderate influenza‐like symptoms. These symptoms are also referred to as acute‐phase reactions (APR), which are characterized by fever, headache, and musculoskeletal pain, and are typically transient. These symptoms usually occur within 72 h after the infusion and are much less likely to occur after later doses than after the first infusion7. These symptoms usually lasted no more than 1 week, with or without symptomatic treatment.

The exact cause of APR induction by bisphosphonates is currently unknown but may be related to the inhibition of farnesyl pyrophosphate synthase in the HMG‐CoA reductase pathway8 and of the suppressor of cytokine signaling‐3 in the macrophages8. Published data indicated that the stimulation of proinflammatory cytokines, such as interleukin‐6 (IL‐6) and tumor necrosis factor α (TNF‐α), and interferon γ (INF‐γ) were involved in the pathogenesis of bisphosphonate‐induced APR9, 10, 11, 12, 13.

According to the results of the HORIZON‐Pivotal Fracture Trial, a phase 3 trial to evaluate the use of zoledronic acid osteoporosis, 20.3% of patients had a fever within 3 days of receiving their first dose, and 19.9% of patients had musculoskeletal pain8. In analyzing the data of a subgroup of postmenopausal women with osteoporosis from Taiwan and Hong Kong who were part of the HORIZON‐Pivotal Fracture Trial, Jawl‐Shan Hwang found the incidence of fever, arthralgia, myalgia, and headache within 3 days after receiving their first dose of zoledronic acid to be 28.2%, 21.5%, 14.7%, and 6.8%, respectively8. Some studies have found that acetaminophen, as well as other non‐steroidal anti‐inflammatory drugs (NSAID), are effective in reducing the incidence and severity of APR following zoledronic acid infusion8, 10. Another study in China focused on 58 postmenopausal osteoporosis patients who were treated with 5 mg of zoledronic acid injection intravenously and followed up between March 2009 and December 2010. Results showed that the early side effects of zoledronic acid included fever (48.3%), muscle pain (25.9%), headache (41.4%), and joint pain (24.2%). The total rate of side effects was 60.3%. The author emphasized that the symptoms they observed were all transient and vanished within 30 days after injection. Bone mineral density (BMD) and osteoporosis fracture were irrelevant to the rates of side effects14. However, the cases were few and the characteristics of the symptoms were not classified in detail.

In a previous study, APR has been reported in a HORIZON‐Pivotal Fracture Trial. However, because the incidence and characteristics of APR following the first intravenous zoledronic acid infusion have not been investigated in Chinese mainland populations, we designed this open label, multicenter, post‐marketing observational study. The aim of the present study was: (i) to clarify the characteristics of APR of 5 mg intravenous zoledronic acid in the treatment of postmenopausal osteoporosis in the Chinese mainland population; (ii) to assess the efficacy of NSAID for dealing with the APR; (iii) to evaluate the safety of 5 mg intravenous zoledronic acid for osteoporosis, including any adverse events. Furthermore, we hope that it can offer some valuable insight for Chinese doctors when treating postmenopausal osteoporosis in the Chinese mainland population using zoledronic acid.

Methods

Study Design

This study was an open label, multicenter, post‐marketing observational study involving postmenopausal women with osteoporosis in mainland China over a 4‐week period. A total of 2601 patients at an average age of 68.14 ± 9.89 years and a mean body mass index of 22.90 ± 3.24 kg/m² from 62 centers in China were treated with 5 mg intravenous zoledronic acid for the first time.

Study Populations

Women with postmenopausal osteoporosis eligible for intravenous zoledronic acid were eligible for inclusion if they had a bone mineral density T score of −2.5 or less, or a T score of −1.5 or less plus fragility fracture history. Meanwhile, they had to be capable of monitoring and recording basic data on their body temperature and the intensity of pain by themselves or with the help of others according to the requirements of the study. Exclusion criteria were as follows: patients who were contradicted to zoledronic acid or who were allergic to any components of zoledronic acid or other bisphosphonates regiments; patients with a serum total calcium level of less than 2.13 mmol/L (8.5 mg/dL), or a serum‐free calcium level of less than 0.95 mmol/L (3.8 mg/dL), or untreated hypocalcemia; patients with a Cockcroft calculated creatinine clearance of less than 35 mL/min; and patients who refuse to take zoledronic acid, those with causes of osteoporosis other than postmenopausal osteoporosis, pregnant or lactating women, and patients with other diseases with an unstable status. All patients were informed of the details of the study and provided written informed consent.

Study Methods

Intravenous zoledronic acid was given at a dose of 5 mg over 15 min, and calcium and vitamin D were given as a basic supplementation following the infusion. Medical history, including fracture history and intake of NSAID, were assessed, and physical examination was performed prior to the infusion. Axillary temperature at baseline and at every morning within 7 days after the infusion was recorded. In addition, patients recorded their body temperature every morning until it returned to normal for 3 days. If their body temperature rose above 38°C, patients were advised to take NSAID; meanwhile, they were required to re‐measure their body temperature within 4 h after the administration of NSAID. A pain grade self‐assessment at baseline and every day within 2 weeks after the infusion of zoledronic acid was also determined, which ranged from grade 1 to grade 5, meaning from without pain or pain‐naïve to mild, moderate, severe, and extreme pain. If patients experienced an increase in pain intensity by more than 1 grade, they were also advised to take NSAID to relieve the pain. In addition to being used to relieve the pain and fever, NSAID were used for prophylactic reasons immediately following the infusion in some patients. All patients were assessed for the inclination to accept another course of zoledronic acid infusion 1 year later. Fever was defined as an increase in body temperature of at least 1°C compared with the basal value.

End Points

The primary endpoints were the incidence of fever and pain, as well as the intensity, the time of occurrence and duration of these acute‐phase responses. Secondary end points included: the dosage of NASID used for preventing APR or alleviating the symptoms of APR, the course of treatments and their efficacy; changes in patient’s adherence to zoledronic acid therapy following the occurrence of APR; and the incidence and intensity of ARP in patients younger than 75 years old. All adverse events (AE) were assessed and recorded, and physical examinations and laboratory tests were obtained for a safety evaluation.

Statistics Analysis

Descriptive statistical analysis was used to determine the incidence, intensity, time of occurrence, and duration of fever and pain. Quantitative variables were described as mean ± standard deviation (SD); the paired sample t‐test or the Wilcoxon signed rank test was used for within‐group comparisons of quantitative variables. Categorical variables were described as numbers and/or percentages; the Wilcoxon matched pairs signed rank test was used for within‐group comparison of categorical variables. All statistical test parameters were two‐sided and values of P < 0.05 were considered statistically significant. All statistical analysis was performed using SAS software (version 9.1.3).

Results

A total of 2709 patients from 62 medical centers in China participated in this study; 2601 of them were included in the analysis. The mean age of patients was 68.14 ± 9.89 years, the mean body mass index was 22.90 ± 3.24 kg/m², and the baseline body temperature was 36.51 ± 0.31°C. Before receiving intravenous zoledronic acid, 1414 (54.36%) patients experienced pain, 986 (37.91%) patients had a history of fracture, and 1323 (50.87%) of the patients had received previous anti‐osteoporosis therapy, including bisphosphonates (127, 9.94%), active vitamin D (925, 72.35%), calcitonin (480, 37.56%), strontium (5, 0.39%), estrogen (5, 0.39%), and others (276, 21.6%); 116 (6.40%) patients had a family history of osteoporosis and 155 (5.96%) patients had connective tissue disease.

Fever and Pain

Eighteen of the patients were eliminated from the fever analysis because of non‐complete recording of body temperature information, resulting in a total of 2583 patients being included in the final analysis of fever. A total of 740 (28.65%) patients experienced fever within 7 days after zoledronic acid infusion, and 727 (98.34%) of had developed fever within 3 days. Fever started at 1.03 ± 0.66 days after infusion and lasted for 1.72 ± 0.93 days. Respectively, the body temperatures of patients with fever were: lower than 37°C (7, 0.95%), between 37°C and 37.9°C (361, 48.78%), between 38°C and 38.9°C (335, 45.27%), and rarely higher than 39°C (37, 5%).

A total of 2601 were included in the analysis of pain. Before zoledronic acid infusion, 1414 (54.36%) patients experienced pain at baseline, including 852 (32.76%) with mild, 483 (18.57%) with moderate, 76 (2.92%) with severe, and 3 (0.12%) with extreme pain. A total of 456 (17.53%) patients had newly developed pain (312 of 1187, 26.28%) or experienced pain aggravation (144 of 1414, 10.18%), mostly occurring within 3 days after zoledronic acid infusion (95.19% and 90.97%). Newly developed pain typically lasted 4.59 ± 5.26 days. The pain remission rate was 98.08% (306 of 312) in patients with newly developed pain and 89.18% (1261 of 1414) in patients who experienced pain aggravation, respectively. The percentage of pain‐free patients increased by approximately 38.34% within 2 weeks after zoledronic acid infusion (Fig. 1).

Figure 1.

The percentage of patients with different pain grade.

Patients were divided into a younger group (<75 years) with 777 patients and an older group (≥75 years) with 1806 patients. The incidence of fever in patients of 75 years or older was 4.53% lower than that in younger patients (200 of 777, 25.74% vs 547 of 1806, 30.29%, P = 0.0194). The incidence of fever at the first day was also higher in younger group than that in the older group (88 of 777, 11.33% vs 272 of 1806, 15.06%, P = 0.0119), whereas at the fifth and seventh day the incidence of fever was significantly higher in the older group (11 of 777, 1.41% vs 10 of 1806, 0.55%, P = 0.025; 4 of 777, 0.51% vs 1 of 1806, 0.06%, P = 0.015). The mean time of onset of fever in the younger group was day 1.00 ± 0.58, and day 1.09 ± 0.86 in the older group. There was no significant difference in the time of onset of fever within 7 days (P = 0.7498). The duration of fever between subgroups was also not significantly different (younger group: 1.68 ± 0.91 days, older group: 1.80 ± 1.00 days; P = 0.1423).

In patients without pain at baseline, newly developed pain occurred more frequently in the younger group than in the older group (older group: 73 of 357, 20.45% vs younger group: 239 of 830, 28.80%, P = 0.0027). The incidence of pain aggravation in patients with preexisting pain (older group: 37 of 426, 8.69% vs younger group: 107 of 988, 10.83%, P = 0.2212) was similar in these two subgroups.

The time distribution of newly developed pain was similar between subgroups (P = 0.7933; older group: 69 of 73, 94.52% vs younger group: 228 of 239, 95.40% during the first 3 days; 3 of 73, 4.11% vs 3 of 239, 1.26% during 4–8 days; 1 of 73, 1.37% vs 8 of 239, 3.35% during 8–14 days). The onset of time of newly developed pain was similar between subgroups (older group: 1.14 ± 1.66 days vs younger group: 1.22 ± 1.80 days, respectively, P = 0.7579). The duration of newly developed pain was also similar between subgroups (older group: 4.70 ± 5.76 days vs younger group: 4.55 ± 5.11 days, P = 0.6749). The time distribution, onset time, and duration of pain aggravation in subgroups was similar to those for newly developed pain.

Meanwhile, there were no significant differences in the pain remission rate between subgroups (older group: 72 of 73, 98.63% vs younger group: 234 of 239, 97.91% of newly developed pain, P = 1.0000; older group: 378 of 426, 88.73% vs younger group: 833 of 988, 89.37% of pain aggravation, P = 0.7222).

Efficacy of Non‐steroidal Anti‐inflammatory Drug Treatment

Among 1187 (45.64%) patients that received NSAID within 14 days after the infusion of zoledronic acid, 602 (50.72%) of these were for prophylactic reasons (prophylaxis group) and the remaining 585 (49.28%) patients were to control or alleviate the APR (treatment group). The incidence of fever and pain in the prophylaxis group and the non‐prophylaxis group are depicted in Table 1 (non‐prophylaxis group includes treatment group and non‐NSAID users). Not surprisingly, the incidence of fever and pain were significantly higher in the non‐prophylaxis group than in the prophylaxis group (30.47% vs 21.76%, P < 0.0001 and 20.31% vs 8.31%, P < 0.0001). The comparison of efficacy between the prophylaxis group and the treatment group is shown in Table 2. The most commonly used NSAID were ibuprofen (30.98%), acetaminophen (17.74%), loxoprofen (18.06%), celecoxib (12.36%), and diclofenac (8.59%). There was no significant difference in body temperature recovery time between patients using different types of NSAID.

Table 1.

The incidence of fever and pain in prophylaxis group and non‐prophylaxis group (treatment group and non‐steroidal anti‐inflammatory drug users)

	Prophylaxis group (n = 602) Number (%)	Non‐prophylaxis group (n = 1999) Number (%)	P‐value
Fever	131 (21.76)	609 (30.47)	<0.0001
Pain	50 (8.31)	406 (20.31)	<0.0001

Table 2.

The efficacy of non‐steroidal anti‐inflammatory drugs in prophylaxis group and treatment group

		Prophylaxis group (n = 131)	Treatment group (n = 487)	P‐value
Increased body temperature [Number (%)]	1°C–2°C	104 (79.39)	359 (73.72)	<0.0001
	>2°C	27 (20.61)	128 (26.28)	<0.0001
Rise in body temperature (°C)		1.73	1.82	<0.0001
Duration of fever (day)		1.51	1.83	<0.0001

Other Adverse Events

During this study, 71 (2.73%) adverse invents were reported, and the most frequently reported adverse events were gastrointestinal symptoms, including vomiting, nausea, and diarrhea. These symptoms were generally rated as mild or moderate. Sixty‐two (2.38%) of these reported adverse events were probably or certainly relevant to the study drug. One patient suffered severe pneumonia leading to death, which was considered not related to treatment with zoledronic acid. Over 96.8% of subjects intended to receive another course of zoledronic acid infusion 1 year later.

Discussion

From the present study it is evident that the incidence of APR is not rare after the first infusion of zoledronic acid. Although APR were common following intravenous zoledronic acid, with fever, pain, vomiting, nausea, and mild‐to‐moderate discomfort occurring, these symptoms would not become worse with continuing drug exposure. The use of NSAID can significantly reduce the incidence and severity of the post‐dose symptoms of zoledronic.

Fever and Pain

Other published research shows that the most frequently occurring APR during the first 3 days after the infusion of zoledronic acid were fever and pain, which is similar to what was found in our study7, 16, 17, 18. The horizon‐pivotal fracture trial was the largest trial in the phase 3 osteoporosis program for zoledronic acid, and this trial reported on the adverse events with cursory assessment of the APR. A study including 7765 postmenopausal women shows that APR was more common in non‐Japanese Asians, younger subjects, and NSAID drug users while less common in smokers, patients with diabetes, those who had previously used oral bisphosphonates, and in Latin Americans (P < 0.05)15. There are some studies focusing on alleviating APR as well16, 17, 18. A randomized clinical trial focused on Hong Kong and Taiwan populations showed that the incidence rate of post‐dose symptoms was significantly higher than for a placebo group16. A randomized, placebo‐controlled trial focused on 45–75 year‐old postmenopausal women with osteopenia showed significantly lower peak oral temperature and slower onset of elevation temperature as well as a faster resolution to baseline temperature in the acetaminophen/paracetamol or ibuprofen groups7. A prospective study from Greece, including 51 postmenopausal women with low bone mass were given a single i.v. infusion of 5 mg of zoledronic acid. Of the 51 patients, 28 (54.9%) experienced an APR, which was clinically defined by the visual analog pain scale for the musculoskeletal symptoms and body temperature17. Recently, the ZONE (ZOledroNate treatment in Efficacy to osteoporosis) Study including 665 Japanese patients administered 5 mg once yearly of zoledronic acid with primary osteoporosis was reported on; the occurrence of APR are given, such as pyrexia (39.3% and 2.7% in zoledronic acid and placebo groups, respectively), arthralgia (10.8% and 0.3%), myalgia (8.1% and 0%), malaise (7.8% and 1.8%), influenza‐like illness (6.9% and 0%), and headache (6.0% and 0.9%)18. However, the APR and safety of zoledronic and the effectiveness have not been investigated in the Chinese mainland population. Therefore, in the present study, we aimed to identify the incidence and characteristics of fever and pain in postmenopausal women of the Chinese mainland population, receiving 5 mg of zoledronic acid over 15 min intravenously for osteoporosis, and 5 mg to evaluate the efficacy of NSAID in preventing or alleviating fever and pain following zoledronic acid infusion. This study included more than 2000 postmenopausal women. In addition, considering the shortcomings of the published data, we tried to improve the study in some ways, such through the definition of fever, the scoring system for pain, and different efficacy of preventing or reducing the use of NSAID, and we observed the age‐related subgroup difference of APR as well.

In this study, we found that the incidence of fever within 7 days after zoledronic acid infusion was 30.47%, which was comparable with the results for Taiwan, Hong Kong, and Japanese postmenopausal women with osteoporosis reported previously by Shan Hwang (28.2%)19 and seemed higher in our population compared to the global data in the HORIZON PFT study reported by Reid et al. (17.2%)15. This discrepancy might be due to the different evaluation methods of fever. In the study of HORIZON, PFT fever was spontaneously reported by patients based on their feeling, whereas we actively measured the body temperature in our study. That may have led to the low fever rate in PFT compared to our study. Moreover, racial differences result in different BMI with the same does of zoledronic, and may also have an effect on fever or pain. The incidence of pain in any part of the body was 17.53%, which was slightly lower compared to the results reported by Reid et al. (19.9%)15 and Shan Hwang (≥21.5%)19. Our study found that newly developed pain and pain aggravation frequently occurred within 3 days after zoledronic acid infusion and using NSAID for 2 days could effectively alleviate the intensity of pain. Moreover, the proportion of pain‐free patients was increased by 38.34% at the 14th day following zoledronic acid infusion. This delayed pain alleviating effect may be related to the infusion of zoledronic acid, because the use of NSAID in subjects in this study lasted no more than 3 days.

Efficacy of Non‐steroidal Anti‐inflammatory Drug Treatment

We had analyzed the efficacy of NSAID treatment as well. The incidence rate of pain (8.31% vs 20.31%, P < 0.0001) and fever (21.26% vs 30.47%, P < 0.0001) is higher in the non‐prophylactic group. The rising level of body temperature (1.73°C vs 1.82°C, P < 0.0001) and duration of fever (1.81 days vs 1.83 days, P < 0.0001) is higher in the non‐prophylactic group as well.

In contrast, we noticed a phenomenon that the incidence of fever in an older subgroup (>75 years old) was significantly lower than that of a younger subgroup (<75 years old), and the onset of fever in the older subgroup (>75 years old) was significantly later as well. We had made an assumption that the lower activity of the proinflammatory cytokines system, which was supposed to be the cause of APR20, in the older subgroup led to this difference.

Limitations

There are some limitations in this study. First, as it is an observational study, a randomized controlled trial (RCT) is more appropriate and more powerful. Second, the evaluation system of pain is 5 degrees, which is different from the visual analogue scales. Further experimental studies can be conducted to confirm the conclusion of this study.

Conclusion

In conclusion, fever and pain were commonly observed acute‐phase responses associated with first zoledronic acid infusion, mostly mild to moderate and transient, and could be effectively prevented and alleviated by NSAID. In addition, the treatment with intravenous zoledronic acid had a favorable safety profile and was generally well tolerated.