Risk Factors for Acute Febrile Reaction after Zoledronic Acid Treatment for Prim

WU Hongliang ,ZHENG Sihang ,ZHANG Enchong ,HOSSAIN Mohammad Showkat ,GONG Helong ,XING Ruida ,JING Shengjie,LI Yan*

1 Department of Orthopaedics,Shengjing Hospital of China Medical University,Shenyang,Liaoning 110004,China;

2 The Second Clinical College of China Medical University,Shenyang,Liaoning 110004,China;

3 College of Basic Medicine,China Medical University,Shenyang,Liaoning 110122,China;

4 Yuncheng Central Hospital of Shanxi Medical University,Yuncheng,Shanxi 044099,China

ABSTRACT Objective:To investigate the characteristics and risk factors of acute febrile reaction after zole‐dronic acid treatment for primary osteoporosis.Methods:A total of 517 patients diagnosed with primary osteopo‐rosis and treated with zoledronic acid from January 2012 to December 2020 were recruited,including 40 males and 477 females,among whom 262 were with type Ⅰosteoporosis and 255 were with type Ⅱosteoposis,245 pa‐tients with mild-to-moderate osteoporosis,272 patients with severe osteoporosis,230 patients with fresh fracture,and 209 patients with operation.The two groups were compared,and the fever rate and clinical characteristics of fever were summarized and further analyzed in the aspects of gender,age,count of white blood cells,neutrophils,lymphocytes,neutrophil-lymphocyte ratio (NLR),type of osteoporosis,degree of osteoporosis,fracture,surgery intervention,medication history,etc.Multivariate Logistic regression analysis was conducted and ROC curve was drawn to explore the main risk factors for acute febrile reaction.Results:The 175 cases(33.85%)developed acute febrile reaction,most of which occurred within 36 hours after treatment,mainly low and moderate fever(<39 ℃),and the duration was generally no more than 60 hours.Univariate analysis showed significant differences in NLR,type and degree of osteoporosis,fresh fracture,surgery intervention,and zoledronic acid medication history be‐tween the fever and non-fever groups (P<0.05).There was no significant difference in gender,count of white blood cells,neutrophils and lymphocytes between the two groups (P>0.05). Logistic regression and ROC curve analysis showed that the surgery group had a higher fever rate (P<0.01,area under ROC curve was 0.65).The fracture group had a higher fever rate(P<0.05,area under ROC curve was 0.60).The group with type Ⅰosteopo‐rosis had a higher fever rate (P<0.01,area under ROC curve was 0.44).The group with medication history had a lower fever rate (P<0.01,area under ROC curve was 0.34).The fever rate of joint fracture group (56.60%) was significantly higher than spine fracture group(38.54%)(P<0.05).Conclusion:Surgery,fracture,type Ⅰosteopo‐rosis and first zoledronic acid medication might be independent risk factors of acute febrile reaction after medica‐tion.Patients who had surgery before medication (especially those with joint fracture surgery),fresh fracture,type Ⅰosteoporosis and first zoledronic acid medication,had a higher risk of acute febrile reaction.

KEY WORDS primary osteoporosis;zoledronic acid;acute febrile reaction;surgery;fracture;type of osteopo‐rosis

1 Introduction

Osteoporosis(OP)is a systemic bone disease charac‐terized by decreased bone mass,damage of bone mi‐crostructure,increased bone fragility,and prone to frac‐ture［1］.Over the past 10 years,the number of osteopo‐rosis patients in China has increased significantly.Os‐teoporotic fracture seriously endangers the health and quality of life of middle-aged and older people.At the present time,surgery combined with anti-osteoporosis treatment has become a recognized new principle of fracture treatment in this field.Moreover,bisphospho‐nate family is the first-line drug recommended by do‐mestic and foreign guidelines,among which zoledron‐ic acid,as the third generation representative product,can strongly inhibit bone resorption and reduce the in‐cidence of osteoporotic fracture［2］.Clinical observa‐tion for many years has confirmed the curative effect.However,acute-phase reaction (APR),especially fe‐ver,often occurs after medication.It greatly affects clinical treatment and patient compliance.

We observed in the clinical work that the incidence of acute febrile reaction in the treatment of primary osteoporosis with zoledronic acid is related to the sur‐gery before treatment,fresh fracture and type of osteo‐porosis,but people pay little attention to these prob‐lems.At present,most of the studies on febrile ad‐verse reactions after zoledronic acid treatment in os‐teoporosis are mainly conducted in the department of endocrinology,little attention has been paid to risk factors of surgery and fracture.In this study,we com‐bined the influencing factors in the department of or‐thopaedics with those in the field of internal medi‐cine.For OP patients who need surgery,how to choose the right time of administration has been a problem for orthopaedics surgeons.To gain more insight,this study retrospectively analyzed the characteristics and influencing factors of acute febrile reaction after zole‐dronic acid treatment for primary osteoporosis to pro‐vide a reference for clinical practice to help doctors better grasp the medication indications and medica‐tion plans.

2 Methods

2.1 Ethics statement

The Medical Ethics Committee of Shengjing Hospi‐tal of China Medical University approved this study（ethics application number:2021PS724K）and waived the need for informed consent in the study.All clini‐cal and laboratory variables included in this analysis were retrospectively collected.All the diagnosis and treatment methods mentioned in this study were all clinical routine methods,and did not change in the study.Patient records/information were anonymized before analysis,and all methods were carried out fol‐lowing relevant guidelines and regulations.Our re‐search was performed under the Declaration of Hel‐sinki.

2.2 Subjects

The clinical data of patients diagnosed with primary osteoporosis were collected (type Ⅰ:postmenopausal osteoporosis;type Ⅱ:senile osteoporosis) in Shengjing Hospital of China Medical University from Jan‐uary 2012 to December 2020.Bone mineral density was measured by dual-energy X-ray absorptionmetry（DXA）,and the machine model was discovery.

According to guidelines for diagnosis and treatment of primary osteoporosis(2017)［3］,those who meet one of the following three criteria can be diagnosed as pri‐mary osteoporosis:1)Brittle fracture of the hip or ver‐tebral body;2)Tvalue of bone mineral density of axi‐al bone or distal 1/3 of radius bone measured by dualenergy X-ray absorptiometry is less than-2.5;3)Bone mineral density:-2.5

Diagnostic criteria for severe osteoporosis:1)tvalue of bone mineral density measured by dual-energy X-ray absorptiometry ≤-3.5.2) The degree of bone mineral density reduction was following the diagnos‐tic criteria of osteoporosis.At the same time,there were one or more brittle fractures,i.e.,tvalue ≤-2.5+brittle fracture.

Inclusion criteria:1) Patients with type Ⅰand typeⅡosteoporosis who met the diagnostic criteria of guidelines for diagnosis and treatment of primary os‐teoporosis in 2017;2) Intravenous infusion of zole‐dronic acid.

Exclusion criteria:1)Secondary osteoporosis,meta‐static cancer and other metabolic bone diseases;2) Not using vitamin D and calcium before zoledronic acid treatment;3)Insufficient hydration before and af‐ter zoledronic acid treatment by intravenous infusion of 0.9% sodium chloride injection;4) The body tem‐perature did not return to normal before discharge from hospital.

2.3 Treatment methods

All patients were given a 5 mg zoledronic acid in‐jection by intravenous drip.The infusion tube main‐tained a constant rate of 20-30 drops per minute,and the infusion time was 30-60 min.Before and after ad‐ministration,500-1 000 mL normal saline was given by intravenous drip for complete hydration.

2.4 Observation indexes

The included patients underwent blood routine tests,liver and kidney function (and the creatinine clearance rate was calculated),blood phosphorus,blood calcium,electrocardiogram,and other tests,and no apparent abnormalities were found.The number of patients with fever and the exact body temperature during fever,the beginning time and duration of fever were recorded.Body temperature ≥37 ℃was considered as fever,with 37-38 ℃as low fever,38-39 ℃as moderate fever and ≥39 ℃as high fever.The corre‐lation between acute febrile reaction and gender,count of leukocytes,neutrophil,lymphocyte,neutrophil-lym‐phocyte ratio (NLR),type of osteoporosis,degree of osteoporosis,fresh fracture,and surgery intervention were analyzed.

2.5 Statistical methods

The collected data were input into Excel software.SPSS 25.0 software was used for statistical analysis.The data conforming to the normal distribution were described as means±standard deviation and compared by independent samplet-test.The data that did not conform to the normal distribution were described by the median (interquartile spacing) and compared by nonparametric test (Mann WhitneyUtest).Thechisquare test was used to determine the association be‐tween the categorical variables.MultivariateLogisticregression analysis was used for multivariate analysis.Receiver operating cure(ROC)curve was used to ana‐lyze the factors with a significant difference.WhenP<0.05,the difference was statistically significant.Graph‐Pad Prism 8.0 drawing software was used to draw the diagrams.

3 Results

3.1 Clinical data of patients

Among the 517 patients who met the inclusion cri‐teria,there were 40 males and 477 females,with an average age of (68.69±9.19) years and an average BMD of (-3.18±0.92).Among female patients,those younger than 70 years old were classified as type Ⅰosteoporosis,and those older than 70 years old were classified as type Ⅱosteoporosis.See Table 1 for spe‐cific grouping information.

Table 1 Grouping information

3.2 Characteristics of acute febrile reaction in⁃duced by zoledronic acid

In this study,among 517 patients,175 patients de‐veloped acute febrile reaction.The fever rate was 33.85%.The average fever temperature was (38.15±0.74) ℃.There were 59 cases of low fever (37.58%),73 cases of moderate fever (46.50%) and 25 cases of high fever (15.92%).The average occurrence time of acute febrile reaction was (16.08±15.08) h,and it oc‐curred between 0 and 12 h in 236 cases (45.65%),be‐tween 12 and 36 h in 269 cases (52.03%),and over 36 h in 12 cases(2.32%)after administration.The average duration of acute febrile reaction was (29.54±21.65) h.The duration of acute febrile reaction in 133 cases was 0 to 12 hours (25.73%).The duration in 206 cases was 12 to 36 hours (39.85%).The duration in 137 cases was 36 to 60 hours (26.50%).The dura‐tion in 41 cases was over 60 hours (7.93%).(Figure 1-2)

Figure 1 Distribution of fever degree and occurrence time of acute febrile reaction after zoledronic ac⁃id treatment for primaty osteoporosis

Figure 2 Distribution of duration of acute febrile reaction after zoledronic acid treatment for primaty os⁃teoporosis

3.3 Univariate analysis of various influencing fac⁃tors on acute febrile reaction induced by zole⁃dronic acid

The results showed that there was significant dif‐ference in age between fever group and non-fever group (P<0.05).The average age of fever group was lower than that of non-fever group.The results showed no significant differences in the number of white blood cells,neutrophils,and lymphocytes before zoledronic acid administration between patients in the fever group and non-fever group (P>0.05).However,the mean NLR of patients in the fever group was higher than that in the non-fever group,and the difference be‐tween the two groups was statistically significant (P<0.05).See Table 2.

Table 2 Comparison of age and inflammatory indexes between two groups before medication（）

Table 2 Comparison of age and inflammatory indexes between two groups before medication（）

Data analysis also showed that the average value of NLR before medication of the surgery group was higher than that of the non-surgery group,and the dif‐ference was significant (P<0.001).The average value of NLR of the fracture group before medication was higher than that of the non-fracture group,and the dif‐ference was significant(P<0.005).See Table 3.The re‐sults suggest that fracture and surgery intervention may promote acute febrile reaction after zoledronic acid administration by enhancing the body's inflam‐matory response.

Statistical analysis showed that the fever rate of pa‐tients with type ⅠOP was significantly higher than that of patients with type ⅡOP(P=0.008).The fever rate of patients with severe OP was significantly higher than that of patients with mild-to-moderate OP(P=0.005),the fever rates of patients with fresh frac‐ture or surgery were significantly higher than those of patients without them (P=0.000).The fever rate of pa‐tients with past zoledronic acid use history was signifi‐cantly lower than patients without zoledronic acid use history (P=0.000).There was no significant difference in fever rate between male and female patients (P=0.592).See Table 4.

Table 3 Comparison of NLR values between different groups before medication（）

Table 3 Comparison of NLR values between different groups before medication（）

Table 4 Influence of various factors on acute febrile reaction induced by zoledronic acid in treatment of primary osteoporosis

3.4 Multivariate Logistic regression analysis of candidate risk factors

Kappaconsistency test was performed for the two factors of fracture and surgery,and theKappavalue was 0.6,indicating consistency.The two factors should not be included in the multivariateLogisticregression analysis at the same time.

3.4.1 Correlation analysis between type of osteopo‐rosis,degree of osteoporosis,fracture,zoledronic acid medication history and acute febrile reaction

Among all factors,acute febrile reaction was taken as the dependent variable,and type of osteoporosis,degree of osteoporosis,fracture,and zoledronic acid medication history were taken as the independent vari‐ables.Results in Table 5 showed that fracture,type of osteoporosis,and zoledronic acid medication history were the independent influencing factors of acute fe‐brile reaction.

Table 5 Multivariate Logistic regression analysis of the influencing factors of acute febrile reaction after medication 1

3.4.2 Correlation analysis between type of osteopo‐rosis,degree of osteoporosis,surgical intervention,zoledronic acid medication history and acute febrile reaction

Among all factors,acute febrile reaction was taken as the dependent variable,and type of osteoporosis,degree of osteoporosis,surgical intervention,and zole‐dronic acid medication history were taken as the inde‐pendent variables.Results in Table 6 showed that sur‐gical intervention,type of osteoporosis,and zoledron‐ic acid medication history were the independent influ‐encing factors of acute febrile reaction.

Table 6 Multivariate Logistic regression analysis of the influencing factors of acute febrile reaction after medication 2

3.5 ROC curve analysis of independent risk fac⁃tors of acute febrile reaction

The results in Figure 3 showed that the areas under ROC curve of surgical intervention,fracture,type of osteoporosis,and zoledronic acid medication history were 0.65 (95%CI:0.61-0.70),0.60 (95%CI:0.55-0.66),0.44 (95%CI:0.39-0.49) and 0.34 (95%CI:0.29-0.39),respectively.

Figure 3 ROC curve analysis of independent risk factors of acute febrile reaction

3.6 Influence of surgical site on the acute febrile reaction of zoledronic acid

The fever rate of patients with joint fracture was significantly higher than those with spinal fracture among surgical patients treated with zoledronic acid(P=0.034).However,in the further comparison of fe‐ver rate within the group,there was no significant dif‐ference between patients with femoral neck and inter‐trochanteric fractures or between thoracic and lumbar fractures(P>0.05).See Table 7.

Table 7 Influence of surgical site on the acute febrile reaction of zoledronic acid

4 Discussion

At present,most researchers believe that zoledronic acid,an analog of pyrophosphate,has a strong affinity for bone,especially in the sites where osteoclasts are active and is easy to be absorbed by osteoclasts.Re‐ducing the adherence of osteoclasts on the bone sur‐face,zoledronic acid inhibits activity of osteoclasts,promotes apoptosis,and reduces osteolytic lesions and bone resorption.It has been suggested that zoledronic acid can induce the apoptosis of osteoclasts and their precursors by inhibiting the mevalonate pathway or interfering with the normal cell cycle,thus playing an anti-bone resorption role.Zoledronic acid inhibits the key enzyme of the malyvalic acid pathway in osteo‐clasts and prevents the isoprene of small G protein,which makes the osteoclasts unable to function nor‐mally and promotes their apoptosis.Bisp-hosphonates can bind to hydroxyapatite in bone,specifically to the bone surface where bone transformation is active and inhibit bone resorption by osteoclasts.Zoledronic acid is a representative drug of the third generation of ni‐trogen-containing bisphosphonates,which has a defi‐nite anti-osteoporosis effect and is widely used in clinics.Fever is the most common APR in the treat‐ment of osteoporosis with zoledronic acid by intrave‐nous drip.Zoledronic acid can inhibit farnil pyrophos‐phate synthetase,thereby preventing the conversion of geranyl pyrophosphate in osteoclasts to farnil pyro‐phosphate.The increased geranyl pyrophosphate acti‐vates γΔT cells in the body,causing them to release many inflammatory mediators,such as IL-6,TNF-a,and IFN-γ,resulting in fever and other symptoms［4-5］.

4.1 Characteristics of acute febrile reaction after zoledronic acid treatment

In this study,the incidence of acute febrile reaction in treating primary osteoporosis with zoledronic acid was 33.85%,and the fever degree was mainly low to medi‐um (85.08%).The onset of fever was mainly within 36 h (97.71%),and the duration of acute febrile reac‐tion was mostly within 60 h (92.06%).All patients with febrile reaction were well tolerated.

4.2 Univariate analysis

Univariate analysis of this study showed that NLR,type of osteoporosis,degree of osteoporosis,fresh fracture,surgery intervention,and history of zoledron‐ic acid use were associated with the acute febrile reac‐tion,which was statistically significant.There was no significant difference in the mean value of leukocytes,neutrophils,and lymphocytes between the fever and non-fever groups.There was no significant gender dif‐ference between the fever group and the non-fever group.The results showed that the higher the NLR value before zoledronic acid treatment,the more prone to acute febrile reaction.The fever rate of patients with type Ⅰosteoporosis was higher than that of pa‐tients with type Ⅱosteoporosis.The fever rate of pa‐tients with mild-to-moderate osteoporosis was higher than that of patients with severe osteoporosis.Fever rate was also higher in patients with fresh fracture.Pa‐tients with surgical intervention had a higher fever rate.Patients with no history of zoledronic acid use had a higher fever rate.

4.3 Multivariate Logistic regression analysis

In multivariateLogisticregression analysis,theKappaconsistency test was performed for the two fac‐tors of fracture and surgery,and theKappavalue was 0.6 indicating,there was consistency.Therefore the two factors should not be included in multivariateLo‐gisticregression analysis simultaneously.The results showed that surgery,fracture,type of osteoporosis,and zoledronic acid medication history were the main in‐fluencing factors of acute febrile reaction in treating primary osteoporosis in the department of orthopae‐dics.Surgery,fresh fracture,type Ⅰosteoporosis and first use of zoledronic acid were the risk factors of acute febrile reaction.The risk of fever was 1.62 times higher in patients with fracture than patients without fracture.The risk of fever was 2.00 times higher in surgical patients than in non-surgical pa‐tients.

4.4 ROC curve analysis

The ROC curve analysis showed that the most im‐portant factors affecting the happening of acute fe‐brile reaction were ranked as follows according to the area under ROC curve:surgery,fracture,type of os‐teoporosis,and zoledronic acid medication history.Therefore,the appropriate medication period can be selected according to the patient's condition to reduce the incidence of acute febrile reaction.

4.5 Summary and analysis of risk factors

4.5.1 NLR

In previous studies,the study of ÖZTÜRK Z A et al.［6］showed that NLR level in patients with osteopo‐rosis was significantly increased,suggesting that in‐flammation may play an important role in the occur‐rence and development of osteoporosis.In this study,the higher the NLR value before zoledronic acid treat‐ment,the more likely the patient was to have acute fe‐brile reaction.The higher the level of NLR before treatment,the stronger the chronic inflammatory re‐sponses of patients,and the more likely it was to cause APR by cooperating with the release of a large num‐ber of inflammatory mediators caused by ZOL intra‐venous infusion.It can be used as an index to predict APR before medication.

4.5.2 Type Ⅰosteoporosis

The study of KO Y et al.［7］showed that the secre‐tion of estrogen in postmenopausal women decreased,the RANKL/RANK/OPG signaling pathway was dis‐orderly,and the inflammatory factors such as interleu‐kin (IL) and TNF,which promoted bone resorption,were constantly increased in the body,leading to the increased expression of RNAKL in the microenviron‐ment of bone metabolism,thus accelerating bone loss.Furthermore,studies has shown that［8-9］,sex steroid hormones may participate in bone metabolism regu‐lating specific gene expression through negative feed‐back in the absence of estradiol (E2),thus accelerating the secretion of pituitary follicle-stimulating hormone(FSH).FSH can promote bone marrow cells,and im‐mune cells secrete tumor necrosis factor α (TNF-α)and interleukin (IL),stimulating bone resorption.Combined with our study,the high fever rate after zoledronic acid treatment in postmenopausal osteopo‐rosis patients may be related to the increase of inflam‐matory factors after estrogen deficiency in the body.

4.5.3 Zoledronic acid medication history

This study showed that the fever rate of patients with previous zoledronic acid medication was signifi‐cantly reduced,which was consistent with domestic and foreign studies.ROSSINI M et al.'s［10］study showed that total lymphocytes and their subsets were significantly reduced 2 days after ZOL infusion in pa‐tients receiving N-BP for the first time.These changes returned to baseline after 1 year,except for a signifi‐cant reduction in the proportion and an absolute num‐ber of γδT cells,suggesting for the first time that both intravenous and oral N-BP therapy are associated with a long-term reduction in circulating γδT cells,which may explain the lower incidence of APR in pa‐tients exposed to N-BP.

4.5.4 Fracture

A growing body of evidence［11-12］has suggested that congenital and adaptive immune responses are re‐quired for fracture healing.Immediately after injury,local infiltration of immune cells and immune media‐tors are required to remove necrotic tissue and initiate angiogenesis.Various cytokines,including interleu‐kin-1β,IL-6,IL-17,IL-23,and TNF-α,are expressed at different stages and play a role in treatment.This initial infiltration of immune cells subsequently sup‐presses the immune system,leading to enhanced dif‐ferentiation of osteoblast mesenchymal stem cells and regulatory T (Treg) cells,both of which inhibit the adaptive T cell response and achieve a hypoimmuno‐genic state at the healing site［13］.In our study,patients with fresh fracture had a higher fever rate after zole‐dronic acid treatment,which was considered to be re‐lated to the early local infiltration of immune cells and immune mediators and the increase of various in‐flammatory factors after fracture injury.This suggests that,for patients with complicated fractures,it is pos‐sible to determine whether new fractures occur,choose the appropriate treatment time,predict the occurrence of APR and do some work of prevention and treat‐ment.

4.5.5 Surgery

Studies have shown that surgical injury can put pa‐tients in a state of inflammatory reaction and increase inflammatory factors during the perioperative period.Different types of surgeries have different surgical sites and methods.The greater the injury to patients,the more the inflammatory factors increased.Com‐pared with open surgery,the increase of inflammatory factors in the patients undergoing minimally invasive surgery is lower.CASSUTO J et al.［14］showed that inflammatory mediators (CRP,IL-6,OPN) in patients undergoing joint replacement increased significantly on the first day after surgery and returned to baseline at 6 W.MARUNA P et al.［15］showed that the com‐mon basis of the systemic inflammatory response to surgical trauma is the activation of cytokine cascades accompanied by the release of soluble cytokine recep‐tors.The major cytokine axis stimulates the release of acute-phase protein (APP) from the liver,regulating metabolic pathways and hormonal responses.The study of LI H et al.［16］showed that the rapid rehabili‐tation surgical nursing program can effectively relieve the negative emotions and pain of patients with hip fractures and reduce inflammation.Our study showed that the higher fever rate of osteoporosis patients in the surgery group after zoledronic acid treatment might be related to the inflammatory state of the body after surgical injury and the increase of inflammatory factors,which were more likely to produce fever reac‐tion occuring together with the APR reaction caused by zoledronic acid.In our study,the fever rate of pa‐tients undergoing joint fracture surgery was 56.60%,and that of patients undergoing spinal fracture surgery was 38.54%,P<0.05.This may reflect that different surgical sites and methods have different effects of the inflammatory response.Total hip replacement and other joint surgeries are level 4 surgeries with a large degree of openness and greater damage than minimal‐ly invasive spinal surgery.In the perioperative period,the body has a higher inflammatory response,more in‐flammatory mediators are produced,and the synergis‐tic effect with zoledronic acid-induced APR reaction is stronger,which increases the fever rate.

This suggests that we should pay attention to the in‐creasing fever rate after zoledronic acid treatment in perioperative patients with a fracture or surgical inter‐vention in the department of orthopaedics.The timing of zoledronic acid treatment after surgery needs fur‐ther study,and it can also be combined with rapid re‐habilitation surgical nursing program.And for the pa‐tients with joint fracture surgery and open surgery,more attention should be paid.

The limitation of this study is that the collection of bone metabolism indicators is not enough,the postop‐erative medication time is not completely agreed.

5 Conclusion

When zoledronic acid is used to treat patients with primary osteoporosis,acute febrile reaction may occur.

1)The incidence of acute febrile reaction after zole‐dronic acid treatment was 33.85%.Acute febrile reac‐tion mostly occurs within 36 hours,and the duration of acute febrile reaction is mostly within 60 hours.2) In the department of orthopaedics,surgical inter‐vention,fresh fracture,type Ⅰpostmenopausal osteo‐porosis and the first use of zoledronic acid medication are the main independent risk factors of acute febrile response after zoledronic acid treatment for primary osteoporosis.3) The fever rate of patients with joint fracture was higher than that with spinal fracture;the fever rate of patients with lumbar fracture was higher than that with thoracic fracture.

It needs further studies to update the zoledronic ac‐id treatment plan and considers whether this medica‐tion should be administerd before surgery or after a period of time.Close attention should be paid close at‐tention to the patients prone to acute febrile reaction according to the above indicators.