美洛昔康与吲哚美辛防治全髋关节置换后异位骨化的比较

doi:10.3969/j.issn.2095-4344.2013.39.002

摘要/Abstract

摘要：

背景：为了避免全髋关节置换后发生异位骨化，常使用吲哚美辛等非类固醇类消炎药进行预防治疗。
目的：对比观察美洛昔康与吲哚美辛对全髋关节置换后预防异位骨化药物的效果。
方法：收集2010至2011年广州中医药大学第一附属医院骨科收治的51例患者，其中9例患者行双侧全髋关节置换，所有患者均由同一位医师采用后外侧入路进行关节置换。根据患者置换后使用的药物不同，分为对照组及实验组，分别在置换后口服吲哚美辛缓释片25 mg/d+奥美拉唑肠溶胶囊20 mg/d或美洛昔康片15 mg/d。
结果与结论：单独使用美洛昔康和使用吲哚美辛+奥美拉唑对关节置换患者异位骨化的发生率、疼痛、改良D'Aubigne和Postel评分的差异均无显著性意义(P > 0.05)，但美洛昔康的胃肠道不良反应较少。因此，认为单独服用美洛昔康能够有效避免异位骨化的发生及缓解疼痛，可以作为预防全髋关节置换后异位骨化及疼痛的推荐用药。

关键词: 骨关节植入物, 人工假体, 异位骨化, 全髋关节置换, 美洛昔康, 吲哚美辛, Brooker分级, 髋关节

Abstract:

BACKGROUND: In order to avoid heterotopic ossification after total hip arthroplasty, nonsteroidal anti-inflammatory drugs are commonly used for prevention.
OBJECTIVE: To compare the effect of meloxicam and indomethacin in the prevention of heterotopic ossification after total hip arthroplasty.
METHODS: Fifty-one patients who treated in the Department of Orthopedics, the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine from 2010 to 2011 were collected. Among the
51 patients, nine patients were treated with bilateral total hip arthroplasty, and all the patients had total hip arthroplasty with the posterior-lateral approach. The patients were divided into the control group and the experimental group according to the drugs used after replacement, and the patients in the two groups were administered with indomethacin sustained-release tablet 25 mg + omeprazole capsule 20 mg or meloxicam tablet 15 mg after replacement.
RESULTS AND CONCLUSION: There were no significant differences in the incidence of heterotopic ossification, pain, modified D’Aubigne and Postel scores after replacement between two groups (P > 0.05). But, the gastrointestinal adverse reactions of the experimental group were less than those of the control group. The application of meloxicam only can effectively avoid the heterotopic ossification and release pain. Consequently, we recommend meloxicam as postoperative drug for the prevention of heterotopic ossification and pain remission following total hip arthroplasty.

Key words: arthroplasty, replacement, hip, prosthesis implantation, anti-inflammatory agents, non-steroidal, ossification, heterotopic

中图分类号:

R318

曾意荣，简林养，冯文俊，李杰，李飞龙，何生. 美洛昔康与吲哚美辛防治全髋关节置换后异位骨化的比较[J]. 中国组织工程研究, 2013, 17(39): 6867-6874.

图/表（结果） 5

Demographic data and clinical information of all participants (Table 1)

In the control group, there were 23 patients (28 hips), 14 males and nine females, whose ages ranged from 26 years to 70 years, mean age (45.96±11.64) years. Besides, the follow-up time was ranged from 3 months to 9 months, mean (5.5±1.8) months. Among those

23 patients, one hip had synovial inflammation, one hip had ankylosing spondylitis involving double hips, nine hips had osteoarthritis, and 12 patients had avascular necrosis of the femoral head.

However, the study group consisted of 28 patients (30 hips), 18 males and 10 females, whose ages ranged from 31 years to 77 years, mean age (52.17±11.58) years. And the follow-up time also ranged from 3 months to 9 months, mean (5.6±2.0) months.

The preoperative diagnosis contained 11 cases of hip osteoarthritis, 16 cases of avascular necrosis of the femoral head and one case of ankylosing spondylitis involving double hips.

Incidence of heterotopic ossification and visual analogue scale score variation in the total hip arthroplasty patients treated with meloxicam and indomethacin

With the respect to the incidence of heterotopic ossification qualified with Brooker classfication, in the control group, 18 cases in level 0, four cases in level Ⅰ, no case in level Ⅱ, one case in level Ⅲ, and no case in level Ⅳ, and the incidence of heterotopic ossification reached 21.74%. While in the experimental group, the 25 cases in level 0, one case in level Ⅰ, one case in level Ⅱ, one case in level Ⅲ, and no case in level Ⅳ, and the incidence rate was 10.71% (Figure 1).

There was no statistical significance between the two groups (P=0.281 4, Table 2). As for pain remission quantified with visual analogue scale score, it also revealed no significance (P > 0.05, Table 3).

Modified D’Aubigne and Postel score and adverse reaction of the total hip arthroplasty patients treated with meloxicam and indomethacin (Table 4)

Hip function was assessed with the modified D’Aubigne and Postel score. In the control group, there were no excellent case, 14 good cases, nine fair cases, and no poor case postoperatively. In the experimental group, there were no excellent case, 18 good cases, 10 fair cases, and no poor case respectively. The excellent and good rate was 61% and 64% respectively (P > 0.05, Tables 4 and 5). The main adverse reaction in the control group was gastrointestinal disorder (37.84%), and one patient was not suggested to take the indomethacin sustained- release tablet because of severe irritation reaction. However, one patient suffered rash disease apart from gastrointestinal disorder (17.85%). There was no statistical significance (P > 0.05, Table 6).

参考文献

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引言

Heterotopic ossification has a definition that non-calcification tissue has a tendency of osteogenesis, and mature lamellar bone occurs in the soft tissue around the articular. It reported that the phenomenon of heterotopic ossification companied by total hip arthroplasty surgeries in 1972 at first, which, to some severe extent, could largely limit the range of motion of the hip^[1] . So did the efficacy of total hip arthroplasty surgeries. With the widely development of total hip arthroplasty surgeries, heterotopic ossification around hip joint has attracted more and more attention about its research^[2-4] , mainly centered on its etiology and pathogenesis^[5-8] , as well as its prevention and treatment. Many documents at home and abroad have reported the possible incidence of heterotopic ossification ranged from 8% to 90%^[9-10] . Schmidt et al^[11] discovered an approximately incidence of 60% to 75% of heterotopic ossification without taking any prevent measures.

To prevent heterotopic ossification, the well-recognized treatments mainly include the use of nonsteroidal antiinflammatory drugs, bisphosphonates and local radiation^[12-16] . However, nonsteroidal antiinflammatory drugs do great harm to patients’ gastrointestinal tract, especially for those who are over 65 years, so its utilization is largely limited. Besides, though nonsteroidal antiinflammatory drugs can prevent the happening of heterotopic ossification, it can also inhibit osteogenesis reaction^{[17 ]} , which may affect the stablization of the uncemented prosthesis. Moreover, it is rarely documented that whether the use of nonsteroidal antiinflammatory drugs can prevent heterotopic ossification after total hip arthroplasty surgeries or not, because of lacking long-term follow-up observation, as well as the reports on the efficacy regarding the improvement of range of motion of hip and prosthesis loosen. Therefore, our study aimed at the clinical observations about meloxicam tablet^[18-21] , a kind of gastrointestinal protective cyclooxygenase-(COX) 2 inhibitor drug, in order to explore its efficacy in the prevention of heterotopic ossification after total hip arthroplasty surgeries, pain remission, safety, and the improvement of range of motion of hip joint.

材料方法

Design

A same period non-randomized controlled trials

Time and setting

The study was conducted in the Department of Orthopedics, the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine from 2010 to 2011.

Subjects

We stated here that our study was compliance with Helsinki Declaration and got the approval of the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine. Nearly 51 patients

(60 hips), who underwent total hop arthroplasty surgeries with posterior and lateral approach in our Department of Orthopedics from October 2010 to October 2011, were recruited in our study. All the patients were informed of relevant benefits and risks though no written consent was not signed at that time.

Inclusion criterion: patients who underwent total hip arthroplasty surgeries, whose ages ranged from 20 to 80 years.

Exclusion criterion: patients who had long-term nonsteroidal antiinflammatory drugs usage history, malignant tumor, forbidden usage of non-selective nonsteroidal antiinflammatory drugs because of relevant diseases (such as peptic ulcer, asthma and so on), clear cardiovascular diseases (such as hypertension, coronary diseases and so on), and history of mental illness.

Patients did not reveal apparently statistical difference in the study and control group, no matter age, gender, surgical approach, and operation time. So, it had comparability between those two groups.

They were randomly divided into the control group (n=23) and the experimental group (n=28).

Methods

Total hip arthroplasty

All the patients underwent the same posterior-lateral approach with the same analgesia approach (mainly continuity epidural analgesia, sometimes general anesthesia). Besides, patients performed neither the greater trochanter osteotomy, nor the proximal femur osteotomy surgeries, and posterior joint capsule was regularly sutured. They were all completed by the same surgeon.

Drug intervention

After the surgeries, all patients used negative pressure drainage tubes in case of formation of hematoma, which were removed for 48 hours. Patients in the control group were administered with indomethacin sustained-released tablet 25 mg twice a day together with omeprazole capsule (one kind of gastrointestinal mucosa protectants, 20 mg once a day postoperatively till 6 weeks, while patients in the experimental group only took meloxicam tablet (15 mg once a day for

6 weeks). The application dose was based on the medicine’s instructions. No other measures were taken to avoid heterotopic ossification formation.

Visual analogue scale score

The visual analogue scale score was counted every day till 1 week postoperatively.

Brooker classification

The patients were suggested to take anterior-posterior X-ray films of double hips and lateral X-ray films of the operated hip follow-up was conducted in 1, 4, 8, 12, 24 and 48 weeks postoperatively, which were used for estimating the degree of heterotopic ossification with standard Brooker^[22-23] classification (1973). The Brooker classification can be described as follows: level 0: no ossification is found in periprosthesis tissue; level Ⅰ: bone islands within soft tissues about the hip; level Ⅱ: bone spurs in pelvis or proximal end of femur, leaving at least 1 cm between the opposing hip surfaces; level Ⅲ: bone spurs extended from the pelvis or the proximal end of femur, which reduces the space between the opposing surfaces less than 1 cm; level Ⅳ: radiographic ankylosis of the hip.

D’Aubigne and Postel score

At the same time, improved D’Aubigne and Postel score^[24] were used to assess the hip function at 12, 24 and 36 weeks postoperatively in the follow-up process.

Main outcome measures

The efficacy of meloxicam tablet and indomethacin sustained-release tablet in the prevention of heterotopic ossification after total hip arthroplasty surgeries was observed. Besides, visual analogue scale score, hip function improvement, and adverse reaction were also observed.

Statistical analysis

A chi-square test was applied to make a comparison about the prevention of heterotopic ossification after total hip arthroplasty. The side effects, and the improvement of range of motion of the hip joint between the study and control group was measured with a SPSS 17.0 system for statistical analysis, which P value less than 0.05 revealed a significant meaning. Remained aspects valued with a T test.

讨论

Causes of heterotopic ossification
Heterotopic ossification may not be the common complication after total hip arthroplasty, which new-born bone appears outside the skeletal system in patients. Medium to severe heterotopic ossification would lead to dysfunction of the hip, which would affect the quality of life of the patients^[25-26] . Additionally, heterotopic ossification shows differences from myositis ossificans, which is discovered commonly companied with muscle damage along with trauma. The pathogenesis of heterotopic ossification has not been recognized clearly so far, but present acknowledged perspective originates from mesenchymal stem cells in the tissues, which can be activated toward to tissue differentiation by some inducing factors, and new-born bone gradually appears. Chalmers et al ^[27] had put forward three mandatory conditions concerning formation of heterotopic ossification in 1975. They included osteogenic precursor cells, osteogenic inducer, and osteogenic organizational environment. Moreover, they also highlighted the critical role of local and systemic stimulator and inhibitor of osteogenic played in the formation of heterotopic ossification. In 1975, Urist et al had claimed that bone morphogentic protein was the explicit inducer which acted as a key factor in the progress of bone morphogentic protein. Scharstuhl et al^[28] had discovered the critical function of transforming growth factor-β in the formation of heterotopic ossification. And Chauveau et al^[29] had found that the amount of osteocalcin and osteonectin in ectopic bone cells was much higher than normal bone cells. So did the higher biological express of mRNA of collagen type Ⅱ.

Risk factors of heterotopic ossification
In total hip arthroplasty patients, the formation of heterotopic ossification has a plenty of risk factors. In published documents, many researchers have concluded that the high risk factors mainly consist of males, hip osteoarthritis patients, osteophyte hyperplasia of the femoral head and acetabulum, preoperative trauma of the hip, AS, degenerative arthritis, contralateral total hip arthroplasty surgery history, hypertrophic osteoarthropathy, rheumatoid arthritis, diffuse idiopathic skeletal hyperostosis, surgical incision, and nutrition condition^[30-35] . In some other literatures, it had been reported that heterotopic ossification was closely correlated with the usage of bone cement and the type of prosthesis. But it had been proved wrong by recent studies which discovered that the correlation between them did not exist[^36-37] . Consequently, it is necessary to make clear the high risks resulting in heterotopic ossification for effective protective management. Patients with heterotopic ossification in our research were largely those who suffered from hip osteoarthritis, or hip surgeries history, which was accord with above results.

Mechanism of indomethacin treatment
In the management of heterotopic ossification after total hip arthroplasty surgeries, many researches have suggested that the usage of nonsteroidal antiinflammatory drugs can be obviously effective in the prevention of heterotopic ossification, especially indomethacin sustained-release tablet. However, they deemed that there was no statistical significance^[38] about the efficacy between the selective COX-2 inhibiting drugs and traditional nonsteroidal antiinflammatory drugs in the management of heterotopic ossification^[38-41] . Nonsteroidal antiinflammatory drugs can stop the production of prostaglandin (osteogenesis inducer) by inhibiting the activity of COX, which can block local inflammation reaction that activates the bone reconstruction and inhibits mesenchymal cells (a kind of osteogenic precursor cells) from differentiating into osteoblasts. After reviewing relevant literature, Fijn et al ^[42] figured out that nonsteroidal antiinflammatory drugs can decrease the incidence of heterotopic ossification after total hip arthroplasty surgeries up to 50%, and meanwhile apparently decreased the incidence of heterotopic ossification with obvious clinical symptoms that low to 0% to 2%. However, the side effects of indomethacin sustained-release tablet can largely limit its widely application, especially for those who are in old age and have gastrointestinal diseases history. In recently, some documents have reported that COX-2 inhibiting drugs can effectively reduce the gastrointestinal side effects^[43-44] . However, it is rarely documented that whether COX-2 inhibiting drugs can acquire pain remission and improve the range of motion of the hip or not, as there lacking of long-term efficacy observation. Consequently, our research aimed to select meloxicam tablet, a gastrointestinal protection selective COX-2 inhibiting drugs, as an observation contrast. Reference to the statistical results, our conclusion is accord to those domestic and overseas documents reported, which said that meloxicam tablet can prevent the formation of heterotopic ossification around the hip joint following with total hip arthropasty surgeries effectively and find no severe heterotopic ossification case (level Ⅲ and Ⅳ). However, the conclusion reveals no significant meaning compared with indomethacin sustained-release tablet. With respect to pain remission, improved range of motion of the hip joint, and the incidence of side effects, both acquire positive efficacy without significance (P > 0.05). The possible reasons for no difference regarding range of motion of the hip improvement showed in two groups may contribute to short follow-up time postoperatively, and no intimate correlation between Brooker classification and modified D'Aubigne and Postel score. Additionally, discovering no apparently decrease in side effects can account for two reasons. Firstly, it was related to the dosage used. Meloxicam tablet, a selective COX-2 inhibiting drug, can produce efficacy largely dependent on the dosage^[45] . When used in 7.5 mg once a day, it tends to inhibit the production of COX-2 induced by kinds of damage factors. Meanwhile, when taken it more than 15 mg a day, it can inhibit the production of COX-1 at the same time, which can increase the incidence of gastrointestinal diseases. Secondly, it might own to the assistance of omeprazole capsule in the control group. Nevertheless, Barthel et al^[46] have reported that the application of 7.5 mg and 15 mg of meloxicam tablet dose not reveal the significant difference in the prevention of heterotopic ossification. Small samples make it not absolutely persuasion whether selective COX-2 inhibiting drugs can reduce gastrointestinal adverse reaction or not. More large samples, strictly designed, and long-term observation studies are essentially needed.

Treatment effect of nonsteroidal antiinflammatory drugs
Nonsteroidal antiinflammatory drugs can affect the healing of fracture, so it may lead to prosthesis loosen for inhibiting osteogenesis reaction surrounding prosthesis. Persson et al^[47] have investigated 96 total hip arthroplasty patients who used Ibuprofen (1 to 2 weeks) for analgesia and prevention of heterotopic ossification, a higher revision rate was reported than the control group (without any nonsteroidal antiinflammatory drugs), which can be explained with the theory that nonsteroidal antiinflammatory drugs can inhibit new-born bone formation. However, all patients in our study took nonsteroidal antiinflammatory drugs for 6 weeks postoperatively, and they were suggested to abandon crutches-assistance walking at one month after surgeries. The last follow-up showed that no lucent line was seen from postoperative X-rays and no hip symptoms were found and checked, indicating that nonsteroidal antiinflammatory drugs nearly had no effect on the osteogenesis reaction. However, there is still controversial on whether nonsteroidal antiinflammatory drugs can prevent heterotopic ossification in none-surgical position of our body or not as there lacks of long-term follow-up study. Without resolving the problem, the usage of nonsteroidal antiinflammatory drugs should be cautious for patients who have underwent total hip arthroplasty surgeries without high risks of heterotopic ossification formation.

Effect of surgical treatment
When surgical intervention in the management of heterotopic ossification should be made? Many researchers insisted that when the ossification focal became mature (usually one year later), surgical resection should be applied. And early surgical resection usually acquired no good efficacy, because it was susceptible to bleeding and recurrence. However, when respecting it too late, if more than 2 years, it was hard to obtain the excellent efficacy, which may account for osteoporosis because of intra-articular stiffness, which usually leads to long-term bed lay. When those patients underwent total hip arthroplasty surgeries, fracture may happen as a normal-seen complication, even lead to more widely heterotopic ossification occurrence. Gibbons et al ^[48]deemed that the perfect operating conditions were as follows. Firstly, at least 6 months postoperatively, it is better when the surgery operated at 12 to 18 months postoperatively. Secondly, no local skin temperature raising and red swelling around hip joint was found. Thirdly, heterotopic ossification was in the stability stage detected by X-ray, CT, MRI. Fourthly, the amount of alkaline phosphatase, a kind of sign manifesting the osteoblast activity, was at the normal reference range. Finally, bone scan (which used for assessing bone metabolic activity) result was normal, or at least next to normal. Heterotopic ossification patients in our study were diagnosed less than 8 weeks, and no increasing in size, so we gave up surgery plan because it did not put much harmful effect in the range of motion of the hip.

Experimental conclusion
We believe meloxicam tablet, a selective COX-2 inhibiting drugs, can decrease the incidence of heterotopic ossification, achieve excellent pain remission, as well as improve the hip function though the efficacy and gastrointestinal safety between meloxicam tablet and indomethacin sustained-release tablet are comparable. Consequently, we recommend meloxicam tablet as the postoperative drugs for the prevention of heterotopic ossification and pain remission after total hip arthroplasty surgeries because of its relative cheap price.