In the current meta-analysis, 10 trials recruited 601 participants with giant cell bone tumors at the start of the study; 295 of them received adjuvant bisphosphonate medication after surgery, and 306 served as the control group [19,20,21,22,23,24,25,26,27,28].
The extent of the postoperative recurrence outcomes in subjects with giant cell tumor of bone and post-intralesional curettage was significantly lower in the bisphosphonates group than that in the control group in all studied populations [19,20,21,22,23,24,25,26,27,28]. The lack of a meaningful difference after extensive resection, which may have been caused by the few studies included (only 3), to be exact indicates the need for additional research to support these conclusions. However, the high p values after wide resection (p = 0.65) indicate that the insignificant difference discovered after wide resection will not change with the inclusion of further research.
According to this finding, patients with giant cell tumors of the bone may experience a lower chance of postoperative recurrence outcomes if bisphosphonates are used as adjuvant therapy after surgery. Since these results are different from the control, there are additional factors to be present [19,20,21,22,23,24,25,26,27,28]. However, due to the small sample sizes of the studies we picked, the small number of studies included in our meta-analysis, and the potential for bias, care should be used when analyzing the results.
Giant cell tumor of bone commonly does not stay latent and tends to progress to destroy the affected bone . The disease is more prevalent in adults (> 18 years old) than in children in general . As a result, surgical intervention should be considered as soon as possible. Since the tumor is completely removed, wide resection provides the advantage of decreased recurrence rates. Notably, it has been applied to tumors in the Campanacci stage III or to tiny bones like the fibula or ulna when there are no evident bone dysfunctions . That could be why we could not find any significant difference between bisphosphonates and control groups in wide resection. Though, this surgical procedure may result in limited movement. Interestingly, the intralesional curettage combined with adjuvant techniques is considered the preferred management of giant cell tumor of bone. It showed better results in bone functions despite the higher risk of recurrence . In addition to their ability to lower the rate of giant cell bone tumor recurrence postoperatively, multiple studies have recently demonstrated that bisphosphonates have a cytotoxic effect on the neoplastic stromal cells of giant cell tumors of the bone [19,20,21,22,23,24,25,26,27,28]. However, it is still unknown how bisphosphonates work to fight tumors. It has been demonstrated that by impeding the mevalonate pathway, bisphosphonates can cause neoplastic stromal cells to undergo apoptosis. Bisphosphonates have also been demonstrated to block the zinc-dependent proteolytic activity of matrix metalloproteinase, which is crucial for the degradation of extracellular matrix proteins, invasion, and migration. This activity is exhibited by the tumor cell-derived matrix metalloproteinases-2 and metalloproteinase-9 . Wide excision eliminates the marginal positive of bone during intralesional curettage and hence lowers recurrence rate, which could be one explanation for the observed difference in result. Another explanation is that soft tissue infiltration causes recurrence, and broad resection removes all the infiltrated soft tissue . Bisphosphonates can help reduce tumor size preoperatively and prevent surgical dissemination, but their usage should be limited because late surgery may result in progressive tumor growth. The duration of postoperative use of bisphosphonates ranges from three months to two years. Long postoperative use of bisphosphonates was considered essential because recurrence occurs mostly in the first two years post-surgery . The main adverse reactions of bisphosphonates are mild and nonfatal including fever and digestive upset. However, bisphosphonates should not be used in subjects with renal dysfunction or stress fractures. Also, some studies reported that long-term and large-dose of bisphosphonates may prompt osteonecrosis of the jaw and atypical fracture of long bones [35, 36]. This meta-analysis showed the influence of bisphosphonates on the giant cell bone tumor recurrence. However, more research is still required to demonstrate these potential connections and contrast the impact of bisphosphonates and denosumab therapy. In patients with giant cell tumors of the bone, denosumab was shown to be associated with respectable rates of tumor remission and decreased the need for morbid surgery . Larger, more homogeneous samples are required for these researches. This was also suggested in an earlier meta-analysis study that revealed comparable encouraging results for bisphosphonates in lowering the recurrence of giant cell bone tumors . Since our meta-analysis study was unable to determine if differences in age, ethnicity, and gender are related to the outcomes, well-conducted RCT are required to evaluate these parameters as well as the interaction of different ages, ethnicities, and other variations of participants.
In summary, the data suggest that using bisphosphonates as an adjuvant therapy may lower the risk of recurrence outcomes post-surgery in subjects with giant cell tumor of bone especially post-intralesional curettage. From the study presented here, we recommend the use of bisphosphonates as an adjuvant therapy to reduce the possibility of postoperative recurrence that could occur in subjects with giant cell tumor of bone.
Since so many of the papers found in this study were not included in the meta-analysis, there may have been selection bias. The excluded papers, however, did not meet the requirements for inclusion in our meta-analysis. Additionally, we were unable to determine whether or not the results are influenced by gender, race, or age. However, most subjects in the selected studies were adults since the disease prevalence is more common in adults. The study's goal was to evaluate the effect of bisphosphonates as adjuvant therapy on the recurrence of giant cell bone tumors and analyze the impact of various tumor stages and surgical techniques on this effect. The study's data came from prior studies, which may have introduced bias due to missing details. In the current meta-analysis, ten RCTs were analyzed, eight of which had small sample sizes (n ≤ 100). The age, sex, and nutritional status of the subjects were all potentially biased-inducing factors. Regrettably, some unpublished articles and incomplete data may bias the effect under study. The dose and he formulation of bisphosphonates were variable in the selected studies and this might induce bias. However, we could not study different formulation or dose effect separately since the number of studies related to each dose and formulation was limited.