Does Denosumab Change the Giant Cell Tumor Treatment Strategy? Lessons Learned From Early Experience

Abstract

Background

Although giant cell tumors (GCTs) are benign, their aggressiveness and tendency to recur locally challenge the orthopaedic surgeon’s ability to perform joint-preserving intralesional surgery with an acceptably low risk of local recurrence. Denosumab has emerged as a possible medical treatment of GCT because it seems to halt the progression of GCT, alleviate pain, and increase perilesional bone formation, but its exact role has been questioned, and specifically its efficacy and associated complications are not well characterized.

Questions/purposes

(1) Does denosumab reduce the risk of recurrence after resection or intralesional surgery? (2) What are the complications associated with the use of denosumab?

Methods

Fifty-four patients with 30 primary and 25 recurrent tumors between November 2013 and July 2016 were treated with denosumab after a confirmed histopathologic diagnosis of GCT. Another 17 patients in the same period were treated without denosumab. During the study period, we encouraged the use of denosumab in all patients except those who refused, could not afford it, or where it was contraindicated (eg, in pregnancy). In all patients undergoing intralesional surgery, we arbitrarily planned six doses before surgery. Variations in total doses before surgery were dependent on patient-related factors; in some, we gave less doses because patients expressed the inability to afford any more doses, whereas in some patients, extra doses were added when the patient wished to delay surgery as well as the because of surgeon judgment wherein in some patients, we stopped before six doses when we thought adequate bone had formed for intralesional curettage. The mean number of doses was 6.8 per patient (median, 6; range, 3-17) preoperatively. The minimum followup was 12 months (median, 27 months; range, 12-42 months). Every patient showed improvement clinically in terms of pain and halting of tumor progression within three to four doses. This was seen radiologically as a sharply defined soft tissue mass as well as hazy ossification within the tumor. For a case-matched comparison study, we identified controls as 34 patients undergoing curettage from the retrospective analysis of 68 patients curetted without denosumab between February 2010 and July 2016 matched to 25 denosumab-treated patients in terms of site, size, Campanacci grade, and recurrent versus primary status, and with a minimum 2 years followup for the control group. Fisher’s exact test was used for statistical study. Patients undergoing resection were planned for surgery after three doses of denosumab to allow the tumor to solidify and potentially decrease tumor spillage at the time of surgery. The resections could not be case-matched for comparison owing to the smaller numbers.

Results

We observed 14 recurrences out of the 37 curetted tumors (38%). In the case-matched analysis, 11 of 25 patients in the denosumab-treated curettage group had recurrences (44%) compared with seven of 34 (21%) in the nondenosumab-treated control group. The risk of denosumab-treated patients experiencing local recurrence as compared with the nondenosumab-treated patients was nonsignificant with a two-tailed p value of 0.085 (significance at p < 0.05) as derived from Fisher’s exact test (odds ratio, 3.03; 95% confidence interval, 0.96–9.54). There was no recurrence in the resection group. Because we do not have a control group for resection, we are unable to comment on the importance of this finding. One major complication that we observed was a recurrence with malignant transformation in a patient with a proximal humeral GCT. We did not observe any other complications related to the denosumab therapy.

Conclusions

Although we could not demonstrate a higher risk of local recurrence with preoperative denosumab for intralesional surgery in the dose and frequency we administered, we advise caution in its routine use for intralesional procedures because it may be important to curette up to margins on pretreatment imaging owing to the potential residual tumor within the denosumab-mediated thick bony shell, which may result in local recurrence. We believe that denosumab treatment before resection of a large tumor aids resection without tumor spillage, particularly where important structures like the neurovascular bundle are dissected away from the tumor margin, although we cannot confirm that it helps lower the incidence of recurrence. We are concerned regarding the malignancy-causing potential from our observation in one patient as well as reports of this by others and recommend judicious use of this drug in patients with GCT.

Level of Evidence

Level III, therapeutic study.

Introduction

Giant cell tumor (GCT) is an aggressive benign tumor with a tendency to recur locally. The subarticular location and extent in bone have challenged the orthopaedic surgeon’s ability to perform joint-preserving intralesional surgery with an acceptably low risk of local recurrence. This is particularly true at locations like the pelvis and spine where access and hypervascularity pose additional challenges for adequate tumor clearance.

Denosumab, a fully humanized monoclonal antibody to receptor activator of nuclear factor kappa-Β ligand (RANKL), generated considerable excitement about the possible medical treatment of GCT because of its rapid and consistent effect in halting the progression of GCT, alleviating pain, and forming bone within and at margins of the lesion. However, concerns have been raised about whether the treatment will actually reduce the risk of recurrence after intralesional curettage or resection in treated patients [4, 14, 17]. It is still unclear whether there are some patients who might benefit from denosumab treatment, whereas others are better treated by traditional surgical treatment. The long-term side effects are also still being elucidated. We have experience with the use of denosumab as an adjuvant so we report our experience to help address some of these issues.

We therefore asked: (1) Does denosumab reduce the risk of recurrence after resection or intralesional surgery? (2) What are the complications associated with the use of denosumab?

Patients and Methods

Between November 2013 and July 2016, 54 patients (25 males, 29 females) with an average age of 32 years (range, 17-67 years) with 30 primary and 25 recurrent tumors presented to our institute and were treated with denosumab after a confirmed histopathologic diagnosis of GCT. Our institute waived approval for the human protocol for this study. Eleven patients had tumor in the axial skeleton only, 42 had in the appendicular skeleton only, whereas one patient had a multicentric tumor in the distal tibia and sacrum. During that same time period, we treated 17 patients without denosumab. Our initial policy was to use denosumab for all patients with the expectation that the direct antitumor effect of denosumab would kill RANKL-expressing neoplastic stromal cells and inhibit osteoclast-like giant cell-mediated bone destruction [16], helping reduce recurrence as well as downstaging disease and making surgery easier by forming a hard bony shell. Sixteen patients declined denosumab either because of patient preference or inability to pay and in one patient, we did not use denosumab because of pregnancy. These 17 patients would not be adequate as a comparison group so we retrospectively assessed the patient records and imaging of all 68 intralesional curettages and 16 resections treated without denosumab from February 2010 to July 2016 as the control group. All of these patients were operated on by the same surgeon (MGA) using the same surgical protocol. After eliminating patients lost to followup and those with < 2-year followup, 45 patients not treated with denosumab remained of which we were able to match 34 patients with intralesional curettage to 25 patients from the denosumab group matched for size, Campanacci grade, whether recurrent or primary tumor, and site (Table 1). No patients in the denosumab group were lost to followup. This case-matched group was analyzed for local recurrence and compared with the denosumab group using the Fisher’s exact test for establishing p value for significance as well as odds ratio and 95% confidence interval. We could not find matched patients for the resection group owing to the smaller numbers.

Table 1.

Case-matched master chart of denosumab-treated patients with a control group of patients not treated with denosumab matched for site, size, Campanacci grade, and primary versus recurrent tumor at presentation

Before starting treatment, all patients underwent a dental check, renal function tests, and baseline serum calcium levels. Serum creatinine and calcium were confirmed normal in all patients. Pregnant women were excluded from denosumab treatment. Patients requiring dental procedures were started on denosumab therapy after completion of dental treatment. All patients were strongly advised to be supplemented with oral vitamin D (> 400 IU, daily up to 60,000 IU every week in case of hypovitaminosis D) and calcium (> 500 mg, daily) while on denosumab treatment. Radiographs were performed at 6 to 8 weeks and then after 3 months of starting therapy. Initially these were patients in whom we judged that intralesional surgery would be easier with a better bony shell formed after denosumab. Subsequently we used it before resections also. All patients were given subcutaneous injections of denosumab (120 mg) every month (with additional doses on Days 8 and 15 during the first month only).

Our criteria for choosing between curettage and resection depended on tumor extent, site, and patient choice. Patients in whom there was no containing bony shell and large soft tissue mass were chosen for resection. In the distal radius, resection was offered to every patient considering the high risk of local recurrence even without denosumab (50% in our experience). All other patients amenable to joint salvage with adequate subchondral bone for reconstruction were curetted after denosumab treatment. In the pelvis, resection was done only if the acetabulum was not involved. No resection was offered for sacral giant cell tumors because morbidity was considered too high for a benign tumor.

In all patients undergoing intralesional surgery, we arbitrarily chose six doses to be administered before curettage. The number of doses was reduced in some patients because of cost constraints and when bone formation was deemed adequate for joint salvage. Once we had generated some experience and data emerged that denosumab did not have much effect on the neoplastic spindle cells [10], we tried to reduce the number of doses before curettage. From experience we learned that three weekly doses were enough to solidify the tumor and decrease spillage. In these patients, additional doses were given if surgery was delayed for any reason. In the initial period, two patients were given three and four injections, respectively, as monthly doses in the postoperative period with the hope of reducing recurrence. The mean number of doses for curettage was 6.8 per patient (median, 6; range, 3-17) preoperatively and for resections was a mean of 4.71 doses (median, 5; range, 3-7). The minimum followup in the denosumab-treated curettage group was 12 months (median, 27 months; range, 12-42 months) with no patient lost to followup. Patients with a minimum followup of 24 months were analyzed for size, site, and grade as appropriate controls for the denosumab-treated group. The minimum followup in the control group was 27 months (median, 60 months; range, 27-90 months).

Every patient showed improvement clinically in terms of pain and halting of tumor progression within three to four doses. This was seen radiologically as a sharply defined soft tissue mass as well as hazy ossification within the tumor. The amount of ossification increased with the number of denosumab doses. On gross appearance, even after just three doses, the tumor became firm and yellow. Gritty ossification was felt within it during curettage. The thicker bony shell made it easier to burr the margin but also tricked the surgeon into stopping short of the actual margin as assessed from pretreatment radiographs. In the sacrum, the hardening and ossification of the tumor made it difficult to separate the tumor away from the neural elements.

An operative procedure was done when it was judged that adequate bone had formed for curettage (sclerotic bony shell) or solidified enough (ossification within the lesion) for resection and also as per patient convenience (additional doses were given if the patient electively desired delayed surgery for any reason). Our criteria for choosing between curettage and resection depended on tumor extent, site, and patient choice. Patients in whom there was no containing bony shell and large soft tissue mass were chosen for resection. In the distal radius, resection was offered to every patient considering the high risk of local recurrence (50% in our experience). All other patients were curetted. In the pelvis, resection was done only if acetabulum was not involved. No resection was offered for sacral tumors because morbidity was considered too high for a benign tumor. All tumor material (curetted/resected) was sent for histopathology. Since the middle of January 2015, we have used intraoperative imaging with a C-arm to ensure that the pretreatment margin was reached during curettage.

Four patients were not operated on after denosumab treatment. In two of these patients, one with metacarpal disease and the other with proximal tibial disease, were radiologically deemed completely healed after 12 and eight doses, respectively, and therapy was stopped. One patient with a very large sacroiliac recurrent GCT declined surgery and has continued on denosumab. Another patient with a distal radius GCT declined surgery and stopped denosumab after nine doses.

All patients were followed up with radiographs at 6 weeks postoperatively, then at 3 months, and subsequently every 3 months. The disease status and complications if any were recorded. Additional imaging like MRI or CT was done wherever recurrence was suspected. Surgical notes were studied by the treating surgeon and the other authors for completeness of tumor excision and postoperative radiographs were compared with predenosumab therapy radiographs to gauge whether we judged that the surgeon had removed the complete tumor by comparing the pre- and postoperative images.

Results

With the numbers available, we were unable to show any significant difference in the recurrence rates between the denosumab-treated patients and the case-matched control group treated without denosumab. The proportion of patients with local recurrence in the denosumab-treated group was 14 of 37 (38%) using denosumab before curettage. The proportion of recurrences in the distal radius was (three of three), sacrum (two of three), and distal femur (four of six). For the purpose of statistical study, only the 25 patients in the denosumab group matched to 34 patients in the nondenosumab group (Table 1) were used. Eleven of 25 denosumab-treated patients had recurrences compared with seven of 34 in the case-matched group without denosumab. A simple two-by-two contingency table was used to calculate the significance (p value) using the Fisher’s exact test; the two-tailed p value was calculated as 0.085, which was not significant at p < 0.05 (odds ratio, 3.03; 95% confidence interval, 0.96-9.54 denosumab-treated patients having local recurrences compared with the nondenosumab-treated patients). There were no recurrences in the 14 resections. Because we do not have a control group for the resection because of the small numbers, we are unable to comment on the importance of this finding. We analyzed the four patients in whom surgery was not done after denosumab. In two patients (first metacarpal and proximal tibia), there was complete ossification and regression of the soft tissue mass after seven denosumab doses. The metacarpal GCT recurred after stopping the treatment and the patient underwent excision of the soft tissue recurrence with curettage and cementing for the intraosseous disease. He recurred twice more in the soft tissues and is now disease-free after the excisions. The proximal tibia (Fig. 1A-B) has remained tumor-free for 24 months (Fig. 1C) after the last injection. Two other patients refused surgery, one with an iliosacral recurrent GCT who has continued with monthly denosumab and another patient with a distal radius that had tumor regrowth and was resected subsequently.

Fig. 1 A-C.

This is a patient with a proximal tibia GCT with (A) a radiograph at presentation who was treated with denosumab only. (B) This is a radiograph after eight injections and 6 months of therapy with denosumab showing sclerosis around and ossification within the tumor. He discontinued denosumab after a total of eight doses and continues to remain disease-free as seen on (C) a radiograph at latest 2-year followup.

One patient with a proximal humerus GCT developed a sarcomatous change 8 months after surgery (Fig. 2A-C). He did not respond to chemotherapy and subsequently died of metastatic disease. We did not do serial blood calcium levels or jaw radiographs because none of our patients had obvious clinical signs of any of the known denosumab-related complications like hypocalcaemia or osteonecrosis of the jaw.

Fig. 2 A-C.

This shows a patient with a proximal humerus GCT with (A) a radiograph at presentation who was treated with eight injections of denosumab, which led to (B) bony shell formation and sclerosis within the lesion after which the patient underwent intralesional surgery for disease clearance. Eight months postoperatively the patient presented with a local recurrence, which as seen on (C) radiography and MRI suggested aggressive malignant transformation. Biopsy confirmed osteosarcoma.

Discussion

The dramatic effects of denosumab on GCT were believed to cause a paradigm shift in our strategy of treating GCT. Interim analysis of large phase 2 studies done in the United States [16] and Canada [14] has shown that tumors had not progressed and that whenever surgery was done, it was usually a less morbid procedure than originally planned (joint salvage rather than resection). Since then, it has been widely used in the neoadjuvant setting with the hope of improving the outcomes of surgery. This article attempts to bring out our initial experience in using denosumab for 55 GCTs.

There were many limitations to our study. Our series is small and heterogenous and includes tumors at multiple sites making it difficult to case-match all patients for controls from retrospective analysis of the data. The dosages and frequencies of administration of denosumab were not standardized because of surgeon-related (doses varied based on radiographic evidence of an ossification shell around the tumor) and patient-related factors (cost of denosumab treatment and convenience of timing of surgery). We could not control for some differences in the surgical techniques between patients undergoing joint salvage intralesional surgery (curettage was limited by adequacy of subchondral bone and adequacy of a bony shell to burr against) as well as resections (dissection of critical structures from close to the tumor boundary led to narrower resection margins in some patients). Addition of matched cases from the nondenosumab-treated group makes the analysis more meaningful because the patients were matched for site, primary or recurrent, tumor size, and Campanacci grade. There was no loss to followup in the denosumab-treated group and the selection bias was limited because all patients who presented within the study period were offered denosumab. The data therefore help to clear some of the confusion regarding denosumab use, particularly the incidence of recurrence and complications, yet a future study with an appropriate sample size for a case-matched prospective analysis would offer stronger evidence regarding the role denosumab in management of GCTs.

Although the proportion of recurrences seemed high in the denosumab group, it was not statistically different from that of our patients treated without denosumab. Interestingly, we found that denosumab aided surgical resection by hardening the tumor and the bony shell potentially reducing the risk of inadvertent contamination, particularly during separation of the neurovascular bundle or tendons from the tumor margin.

We found that 14 of 37 patients treated with curettage (38%) developed local recurrence, which seems high. We started using denosumab with the belief that it had a direct effect on destroying the tumor, much like chemotherapy or targeted therapy in malignant tumors [13]. In our initial few patients who underwent curettage, we found that the solid tumor made curettage easier and soft tissue spillage much easier to handle. The hard wall also made burring easy (Fig. 3A-B). Because we earlier wrongly believed that denosumab affected stromal cells also, our initial patients undergoing joint salvage thus treated did not receive aggressive curettage in an attempt to preserve subchondral bone and decrease surgical morbidity. We stopped burring once we reached the thick bony shell (Fig. 3C), wrongly assuming that any remaining cells in the cortical shell were dead. This led to a very high proportion of local recurrences (eight of 14 [57%]) (Fig. 3D-E). After mid-January 2015, we used a C-arm intraoperatively to ensure that we curetted until the pretreatment margin had been reached. Six of 23 patients treated with this method experienced a recurrence. Although we cannot definitively substantiate this with our small series, we believe based on our experience that curettage after denosumab therapy should cover the complete pretreatment tumor margin. Large tumors in difficult locations like the pelvis and sacrum, tumors with a high risk of recurrence like in the distal radius, and all tumors with massive bone destruction, which would be a challenge to curette while preserving the joint, were the most attractive indications for us to use denosumab. We started using denosumab before curettage surgery with the aim of downstaging the disease and performing less morbid surgery as shown in large trials [14, 16]. We did not know the optimum dosing, so we began with a plan of using six doses (arbitrarily chosen) initially before curettage (monthly 120 units for 4 months with two additional doses on Days 8 and 15 in the first month). Because we believed it can reduce the recurrence, two of our initial patients were given the drug even postoperatively. In two of our four patients who were treated with denosumab alone, the bone healed completely and soft tissue swelling disappeared making us believe that the tumor had completely resolved. Interestingly, one of these patients with a proximal tibial tumor has remained in remission now > 2 years after stopping his last injection. The other patient with a metacarpal tumor had a recurrence. One other patient who refused surgery after pain relief also had a recurrence. Mak et al. [10] were able to culture the stromal cells from denosumab-treated patients. This showed that denosumab strongly affects giant cells [12], as expected from the mechanism of action on RANKL, but affects stromal cells only through their dependency on the giant cells. Once the antibody is withdrawn, these stromal cells could still multiply (slower compared with untreated cells) [10]. This can explain the recurrence after denosumab withdrawal. Lau et al. [8] also reported a weak effect of denosumab on GCT stromal cells as compared with zoledronic acid, which had a more potent effect. We therefore subsequently performed surgery on every patient treated with a short course of denosumab and “denosumab-only” therapy is reserved for unresectable tumors or resections that may cause serious morbidity [9].

Fig. 3 A-E.

This is a (A) radiograph of a patient with a distal radius GCT who was treated with denosumab to allow formation of a (B) bony shell and sclerosis to solidify the tumor to allow joint salvage intralesional surgery, but we observed on the (C) postoperative radiograph that margins of curettage (space filled with bone cement) are confined within the bony shell formed postdenosumab and have not been extended beyond the pretreatment tumor. Ten months postsurgery, a radiograph (D) with presence of pericement lysis was suggestive of local recurrence and the patient underwent resection for local recurrence; (E) split section of the resected specimen showing disease in the subchondral area beyond the cement.

The high risk of local recurrence after denosumab therapy can be explained [17]. Denosumab causes irregular ossification within the tumor. As the bony wall thickens, it is likely that stromal cells get trapped within the bone [5]. Other reports suggest that the rim of new bone may contain neoplastic cells that may reactivate once denosumab treatment is finished [18]. Gaston et al. [5] observed that denosumab renders the tumor less defined macroscopically and microscopically from the surrounding normal bone, therefore making the extent of surgical excision more difficult. Thus, the benefit of denosumab use in terms of bone formation needs to be balanced against the higher risk of local recurrence. We also feel that a longer duration of denosumab therapy before surgery makes the chance of recurrence higher by thickening the shell and trapping more neoplastic cells within it. The surgeon may need to reduce the doses to just adequate for bone formation without seriously compromising the ability to obtain tumor clearance.

The higher risk of recurrence (although not statistically significant) has dampened our enthusiasm about using denosumab as an adjuvant for intralesional surgery. We now limit our use to tumors in the spine, pelvis, and sacrum to reduce the vascularity and we use only three doses given weekly. We found three doses to be effective in decreasing the vascularity as confirmed by the angiograms performed preoperatively. Particularly in the sacrum, a larger number of doses increases the difficulty in separating the neural elements away from the tumor.

The bone formation caused by denosumab allows better preservation of the bony shell, especially when large parts have been destroyed by the tumor [18]. In three of our patients, one in the phalanx, one in the patella (Fig. 4A), and one in the tibial tuberosity (Fig. 5A), we feel our ability to curette and reconstruct improved because of the bone formation (Figs. 4B, 5B) helped by denosumab therapy, thereby allowing salvage of the articular surface of the joint (Fig. 4C) and patella tendon insertion (Fig. 5C), respectively. These have not shown any local recurrence until last followup. The exception to use more than three doses now has been where a bony shell is desired. In such patients, we have used additional doses of denosumab monthly until we deemed the shell to be radiologically appropriate for providing a bony end for burring while maintaining the shell for reconstruction.

Fig. 4 A-C.

This patient with an (A) expansile and lytic destructive GCT of the patella as seen on radiographs and CT scan was able to undergo joint salvage by the use of denosumab. Denosumab treatment with six injections led to (B) sclerosis and bony shell formation as seen on radiographs and CT scan. (C) Radiograph postcurettage and bone graft reconstruction shows salvage of the articular surface of the patella, thereby preserving the patella-femoral joint.

Fig. 5 A-C.

This is a patient with proximal tibial GCT involving the tibial tuberosity (A) as seen on the radiograph. Denosumab induced a bony shell after nine injections (B) showing anterior sclerosis and bone formation within the lesion made joint and function preservation possible for this patient. Postcurettage and “sandwich” reconstruction (C) with an anterior sclerotic shell allowed salvage of the patella tendon insertion providing great function with no extension lag for the patient.

With our experience of using three doses for resections (Fig. 6A), we realized that this was enough to stiffen the shell (Fig. 6B) even when resection was planned. This allowed us to isolate and protect the nerves, tendons, and other important structures near the tumor without causing inadvertent tumor spillage (Fig. 6C). In the 14 patients with resection thus done, we did not have any recurrences in a followup period of 12 to 33 months. The value of three doses was arbitrary with the intention of primarily achieving enough hardening to reduce tumor spillage and bleeding while not increasing the cost of treatment, but because the likelihood of recurrence after resection of GCTs is very low [11], we cannot confirm that denosumab actually reduces the proportion of recurrences after complete resection.

Fig. 6 A-C.

This patient with a proximal radius GCT with (A) a radiograph at presentation was maintained in an above-elbow plaster to prevent fracture while being treated with denosumab for (B) maintaining position and sclerosis and bony shell formation after three doses of denosumab to facilitate resection, reduce spillage, and allow separation of important structures away from the tumor. (C) Resected specimen cut longitudinally showed firm fibroosseous tumor with a well-defined shell. No break or spillage was encountered during the resection.

One patient with a proximal humerus GCT developed malignant transformation (biopsy-confirmed osteosarcoma) at the site of surgery after 8 months of curettage. We initially thought that we had missed a malignant GCT. We therefore reviewed the initial biopsy, which did not suggest any malignancy. We studied the entire curetted material for the possibility of a sampling error in the needle biopsy, but again there was no suspicion of malignancy. The biopsy from the recurrence clearly showed a malignant tumor, which was finally labeled as an osteosarcoma. Despite doxorubicin and cisplatinum chemotherapy, this patient developed pulmonary metastases and died of disease. Sarcoma developing after denosumab therapy has been reported recently [1, 3]. All three reported patients did not respond to treatment similar to our patient. The potential relationship between, and mechanism of, sarcomatous transformations of GCT during denosumab therapy is unclear. In vivo and in vitro studies of the effect of denosumab on GCT at the cellular level show a reduction in the neoplastic stromal cells with reduced RANKL expression and proliferation of spindle cells with reactive bone, which may be the key to sarcomatous transformation [2, 6, 10]. We do not know the causal relation of this to denosumab and a single patient does not allow us to make a strong inference, but we recommend caution in selecting patients for denosumab therapy, particularly for a longer period of time. None of our patients had any of the other known denosumab-related complications like hypocalcemia or osteonecrosis of the jaw [7, 15]. This is probably the result of the short duration of therapy in most of our patients.

In conclusion, we advise caution in the routine use of denosumab for intralesional procedures owing to the potentially higher risk of local recurrence. Although it helps thicken the shell of bone containing the tumor and may ease curettage, more carefully controlled studies are needed to confirm our findings. We now believe that three doses administered preoperatively are reasonable except in patients in whom restoration of the bony shell is desired for joint salvage. Where intralesional curettage is done postdenosumab, we believe it is important to curette and burr up to margins on pretreatment imaging. Although we cannot confirm this by comparison to resections without the use of denosumab, we feel that denosumab treatment before resection of a large tumor aids resection without tumor spillage, particularly where important structures like the neurovascular bundle are dissected away from the tumor margin. We are concerned regarding the malignancy-causing potential from our observation in one patient and recommend judicious use in GCT. Several questions remain regarding its proper use: is surgery always indicated or is denosumab alone effective? Does treatment with denosumab facilitate the ability of a joint to be salvaged by intralesional surgery instead of resection? What is the appropriate number of doses to give? What are the best indications? Most of these questions have not been answered, but we attempted to look at our patients to answer some of these issues. Future multicentric studies with larger numbers may help decide the appropriate number of denosumab doses and the best indications for using denosumab for GCTs.