Abstract
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Denosumab is a fully humanised monoclonal antibody to RANK ligand, inhibiting the RANK–RANKL pathway. It promotes the apoptosis of osteoclast-like giant cells, a secondary ossification and connective tissue formation.
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Given its high efficacy, denosumab is the standard treatment of unresectable or metastatic giant cell tumour of bone (GCTB) requiring morbid surgery.
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Neoadjuvant administration of denosumab may be justified to enable the resection of the tumour in certain cases; it should be considered, however, with caution for joint-saving surgery due to high local recurrence rates.
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In cases of unresectable or metastatic GCTB, however, denosumab treatment should be administered for years or even as a lifelong therapy. This poses many yet unanswered questions concerning the frequency of denosumab treatment as well as the ratio of the adverse events in the following years.
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Denosumab suppresses, not directly targets, the neoplastic stromal cells of GCTB. Ongoing in vitro studies suggest that other drugs alone or in combination (e.g. sunitinib) with denosumab may target both the neoplastic and the giant cells.
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Promising results have been reported regarding the off-label use of denosumab in other giant cell-rich tumours/tumour-like lesions, i.e. aneurysmal bone cysts and central giant cell granulomas. Data are derived, however, mostly from case reports and case series. Large prospective clinical trials are needed to evaluate the role and also the side effects of denosumab in the treatment of these rare diseases.
Introduction
Denosumab is a fully humanised monoclonal antibody of the RANK ligand (nuclear factor kappa B ligand) which inhibits the RANK–RANKL interaction. The mononuclear stromal cells of giant cell tumour of bone (GCTB) overexpress RANKL, which is an essential mediator for recruitment, formation, enhanced function and survival of osteoclast-like giant cells. For this effect, RANKL interacts with the RANK on the surface of giant cells. This interaction is prevented by denosumab as it binds to the RANKL. As a consequence, osteoclasts disappear from the tumour tissue, and they are mostly replaced by loose connective tissue and newly formed bone. H3F3A-positive stromal cells can, however, be detected in the remaining tumour tissue underlining the ineffectiveness of denosumab on the tumourous stromal cells (1).
Following the successful use of denosumab in the treatment of osteoporosis and metastatic bone lesions (2, 3), it has been approved by FDA in 2013 and later on by the European Medical Agency (EMA) for GCTB under certain indications (tumours requiring morbid surgery, unresectable or metastatic GCTB).
GCTB is defined by the WHO as a locally aggressive, rarely metastasising bone tumour of intermediate dignity (4). GCTB is not rare; it represents approximately 15% of the benign and 3–6% of all bone tumours (5). Incidence is estimated to be at around 1.3 per million persons annually (6) in Europe and the USA, but it is more common in the Asian population (7) where it represents about 20% of all primary bone tumours. Growth of the GCTB may remain latent (Campanacci stage 1)); it may deform the bone and thin its cortex (Campanacci stage 2)) or break through the cortical bone and form an extraosseal tumourous component (Campanacci stage 3) (8).
Histologically, GCTB consists of two types of mononuclear cellular components and reactive osteoclast-like giant cells. The latter can have as many as 100 nuclei and show both TRAP (tartrate-resistant acid phosphatase) and calcitonin-receptor positivity (9). It also expresses RANK. One type of typical mononuclear components are round histiocytic cells without cytogenic alteration, expressing monocyte–macrophage markers. The other type are more elongated (spindle-shaped or oval) presenting chromosomal alterations (10, 11) and histone 3.3 mutations of the H3F3A gene. The latter is highly characteristic for GCTB (12). These neoplastic stromal cells show enhanced synthesis of RANK ligand (RANKL). The RANK ligand interacts with RANK and this RANK/RANKL signalling pathway is responsible for promoting multinuclear osteoclast formation, cell survival and activity, resulting in bone resorption (13). Mitotic activity in GCTB may vary from a few to as high as 20 per 10 high-power fields. The presence of atypical mitoses may be considered to be warning signs regarding malignancy. There is, however, no direct correlation between the results of conventional histological examinations and the behaviour of the tumour (10, 14).
GCTB may metastasise to the lungs in 1–4% of all cases (15, 16) even when histological features appear benign. Based on results from large cohorts, malignant transformation of GCTB occurred in about 1 to 1.6% of cases mainly during the course of recurrences (17, 18) or at an even higher percentage following radiotherapy (19, 20). Very rarely, primary malignant GCTB may develop if characteristic sarcomatous areas (mainly osteosarcoma or fibrosarcoma) appear in otherwise typical GCT tissues (5, 18). It may therefore be calculated that the 5-year overall survival in GCTB with intermediate dignity is over than 95%.
Treatment options in GCTB
The mainstay of GCTB treatment is surgery: either curettage of the defect with or without local adjuvant therapy or resection in healthy tissue. Bisphosphonate, effectively used in osteoporosis and metastatic bone diseases, was the first systematic drug studied regarding treatment of GCTB. The most commonly used zoledronic acid binds to bone mineral, inhibits osteoclast formation, migration and promote apoptosis. In a comparative in vitro study between the zoledronic acid and denosumab, the former showed a direct effect on the neoplastic stromal cells, i.e. reduced cell growth and promoted apoptosis, which denosumab did not demonstrate (21). The RANK–RANKL interaction is also influenced by bisphosphonates by inhibition of messenger RNA expression of RANKL.
The efficacy of denosumab treatment
The first multicentric open-label, phase 2 study analysing the results of denosumab in patients with giant cell tumour of bone was published in 2010 (22). Thirty-seven patients with recurrent or unresectable GCTB were enrolled and treated by denosumab. The method of administration and dosing of denosumab they implemented is widely accepted now: 120 mg of denosumab subcutaneously every 28 days (loading doses on day 8 and 15 in the first month). In a second larger multicentric phase 2 clinical trial (23) 282 patients were enrolled and evaluated for clinical response and adverse events. Short-term administration of denosumab means four to six cycles (in 4–6 months) preoperatively in the form of neoadjuvant treatment. In this timeframe clinical complaints (pain, swelling) decrease, progression of the disease is absent on radiographs and other imaging techniques, and reactive ossification appears mostly on the periphery of the lesion. This treatment is useful for downstaging a GCTB otherwise requiring mutilation surgery. Metastasising or unresectable GCTB indicates denosumab treatment for years or even much longer.
Good clinical response was detected even after two to four cycles of denosumab treatment from 80% (24) to 86% (38). Radiologically, a positive response (no progression in size, new bone formation in the inside or at the peripheral region of the lesion, stable disease) to treatment according to the RECIST or EORTC criteria was observed to be between 66% and 81–90% (22, 23, 25). Histologically good response is achieved, when the elimination of giant cells is complete or near complete (remaining ratio of giant cells are less than 10%), mitotic activity is reduced and new woven bone is present. Good histological response was found in cases between 100% and 79–83% following denosumab treatment (22, 25). In the study performed by Chavla and coworkers (2013), overall good response was found to treatment (good clinical, radiological and histological response) in 72% of the studied 283 patients treated with denosumab (median time: 3.2 months) (23).
Surgical downstaging and local recurrence
In GCTB patients with resectable tumours where mutilating surgery is indicated, it is of great importance whether downstaging of the tumour is achievable through preoperative neoadjuvant denosumab treatment (Figures 1 and 2). Encouraging results from a large open-label phase II trial are presented by Rutkowski and coworkers (26). In a 222 patient cohort, 106 patients (48%) could avoid surgery with continuous denosumab administration and 38% had a surgical downstaging of the lesion and a less morbid procedure performed. Ninety six per cent of the affected joints could be preserved. Similar good results were published by Perrin et al. (27), Zhang et al. (28) and Müller et al. (29) in smaller series. Moreover, the tumour volume and vascularity decreased in many cases and resection became more feasible after solidifying the extraosseous component (30).
A 20-year-old female patient. Radiograph (A), MR (B) and CT (C) images present a large lytic lesion in right the ischial bone. Histological examination revealed an aggressive otherwise benign GCTB.
Citation: EFORT Open Reviews 8, 12; 10.1530/EOR-23-0138
Denosumab treatment (120 mg denosumab monthly following the usual saturation period) was started to avoid a morbid surgery of the os ischii. After 9 months, thickening of the cortical bone and solid ossification inside of the lesion could be observed on the radiograph (A) and CT pictures (B and C).
Citation: EFORT Open Reviews 8, 12; 10.1530/EOR-23-0138
However, evidence is mounting that the incidence of local recurrence increases significantly following neoadjuvant denosumab treatment of GCTB prior to curettage (Figures 3 and 4) (31, 32, 33, 34). The underlying reason being the entrapped surviving tumour foci within the areas surrounded by the thickened neocortex. This phenomenon is often observed on different imaging studies as small lytic–cystic areas following long-term denosumab treatment (29). The surgical technique of curettage is therefore more difficult in these cases compared to de novo GCTB. In many cases incomplete excision leads to reactivation of the tumour cells after denosumab treatment is discontinued. Rutkowski and coworkers (35) reported a 32% recurrence rate following curettage in 138 patients following a median 8-month neoadjuvant denosumab treatment. Perrin et al. (27) were able to perform joint salvage procedures in 92% of their 25 patients. However, local recurrence rates were 44% at 57 months follow-up. In their meta-analysis Chen et al. (36) could also demonstrate a higher risk of local recurrence following denosumab treatment prior to curettage compared to curettage only.
Radiograph (A) and CT (B) images taken following a curettage of the defect combined with adjuvant phenolisation and bone grafting.
Citation: EFORT Open Reviews 8, 12; 10.1530/EOR-23-0138
Recurrence of the GCTB occurred 7 months after the curettage and discontinuation of the denosumab therapy presented on radiograph (A) and CT (B). Resection of the tumour was decided.
Citation: EFORT Open Reviews 8, 12; 10.1530/EOR-23-0138
Hindiskere and coworkers (25) analysed 161 patients with GCTB, and could not find any statistical differences between the results of short-term and long-term administration of denosumab when comparing radiological and histological tumour responses and local 5-year recurrence-free survival rates (73% vs 64%: P = 0.50) (41).
Similarly, a relatively high recurrence rate was found when denosumab was administered after the curettage of GCTB. Rutkowski et al. (35) reported a 34% recurrence rate, and Errani et al. (32) reported a 60% (15 out of 25 patients) local recurrence rate; the latter one was twice as high when curettage alone was performed.
There are controversial reports regarding local recurrence rate with or without the short-term preoperative administration of denosumab and curettage. Scoccianti et al. (31) did not find any differences between the two groups, Agarwal and coworkers (37) found, however, a 44% recurrence in the denosumab-treated curettage group and 21% in the curettage only group. The difference was not, however, statistically significant.
Excellent results – 0% local recurrence – were published when denosumab treatment was combined with resection of the tumour (34, 37, 38).
However, most of these publications are based on small cohorts or case series. There is a need for larger prospective multicentric and randomised studies to evaluate the effect of short/long-term neoadjuvant treatment prior to or after surgery on the rate of local recurrences. To date the appropriate length of preoperative treatment has not yet been established (Strauss et al. ESMO 2021) (39). Nevertheless, neoadjuvant administration of denosumab may be justified to enable the resection of the tumour in certain cases. However, it should be considered with caution for joint-saving surgery due to high local recurrence rates (39).
In cases of unresectable or metastatic GCTB the long-term administration of denosumab is unavoidable. Evidence is accumulating that long-term administration of denosumab results in stabilising the disease in the majority of the unresectable/metastatic GCTB cases. Chawla et al. reported a 96% success rate (163 out of 169 pts) at a median follow up of 13 months (23). In a second large multicentre phase 2 clinical trial, 267 patients had surgically unsalvageable GCTB, in 88% of them the disease was still stable (lack of progression) after 60 months median follow-up with denosumab administration (24). Other authors reported on similar good results in smaller cohorts (30, 35, 40).
Many unanswered questions arose concerning long-term denosumab treatment, side effects and eventual malignant transformation of the tumour (41). Chawla et al. (24) found a probability of disease progression by increasing time of denosumab administration: 1.6% at week 25, 3.0% at week 49 and 5.3% at week 98, respectively. They also noted risk relapse of 25%, an increased ratio of drug toxicity and other adverse events (hypercalcaemia, atypical stress fractures and osteonecrosis of the jaw) after discontinuation of denosumab treatment. Ultrashort-term (less than 3 months) denosumab treatment prior to surgery achieves the therapeutic effect of a conventional course and reduces the risk of local recurrence, as well (42). Maintenance of a stable disease in patients with unresectable/metastatic GCTB might be possible by administering reduced doses or less frequent administration of denosumab which was proposed by Lipton et al. (43) in case of treating breast cancer. The ongoing phase 2 EORTC-REDUCE study (ClinicalTrials.gov ID: NCT03620149) investigating reduced dose administration aims to provide guidelines for optimal administration of denosumab.
Safety analysis of denosumab treatment in adults
A careful analysis of adverse events related to denosumab treatment of GCTB is presented in Chawla et al. (23) interim analysis and in their large multicentre phase 2 study conducted including 532 patients (24). The long follow-up in the latter study (median 58.1 months) enabled the authors to evaluate the tolerance of denosumab treatment long-term. 84% of the patients in their interim analysis experienced at least one treatment related adverse event. Mild adverse events like arthralgia, headache, nausea, fatigue back or extremity pain occurred in more than 10% of the patients. Grade 3–4 adverse events were reported in 18% and serious adverse events in 9% of the patients. Osteonecrosis of the jaw occurred in 1%, serious infections occurred in 2%, and new primary malignancy occurred in 1%. In 5% of the patients the adverse events led to discontinuation of the participation in the study. Similar data were obtained in the large multicentre study (24) of denosumab treatment with longer follow-up. The authors found, however, that the ratio of osteonecrosis of the jaw increased with increasing denosumab exposure and all of the rare atypical femoral fractures in their patients occurred following long-term denosumab treatment. Nevertheless, longer denosumab administration led to a higher per cent of patients (12%) who discontinued the study due to adverse events. The authors found that the types and frequencies of adverse events were consistent with the known safety profile of denosumab treatment.
The topic of denosumab treatment and pregnancy is a highly interesting one. Animal studies (44) demonstrated an increased rate of still births associated with denosumab administration. Therefore, pregnancy is not advocated for women who are candidates for treatment. It is a different question if the inoperable or metastatic GCTB is recognised during pregnancy. A case was reported by Dürr et al. (2019) where the patient had an accidental but uncomplicated pregnancy during her denosumab treatment (45).
Denosumab administration in children
There are numerous diseases, such as, fibrous dysplasia, McCune–Albright syndrome, aneurysmal bone cyst, giant-cell tumour of bone, etc., where denosumab treatment may be a promising treatment option for advanced stages and complex cases. There are, however, major concerns regarding the possible side effects of denosumab on the growing human frame, as previous studies reported on inhibition of bone growth and tooth eruption in rodents and primates (Kong et al. (46)). In fact, sclerotic epiphyseal bands appear during denosumab treatment parallel to the growing plate following some months of treatment (47, 48). This seems, however, not to influence normal bone growth, the sclerotic band migrates distally and tends to disintegrate with time following cessation of denosumab treatment (49, 47). There is also a theoretical risk of impaired fracture healing but it could not be observed in the case report from (48). It seems that osteonecrosis of the jaw and atypical femoral fractures occur less frequently in children over the course of long-term denosumab therapy compared to adults. Rebound hypercalcaemia with acute kidney injury, however, has been detected to develop more frequently and in more severe form following cessation of denosumab treatment (50, 45). This may occur 4–7 months after discontinuation of the treatment. Hence, Wang et al. (49) suggest close monitoring of bone metabolism markers and education of the parents regarding the common symptoms of hypercalcaemia. The best treatment for hypercalcaemia appears to be administration of low-dose bisphosphonates to patients with normal renal function, otherwise treatment with hyperhydration and calcitonin is preferred (50). Unfortunately, there is no guideline regarding optimal dose, duration and interval for denosumab treatment in children. Some authors used standard doses and interval treatment for adolescents over 15 years of age and 45 kg (50), or for children with GCTB. Others reduced the dose (half of the standard dose or 1–1.5 mg/kg monthly) and extended the flexible interval (from 8 to 20 weeks) taking into consideration the diagnosis and the planned duration of the denosumab treatment (49). In conclusion, the data discussed here are mostly drawn from case series; so larger clinical trials are warranted to define the optimal dose and interval of denosumab treatment in children.
Malignant transformation in GCTB during denosumab treatment
Primary malignant transformation can occur in histologically proven typical giant cell tumour of bone without previous radiotherapy, but this is a rare event. Authors evaluating large GCTB patient cohorts estimate the incidence of spontaneous malignant transformation to be around 1–2% (17, 51, 52). The question arises, whether denosumab treatment – which interrupts the RANK–RANKL interaction, and alters a number of pathways in stromal cells – may play a role or promote malignant transformation in GCTB. In the literature, case reports present sarcomatous transformation of GCTB following denosumab treatment (53, 54). A detailed analysis of 532 patients in a phase 2 multicentre open-label study revealed 20 malignancies during the course of denosumab administration (55). Five primary malignant GCTB, six different giant cell-rich sarcoma cases misdiagnosed as GCTB, five secondary malignant GCTB (four out of five previously received radiotherapy) most of them already present before the onset of denosumab treatment. Only four cases of sarcomatous transformation (1%) could have been the consequence of denosumab treatment which ratio is, however, consistent with historical reports. Nevertheless, these data underline the importance of tissue sampling, a proper diagnosis before treatment both for radiological and pathological point of view. In their review article Vari et al. (56) suggest a close follow-up of the denosumab-treated GCTB patients to detect early malignant transformation even considering that this is a rather rare event.
Hasenfratz et al. (57) analysing three secondary malignant GCTB cases treated with denosumab was able to present diverging pathways during progression and malignant transformation also. They came to the conclusion that even if the suppression of RANK signalling may generate a micromilieu favourable for malignant transformation, it cannot be determined whether or not the transformation is a spontaneous event that may occasionally be associated with denosumab treatment.
Longer follow-up and larger multicentre studies are necessary to evaluate the role of denosumab treatment regarding secondary malignancy.
Future directions, potential targets
As many authors report that denosumab is a highly effective treatment option through the inhibition of the RANK–RANKL pathway in GCTB (21, 24, 26, 58). It has, however, little or no direct effect on the tumourous stromal cells, as H3F3A positive stromal cells are present in the remaining tumour tissue after denosumab treatment of GCTB. There is a need, therefore, to identify new targeted therapy directed at the neoplastic stromal cells which could be administered in combination with denosumab.
Mahdal et al. (59) in their in vitro study observed that the addition of sunitinib to the standard treatment of GCTB with denosumab resulted in the complete depletion of multinucleated giant cells and mononuclear stromal tumour cells in the tumour tissue culture. They pointed out that denosumab inhibits osteoclast-like giant cells and probably alters the phosphorylation profiles of receptor tyrosine kinases and downstream signalling proteins in the tumourous tissue. Furthermore they performed an off-label treatment with sunitinib in combination with denosumab in a patient with aggressive GCTB and achieved complete remission. They suggest a combination of denosumab with sunitinib as an effective targeted therapy in locally advanced and metastatic GCTB.
Recently, our workgroup (1) published results about the activation of the tyrosine kinase receptor (PDGFRß) on mononuclear tumour cells in GCTB during denosumab treatment. According to the retrospective immunohistochemical investigation of our five patients with local recurrent GCTB we found that during denosumab treatment the giant cells were completely absent with severe or mild fibrosis, but H3F3A-positive tumour cells could be observed continuously in all cases. Furthermore, an increased immunopositivity of PDGFRß in stromal cells was evident in all recurrent cases during denosumab treatment. After discontinuation of denosumab treatment the intensity of PDGFRß immunostaining in tumour cells decreased significantly to baseline. Based on our experience, the increased activity of PDGFRß during denosumab treatment warrants an eventual combined administration of denosumab and sunitinib in unresectable or metastatic GCTB. Sunitinib is a multitargeted tyrosine kinase inhibitor drug, highly effective regarding anti-angiogenesis. It is approved and successfully used in the treatment of hypervascularised bone metastases of renal cell carcinoma.
Wang et al. (60) presented a case report in 2019 of an effective combined treatment of denosumab and sunitinib. Detailed examinations revealed an extensive paravertebral tumour mass in the patient compressing the spinal cord and a node in the upper lobe of the lung. GCTB was diagnosed via histological evaluation of biopsy material. Two months after surgical resection and posterolateral fixation, local recurrence occurred; therefore, denosumab therapy was initiated. It failed, however, to stabilise the recurrent lesion and the formation of pulmonary metastases, and a rapid progression occurred. Reevaluation of the histology confirmed the original diagnosis of GCTB. The authors complemented the denosumab with tyrosine kinase inhibitor sunitinib, which resulted in a dramatic improvement of clinical symptoms and decrease in the size of the multiple pulmonary metastases. At 4-year follow-up the patient is still alive.
The role of denosumab in other giant cell-rich tumours
The encouraging results of denosumab treatment in GCTB and the pathogenic similarity between aneurysmal bone cysts, central giant-cell granulomas, and GCTB suggests, that the use of denosumab may also be beneficial and effective in these diseases. Information on the off-label use of denosumab is mostly published in case reports and case series meaning divergency regarding patient cohort, treatment protocols and follow-up periods.
Central giant cell granuloma (CGCG) is a rare benign bone tumour that most commonly affects the jaw. The mainstay of surgical treatment is curettage. Resection may result in unacceptable functional or cosmetic results. Recurrence rates are high in this group; between 49% and 72% (61). Several case reports and case series reported on denosumab treatment in recurrent or highly aggressive CGCG (62, 63, 64, 65). Similar to the results of denosumab treatment in GCTB, ossification, and, on occasion, regression of the lesion was recorded along with a complete clinical response. The authors concluded that denosumab may be considered as an alternative treatment option in selected cases of CGCG (66). For a more detailed analysis of the role of denosumab in the treatment of giant cell-rich tumours, there is an ongoing European prospective phase II trial being conducted (http://clinicaltrials.gov, NCT03605199).
Aneurysmal bone cyst (ABC) is an infrequent, benign but locally aggressive tumour that most commonly occurs in childhood and early adulthood. Cytogenetic studies reported a specific translocation of the ubiquitin-specific protease (USP) 6 gene in 75% of primary ABCs, which allows for differentiating primary ABCs from other secondary ABC often present in GCTB, chondroblastoma or even in osteosarcoma (67). This pathway is different from that seen in GCTB, but overexpression of the receptor activator RANKL plays a key role in bone remodelling in both diseases (68). There is a broad spectrum of treatment options available for ABC including surgical resection, curettage with or without adjuvant treatment (phenolisation, hydrogen peroxide, etc.), embolisation of the supplying arteries or sclerotherapy with Ethibloc or polidocanol. However, the rate of local recurrences and complications related to these therapeutic measures are rather high and a tumour location in the spinopelvic or the skull area may make surgery extremely difficult. In these highly selected cases the implementation of further innovative therapies like denosumab treatment may be justified.
Recently the results of two case series regarding the off-label use of denosumab treatment in ABC were published. Palmerini et al. (69) presented nine patients with ABC. The indications included cases where surgery was associated with severe morbidity (spine) or arterial embolisation failed. Administration and dosage of denosumab was similar to that used in GCTB. Pain relief and improvement of paresthesia occurred in all symptomatic patients, sustained tumour control was achieved in all cases, however, the follow-up time was short, only 23 months on average. No major adverse events were reported. Dürr et al. reported on six ABC patients with sacral and pelvic involvement (45). A talar lesion was resistant to therapy, and one lesion in the pelvis improved but recurred after 1 year. Severe hypercalcaemia occurred in a 7-year-old boy 6 months after discontinuation of denosumab.
Most recently, Maximen et al. (70) evaluated the role of denosumab in ABC based on a systematic literature review and meta-analysis. They summarised the results of 43 cases from 17 articles. Improvement of both pain and neurological deficits was reported in all of the patients suffering from these symptoms. In 36 out of 39 cases, ossification of the lesion and reduction in size were demonstrated on radiological findings, and in further two cases the lesions remained stable. There were eight recurrences (19%) in the series (mean duration of denosumab treatment: 13.2 ± 6.1 months) 11 ± 6 months after discontinuation of treatment, most of them in adult patients. Histology could be performed in eight cases following denosumab treatment. The results were similar to that found in GCTB: hypocellular fibrous stroma, new bone formation, no osteoclast-like giant cells. During the relatively short follow-up period 25% of the patients mainly reported having mild adverse events related to denosumab therapy. Only one child presented with ossification of the growth plate in the lower limb, and there were six cases of hypercalcaemia (5.3 months after cessation of the treatment), typically in the paediatric population.
In conclusion, presently the administration of denosumab is contraindicated in children before skeletal maturity due to cancers regarding linear growth (due to growth plate ossification) or teeth eruption. Encouraging results were published, however, with off-label use of denosumab in children with fibrous dysplasia, osteogenesis imperfecta, juvenile Paget’s disease, Langerhans cell histiocytosis, etc. with reassuring tolerance in children (49), (ClinicalTrials.gov ID: NCT03620149). Therefore, denosumab treatment in ABC – including the younger population – may be a useful treatment option in selected cases.
Conclusions
At present, denosumab presents a highly effective therapeutic measure in advanced, unresectable or metastatic GCTB. Even a short-term (4–6 cycles) neoadjuvant administration of denosumab (4–6 months) may stabilise the disease, decrease clinical symptoms, alter histological characteristics and enable a downstaging of the tumour; therefore, a less morbid surgery may be performed (salvaging the adjacent joint, avoid amputation, etc.). Dosage has been well-established, short-term adverse effects are consistent with those observed during administration for other metastatic lesions. Lifelong treatment should be avoided if possible, as the risk of side effects increases with time and the overall administered volume of denosumab. This poses many yet unanswered questions, i.e. how long should the drug be administered, what is the optimal dose and frequency of denosumab for the long run?
Data from the literature confirm that the local recurrence rate following neoadjuvant denosumab treatment and curettage of the defect is the same or even higher than reported following curettage (+/− local adjuvants) only. The underlying reason being more advanced stages and the commonly observed survival of tumour cells in the newly formed peripheral bone. On the other hand, in most cases the affected joint can be preserved.
Denosumab is an effective suppressive therapy in GCTB, it has, however, only a limited effect on the stromal cells of the tumour. Promising ongoing in vitro studies suggest the administration of further drugs (e.g. simvastatin) or of a combination of a new drug (e.g. sunitinib) with denosumab. Further in vitro and in vivo studies are, however, necessary before implementation of these new targeted therapies.
Denosumab treatment was also published in off-label use in other giant cell-rich bone tumours like giant cell granuloma or aneurysmal bone cyst, which also present a RANK/RANKL overexpression. The results are encouraging and similar to that found in GCTB. These case reports and case series, however, present a divergency regarding patient cohort, treatment protocols and follow-up periods. Large prospective clinical trials are needed to evaluate the role and also the side effects of denosumab in the treatment of these rare diseases.
ICMJE Conflict of Interest Statement
The authors, declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding Statement
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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