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Curr Oncol, Vol. 20, pp. e442-447; doi: http:/ dx.doi.org/10.3747/co.20.1497 DENOSUMAB AND GIANT CELL TUMOUR OF BONE R E V I E W A R T I C L E
Denosumab and giant cell
tumour of bone—a review and future management considerationsS.F. Xu md phd,* B. Adams md,† X.C. Yu md phd,* and M. Xu md* specimen revealed a tumour mass with histologic features of pronounced osteogenesis and no more Giant cell tumour of bone (gctb) is one type of giant- evidence of gctb. This case demonstrated a major cell-rich bone lesion characterized by the presence tumour response to denosumab in the neoadjuvant of numerous multinucleated osteoclast-type giant setting, with a complete pathologic response.
cells. Giant cells are known to express rankl (re- Is denosumab a breakthrough in the treatment ceptor activator of nuclear factor κB ligand) and are of gctb? We reviewed the literature focusing on de- responsible for the aggressive osteolytic nature of the nosumab and gctb, and here we discuss the biggest tumour. No available treatment option is definitively questions related to the future management of gctb.
effective in curing this disease, especially in surgi- cally unsalvageable cases. In recent years, several 2. GIANT CELL TUMOUR OF BONE
studies of denosumab in patients with advanced or unresectable gctb have shown objective changes in As one type of giant-cell-rich lesion of bone, gctb tumour composition, reduced bony destruction, and is characterized by the presence of numerous mul- clinical benefit.
tinucleated osteoclast-type giant cells, and in this Denosumab is a fully human monoclonal anti- mesenchymal tumour, the mononuclear stromal body that targets and binds with high affinity and cells are the neoplastic cell type2. The giant cells specificity to rankl. Several large phase iii studies have been confirmed to express rankl and are re- have shown that denosumab is more effective than sponsible for the aggressive osteolytic nature of the bisphosphonates in reducing skeletal morbidity aris- tumour3. Although generally benign, atypical gctb ing from a wide range of tumours and that it can delay may be associated with multiple local recurrences, bone metastasis. The relevant articles are reviewed multicentricity, pulmonary metastases, or lesions that here. The controversies related to the future use of cannot be removed surgically without causing sub- denosumab in the treatment of gctb are discussed.
stantial morbidity4. The World Health Organization therefore classifies gctb as "an aggressive, potentially KEY WORDS
malignant lesion"5.
In the United States, gctb accounts for ap- Denosumab, giant cell tumour of bone, receptor acti- proximately 5% of all primary bone tumours and vator of nuclear factor κB ligand, rankl, bone turnover 20% of all benign bone tumours in adults6. About 50−60 new cases of gctb are managed by special- ist health care services each year in the United Kingdom7. The disease is more common in China Recently, successful cure in a case of unusual giant and India, where it constitutes approximately 20% cell tumour in the thyroid was reported1. A 38-year- of all primary bone tumours5. Giant cell tumour of old man with a giant cell tumour of bone (gctb) in bone occurs most commonly during the second to the thyroid cartilage—initially treated as a thyroid fourth decades of life (60%–75%) and has a male- cancer—was proposed for treatment with denosum- to-female ratio in the range 1:1.2 to 1:1.52,5. Most ab, a rankl (receptor activator of nuclear factor κB lesions develop in the long bones (75%–90%), with ligand) inhibitor. After 3 months, computed tomog- most cases (50%–65%) occurring near the knee1,2,8. raphy imaging showed significant modification of Other frequent sites are the distal radius, proximal the lesion, with several calcifications involving more humerus, fibula, sacrum, and vertebral body (fewer than 50% of the initial tumour volume. The surgical than 3% of cases)2,8. In no reported case has gctb e442 Current OnCOlOgy—VOlume 20, number 5, OCtOber 2013
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extended from the metaphysis into the epiphysis most commonly used drug in oncologic settings19. across an unfused physis8.
However, elucidation of the signalling pathways that In 80% of cases, the course of gctb is benign, but regulate bone cell function and, in particular, rec- the local recurrence rate is 20%–50%. About 10% of ognition of the role of rankl in bone resorption has tumours undergo malignant transformation at recur- provided potential therapeutic targets for inhibiting rence, and 1%–4% give rise to pulmonary metastases even in cases of benign histology5,9. Most pulmonary Expression of rankl on stromal cells is regu- lesions are histologically benign, with an appearance lated by a wide range of endogenous hormones and similar to that of the primary bone tumour. Although factors that either upregulate rankl itself or inhibit some patients live a long time with pulmonary me- the expression of osteoprotegerin (opg). rankl is tastases, distant metastasis of gctb typically does essential to the formation, function, and survival not respond well to chemotherapy2. Recurrent gctb of osteoclasts. In bone metastasis, stimulation of may undergo malignant transformation to malignant osteoblasts by tumour-secreted factors increases osteoclastoma, fibrosarcoma, or osteosarcoma. Ra- the expression of rankl, which binds osteopro- diation therapy can lead to a transformation to high- tegerin and leads to increased bone resorption. grade sarcoma (fewer than 1% of treated patients) or Denosumab interrupts that cycle by binding to development of secondary malignancies (up to 15% rankl and preventing the formation and function of treated patients)2,5,8.
of osteoclasts20,21. Surgery is the typical treatment for gctbs, with The first study to test the therapeutic potential of recurrence rates of 15%–45%8,10. The recurrence rankl inhibition with respect to osteoclast function rate after intralesional surgery dropped to 12%–14% used a recombinant opg molecule (AMGN0007)22. with the use of a high-speed burr and allograft An antiapoptotic role of opg has also been proposed or bone cement11,12. In cases of local recurrence, in various preclinical tumour models23, and although therapy consists of repeated intralesional curettage its relevance in human malignancy is unknown, this or wide surgical resection, avoiding mutilating pro- potential adverse effect of opg in the cancer setting cedures. Compared with intralesional surgery, wide led to the selection of alternative (antibody-based) ap- resection is associated with a lower recurrence rate proaches to rankl inhibition for further development.
(5% vs. 25%), which raises the complicated problem Inhibition of rankl not only reduces the rate of of reconstruction9.
bone resorption, but might also inhibit the develop- When pulmonary involvement is diagnosed, ment of bone metastases. In animal models, inhibi- surgical resection of the metastasis, if feasible, may tion of rankl activity by binding to recombinant be proposed, because prognosis remains favorable antibody constructs of either opg–Fc or rank–Fc have in 80% of cases13. About 20% of the patients with unequivocally demonstrated a functional inhibition metastases of the continuously slow-growing and of rankl-induced osteoclastogenesis24. Furthermore, rapidly growing types would die of their disease inhibition of rankl prevents invasion and metasta- if untreated. Radiation therapy can be considered. sis by human osteosarcoma cells25 and reduces the Recently, seemingly improved local control in 65 of development of lung metastases in a murine model 77 patients (84%) was reported14. However, the main of osteosarcoma26.
limitation of irradiation is the potentially high risk Denosumab is a fully human monoclonal rankl of sarcomatous transformation (5%–29%), especially antibody (IgG2) that targets and binds with high af- for doses above 45 Gy15.
finity and specificity to rankl, preventing its binding Medical therapy for gctb is experimental and to rank on the surface of osteoclast precursors and based largely on theories about the causes of the osteoclasts, thereby inhibiting osteoclast differentia- disease. Bisphosphonate therapy is currently used tion, activation, and survival. Denosumab inhibits in gctb because of its anti-osteoclastic effects. The osteoclast-mediated bone destruction and provides local recurrence rate was 4.2% in patients treated rapid and sustained suppression of bone turnover with bisphosphonate and 30% in a control group16. in patients with multiple myeloma, osteolytic bone Combined treatment followed by administration of disease, and bone metastases from breast and prostate interferon alfa resulted in a high rate of gctb control cancers27–29. Inhibiting rank and rankl may elimi- and reduced surgical morbidity17. Based on the thera- nate osteoclast-like giant cells and their associated peutic effect up to 6 years, it has also been supposed mononuclear cells in gctb7.
that there is a role for interferon in chemotherapy- Studies in cynomolgus monkeys show a dose-de- refractory gctb18.
pendent inhibition of bone resorption and an increase in bone mineral density (bmd) with denosumab30. The 3. RANKL SIGNALLING
first clinical study of denosumab in postmenopausal women showed that a single dose of denosumab Since the early 1990s, bisphosphonates have been (3 mg/kg) resulted in a rapid, dose-dependent, and the standard treatment for benign and malignant sustained decrease in urinary N-terminal telopep- bone diseases alike, with zoledronic acid being the tide, which remained suppressed for 6 months after Current OnCOlOgy—VOlume 20, number 5, OCtOber 2013 e443
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DENOSUMAB AND GIANT CELL TUMOUR OF BONE treatment31. Studies in patients with breast cancer Because denosumab has been shown to inhibit os- and bone metastases indicated that treatment with teoclast function via the rank/rankl pathway, it has 120–180 mg of denosumab every 4 weeks provided been thought to inhibit the activity of osteoclast-like the most reliable and consistent suppression of uri- giant cells in gctb.
nary N-terminal telopeptide29. As a result, treatment Given the clear role of rankl in gctb, denosumab with denosumab 120 mg every 4 weeks was chosen was studied in a proof-of-principle phase ii study in in subsequent studies to provide the optimal balance 35 patients with recurrent or unresectable gctb39. of efficacy and tolerability.
Denosumab was administered by subcutaneous in- A study of 252 postmenopausal women with jection at 120 mg every 4 weeks, with an additional early-stage breast cancer found a significant dif- loading dose of 120 mg on days 8 and 15 of the first ference of 7.6% in lumbar spine bmd between the cycle. Of 35 evaluable patients, 30 (86%) experienced denosumab and placebo groups32. In a placebo- a tumour response, defined as near-complete elimina- controlled trial of denosumab in 1468 men receiv- tion of giant cells upon repeat biopsy after treatment ing androgen-deprivation therapy for nonmetastatic (all evaluable patients) or radiographic stabilization prostate cancer, 36 months of denosumab treatment of disease at 6 months (10 of 15 evaluable patients). was associated with a significantly reduced incidence Although formal assessment of pain and quality of new vertebral fractures33.
of life was not mandated in this proof-of-principle A study published in The Lancet reached the study, data collected from 31 patients showed that 26 conclusion that denosumab treatment significantly reported reduced pain or functional improvement. increased bone metastasis–free survival and signifi- Radiologic evidence of bone repair was reported in 9 cantly delayed both the time to first bone metastasis patients. Response was usually associated with rapid and the time to first symptomatic bone metastasis34. changes in metabolic uptake as measured by fluoro- The first evidence suggesting that denosumab deoxyglucose positron-emission tomography imag- might be superior to bisphosphonates in terms of ing, usually within 4 weeks of treatment start. As preventing skeletal morbidity was reported in a noted earlier, marked suppression of bone turnover randomized phase ii study conducted in patients was observed, with reductions in urinary N-terminal with bone metastases caused by various tumour telopeptide and serum C-telopeptide as early as 28 types28. Subsequently, three identical double-blind days after the first dose that were sustained for the phase iii registration studies of denosumab were duration of the study. The treatment was generally completed35–37. Denosumab treatment delayed the well tolerated, without serious treatment-related occurrence of all types of skeletal-related events adverse events. Blockade of rankl signalling in pa- (sres), including pathologic fractures, the need for tients with recurrent or unresectable gctb resulted in either radiotherapy or surgery to bone, and the oc- objective changes in tumour composition, reduced currence of spinal cord compression. The suppres- bony destruction, and clinical benefit—at least to the sion of markers of bone resorption was significantly extent measured in this particular study.
higher with denosumab than with zoledronic acid in In a recent phase ii study, denosumab given to pa- all three studies. Overall, efficacy with denosumab tients with surgically salvageable and unsalvageable was significantly superior to that with zoledronic gctb was well tolerated and associated with inhibited acid35–37. Because of those findings, denosumab disease progression (99%) and a reduced requirement was granted marketing authorization in the United for surgery40. At least 90% tumour necrosis was also States in 2010 and in Europe in 2011 for the preven- reported to have been found among gctb cases after tion of sres in adult patients with solid tumours. On the administration of denosumab8. Preoperative October 24, 2012, the U.K. National Institute for denosumab treatment was also suggested to poten- Health and Clinical Excellence published guidelines tially make subsequent surgical resection easier in for the use of denosumab to prevent sres in adults patients with aggressive gctb who are poor surgical with bone metastases from solid tumours38.
candidates or in whom the tumour is in a location difficult to treat surgically.
4. ACTIVITY OF DENOSUMAB IN GCTB
Given all of the foregoing findings, denosumab can be used for the treatment of recurrent gctb and In 2000, it was reported that, in patients with gctb, surgically unsalvageable gctb (for example, sacral inhibition of rankl by denosumab could potentially or spinal gctb, or multiple lesions including pul- inhibit the destructive process and eliminate the monary metastases), and in patients whose planned population of giant cells3. The osteoclast-like giant surgery includes joint resection, limb amputation, cells and their precursors express rank, and some hemipelvectomy, or another procedure resulting in mononuclear cells (stromal cells) express rankl. severe morbidity.
It is possible that the recruitment of osteoclast-like The most common adverse events associated with giant cells is related to stromal cell expression of denosumab during use for its licensed indications in- rankl and that the giant cells are responsible for clude urinary tract infection, upper respiratory tract the aggressive osteolytic activity of the tumour39. infection, dyspnea, sciatica, cataracts, constipation, e444 Current OnCOlOgy—VOlume 20, number 5, OCtOber 2013
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diarrhea, rash, hyperhidrosis, pain in extremities, contraindicated in patients on denosumab, but ra- hypocalcemia, hypophosphatemia, tooth extraction, diotherapy to the pelvis is likely to affect gonads and osteonecrosis of the jaw41. Daily supplements of and uterus. A decision either way depends on how calcium 500 mg and vitamin D 400 IU are recom- long denosumab is required, because gctb is rarely mended to prevent these adverse events39.
life-threatening and can be considered a chronic In all three of the phase iii registration studies disease. The initial phase ii study of denosumab discussed earlier, osteonecrosis of the jaw was as- in gctb did not address outcomes in participants sociated with both denosumab (1.8%) and zoledronic who stop treatment39. Oral side effects (suspected acid (1.3%)35–37. Acute-phase reactions characterized by investigators to be osteonecrosis of the jaw, or by fever, myalgia, and bone pain were observed meeting predefined criteria for osteonecrosis of within the first 3 days of treatment in about 20% of the jaw) should be assessed46. The relapse rate, the patients treated with zoledronic acid; only 8.7% of biomarkers that predict relapse, and the options patients treated with denosumab experienced such for therapy after relapse also need to be defined. reactions42. Hypocalcemia was more frequent with Follow-up to the study might not have been adequate denosumab than with zoledronic acid (9.6% vs. to document the safety and efficacy of denosumab 5.0%), although all patients were encouraged to take in the treatment of gctb47.
calcium and vitamin D supplements42. Reassuringly, A separate issue is whether denosumab can fa- the incidence of infectious episodes was similar in the cilitate definitive therapy. Whether denosumab can groups of patients treated with denosumab and zole- reduce the extent of surgery required for patients dronic acid in all three studies35–37. No statistically with Campanacci iii48 gctb and can reduce recur- significant differences were reported in the incidence rence rates after definitive surgery is unknown. If of cardiovascular adverse events, new malignancies, lifelong denosumab is required for gctb, what is or injection site reactions, and no patient developed the optimal schedule of therapy? If patients have neutralizing anti-denosumab antibodies.
to receive long-term therapy, is a monthly dosing A systematic review of 25 studies for denosumab schedule optimal? The effect of denosumab on the in osteoporosis concluded that, compared with pla- developing skeleton has not been established. More cebo and alendronate, denosumab was associated generally, a long-term safety program in younger with greater and sustained increases in bmd and a patients who receive prolonged therapy with deno- reduction in bone turnover markers. Denosumab sumab ought to include formal measures of bmd as was also associated with a risk of urinary infections well as sres. The question of whether the effect of and eczema43.
denosumab for gctb is only temporary or whether In a network meta-analysis, denosumab was long-term or definitive control can be achieved found to be more effective than zoledronic acid, pla- remains open. The genetic basis for stromal over- cebo, and pamidronate in delaying the time to a first expression of rankl is unknown, and it is possible sre and in reducing the risk of first and subsequent that gctb represents a pathologic variation of the sres during treatment of bone metastases secondary to normal physiologic interdependence of osteoblast solid tumours44. Recently, a systematic review of the and osteoclast populations in bone. Support for the literature that included 6142 patients set out to deter- latter possibility is found in the existence of cur- mine the efficacy and safety of denosumab in reducing rently unknown reciprocal signals that maintain the sres in patients with bone metastases45. Denosumab stromal population in an immature and presumably was more effective than zoledronic acid in reducing rankl-expressing state. Hopefully, a current clini- the incidence of sres; it also delayed the time to sres. cal study (search for NCT00680992 at No differences were found between denosumab and ) with 511 enrollments, whose zoledronic acid in overall mortality reduction or in eligibility criteria now extend to skeletally mature the overall frequency of adverse events.
patients 12 years of age and older will address those questions; however, randomized studies will ultimately be required.
Finally, denosumab may offer clinical utility in Clearly, for some patients with advanced, progres- other giant-cell-rich neoplastic disorders, including sive, or symptomatic heavily pretreated gctb, deno- giant cell reparative granuloma of the mandible, sumab provides a therapeutic option not previously tenosynovial giant cell tumour, chondroblastoma, available. However, the risk–benefit balance of ther- giant-cell-rich pilar tumours, and perhaps malignant apeutic alternatives (including denosumab) remains conditions associated with giant cell infiltration.
a complex problem requiring more data. A common scenario is a large sacral gctb for which surgical or radiotherapeutic approaches carry significant long-term consequences. In particular, reproductive Denosumab is a highly effective and specific antago- decision-making appears to be an important factor nist of rankl, which represents an exciting paradigm in a younger population. Pregnancy is absolutely for targeted translational research in diseases such Current OnCOlOgy—VOlume 20, number 5, OCtOber 2013 e445
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DENOSUMAB AND GIANT CELL TUMOUR OF BONE as gctb. Denosumab clearly interdicts bone destruc- with curettage and bone-grafting. J Bone Joint Surg Am tion and may offer symptom and disease control for patients with few other options. The optimal use and 12. Klenke FM, Wenger DE, Inwards CY, Rose PS, Sim FH. long-term effects of denosumab in the young popula- Recurrent giant cell tumor of long bones: analysis of surgical tion primarily affected by gctb remain to be defined. management. Clin Orthop Relat Res 2011;469:1181–7.
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