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  • Numerous clinical trials phase II and

    2019-05-15

    Numerous clinical trials (phase II and phase III) have been then designed to evaluate the efficacy of denosumab in oncology mainly in breast and prostate bone metastases (Table 1). These studies revealed that denosumab reduced significantly bone turnover markers similarly to osteoporotic patients. More specifically, it reduced levels of uNTX/Cr as well as serum TRAP5b thus showing a marked inhibition of osteoclastogenesis. According to the results obtained, the recommendations for the use of denosumab are 120mg s.c. every 4 months in oncology. Using this dose, bone resorption markers are suppressed around 90% in most patients independent of the tumour types [103]. Various studies have been set up to compare denosumab versus bisphosphonate treatment mainly zoledronic CA074 [95–97,103,109]. Single dose of pamidronate for instance (90mg i.v.) reduced in a similar intensity the levels of bone resorption markers but the effects of denosumab were more sustained [95]. Phase III study demonstrated that denosumab significantly delayed the time of first SRE (Skeletal Related Event) but also the risk of multiple SRE and whether zoledronic acid showed similar effects, statistical analyses are in favour of superiority for denosumab (Table 1). The time of disease progression and the overall survival rate were similar between anti-RANKL treatment and bisphosphonate. Zoledronic acid treatment requires a strict monitoring of kidney function due to its toxicity in contrast to denosumab even if a greater hypocalcemia requiring specific monitoring has been classically observed after denosumab treatment [111]. In addition to the phase acute phase reaction observed in patients after the first administration of zoledronic acid, osteonecrosis of the jaw occurred infrequently after long-term treatment by nitrogen-bisphosphonates, in around 2% of patients [97,108,109,112–115]. This incidence appears similar in bisphosphonate- and denosumab-treated patients. Consequently, the establishment of meticulous oral hygiene and surgical procedures prior to the administration of bisphosphonates and denosumab is the best method for preventing osteonecrosis of the jaw; prevention being better than treatment. In all studies, denosumab was well tolerated with the convenience of a subcutaneous administration and no requirement for renal monitoring. Overall, these clinical trials demonstrated that denosumab represents a potential treatment option economically viable for patients with bone metastases [116]. Very recently, a novel anti-RANKL antibodies derived from camelidae has been assessed in postmenopausal patients [117]. The results from this Phase I trial, including the one year follow-up information, indicate that ALX-0141 is well tolerated and can be administered safely over a wide range of doses. ALX-0141 exhibited a strong and sustained inhibitory effect on bone resorption markers.
    The other anti-resorptive in therapies of bone cancer Bisphosphonates have been used successfully for many years to treat the skeletal complications associated with the benign and malignant bone diseases [118–121]. Bisphosphonates became progressively a standard treatment for cancer-associated with hypercalcemia and to control metastatic bone pain. Bisphosphonates are chemical compounds based on a phosphorus–carbon–phosphorus template and are characterised by their strong affinity for bone hydroxyapatite crystals and their anti-resorptive potency. Three families of bisphosphonate have been produced: the first possesses simple substituents attached to the central carbon and inhibits weakly the bone resorption; the second family possesses an aliphatic side chain containing a single nitrogen atom and exerts a more potent anti-resorptive activity; the third generation contains a heterocyclic substituent with one or two nitrogen atoms and are powerful bone resorption inhibitors and anti-tumour agents [118,119]. The members of the first family which do not contain nitrogen atom are metabolised in cytotoxic analogues of ATP leading to cell death. Nitrogen-containing bisphosphonates inhibit the activity of two enzymes involved in the mevalonate pathway: farnesyl diphosphate synthase (FPP) and geranylgeranyl diphosphate synthase (GGPP). This inhibition results in osteoclast apoptosis by the strong reduction of the prenylation process, the loss of osteoclastic ruffled border and modifications of cell cytoplasmic actin ring [118,119]. Additionally, nitrogen-containing bisphosphonates exert direct activities on tumour cells (breast, prostate, lung renal carcinoma, osteosarcoma, chondrosarcoma, etc.) through the inhibition of prenylation mechanim which induces tumour-cell apoptosis, inhibits cell proliferation, modulates tumour-cell adhesion and inhibits tumour-cell dissemination [118–124]. Thus, bisphosphonates inhibit the development of bone tumours through direct activity on tumour cells and indirect activity on osteoclasts. Pre-clinical studies revealed the therapeutic benefits of bisphosphonates for the treatments of primary bone tumours and bone metastases alone and in combination with chemotherapy or signalling pathway inhibitors [125–133]. Clinical trials have clearly confirmed their therapeutic interests (Table 1).