Bisphosphonate and Denosumab Therapy: Fields of Application

Fig. 2.1

Mechanisms of action of denosumab and bisphosphonates. RANKL is secreted by osteoblasts and binds to the RANK receptor on osteoclasts, promoting osteoclast differentiation and activation. Denosumab binds RANKL and thereby inhibits the RANKL-RANK pathway. Bisphosphonates bind to the bone and enter and thus inhibit resorption by activated osteoclasts (Modified according to Yee and Raje [54] with kind permission of dove medical press)
Denosumab is injected subcutaneously. Dosing ranges from 60 mg every 6 months in order to preserve bone density in postmenopausal women to 120 mg every 4 weeks in the setting of malignant disease metastatic to the bone. In contrast to bisphosphonates, denosumab does not accumulate in the bone and its effect is reversible after treatment discontinuation. The circulatory half-life is about 26 days [54].
The indications of denosumab are principally similar to bisphosphonates. However, certain aspects have to be taken into account for the therapeutic decision. The efficacy of denosumab in preventing skeletal-related events was demonstrated to be at least equal to zoledronate [55, 56] but seems to partly depend on the disease type. Denosumab treatment in postmenopausal osteoporosis results in a rapid and sustained reduction of bone turnover markers, a marked increase in bone mineral density and a decrease in fracture risk [57]. In breast [58] and prostate cancer [59] patients, suppression of bone turnover markers is greater than by zoledronic acid. In patients with cancer types other than breast or prostate (mainly lung and multiple myeloma) [55], denosumab was equipotent to zoledronate in preventing skeletal-related events.
The side effect profile of denosumab and bisphosphonates is partly overlapping. Especially adverse effects directly mediated by bone remodeling inhibition, namely, osteonecrosis of the jaw (ONJ), occur with similar frequency under treatment with denosumab and zoledronic acid [55, 56]. Acute-phase reactions, which are frequent after zoledronic acid application, occur rarely after denosumab [55]. Yet it has to be taken into account that the RANKL-RANK signaling pathway is not restricted to osteoclastogenesis: RANKL is a co-stimulatory cytokine for T cell activation [60] and lymphocyte development [61]. Concordantly, an increased infection rate was shown in patients with osteoporosis or early breast cancer treated with denosumab [62]. The interference with the immune system may also increase the risk of neoplasms [57]. Importantly, there is evidence hinting at a worse survival in patients with multiple myeloma treated with denosumab compared to zoledronate [55]. Thus, denosumab is thus currently not indicated in the setting of multiple myeloma. On the other hand, preclinical data from animal models of breast cancer and melanoma suggest a role of the RANKL-RANK signaling pathway in tumor genesis and metastasis [63, 64], and limited data indicates that denosumab may reduce disease progression in prostate cancer patients [54]. Furthermore, overall survival was not different in breast [58] and prostate cancer [59] patients treated with denosumab or zoledronic acid. Altogether, data concerning the possible antitumor effect of denosumab in comparison with bisphosphonates is still insufficient. The post-market period of denosumab is still comparably short and yet unknown side effects may emerge. Therefore, vigilance regarding adverse events related to possible effects of RANKL inhibition in tissues other than bone or to bone turnover over-suppression is mandatory [65].
In contrast to bisphosphonate clearance, denosumab clearance is largely independent of renal function, since, similarly to other monoclonal antibodies, denosumab is cleared by the reticuloendothelial system [66]. Subsequently, denosumab does not require dose reduction in case of renal dysfunction, is not contradicted in patients with renal failure [54], and thus seems to be the safest treatment option for patients with impaired renal function [65].
Denosumab is cost-effective compared to no treatment for fracture prevention in postmenopausal women with osteoporosis [57]. However, the estimation of the cost-effectiveness in comparison to bisphosphonates depends on the analytical perspective and model parameters and varies in different economic evaluations [67, 68].
Taken together, denosumab may be a suitable alternative to bisphosphonate therapy in certain settings, for example, for patients with postmenopausal osteoporosis or breast or prostate cancer, who suffer from renal impairment or are unable or refuse to take bisphosphonates.

Conclusions

Bisphosphonates and denosumab are routinely used in the treatment of malignant and nonmalignant diseases with increased osteoclast activity. They effectively reduce skeletal-related events in patients suffering from osteoporosis and metastatic bone disease. Generally, side effects of bisphosphonate and denosumab treatment are infrequent, and they always have to be interpreted with regard to the underlying disease.
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Nov 4, 2015 | Posted by in General Dentistry | Comments Off on Bisphosphonate and Denosumab Therapy: Fields of Application
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