21 July, 2014

Bone antiresorptives, mostly bisphosphonates, are used in the treatment of metastatic bone disease from solid malignancies to reduce bone destruction, pain and skeleton-related events (SREs). Von Moos and colleagues [1] have reported pooled results from three randomized, identically designed, double-blind trials comparing subcutaneous denosumab (120 mg every 4 weeks) and intravenous zoledronic acid (4 mg/month) in patients with bone metastases from breast cancer (n = 2406), castration-resistant prostate cancer (n = 1901) or other solid tumors (n = 1597). The endpoints were pain severity, pain interference, health-related quality of life and analgesic use. Onset of moderate/severe pain was delayed by 1.8 months by denosumab treatment (hazard ratio (HR) 0.83; 95% CI 0.76–0.92; p  <  0.001) and clinically meaningful increases in overall pain interference by 2.6 months (HR 0.83; 95% CI 0.75–0.92; p <  0.001) as compared with zoledronic acid. In addition, the need for strong opioids and reduction of health-related quality of life were less common with denosumab.

Comment

Breast cancer and prostate cancer are the most prevalent malignancies in women and men, respectively. Many adjuvant treatments are associated with reproductive hormone alterations which are involved in bone mass and quality. Thus, adjuvant aromatase inhibitors and gonadotropin-releasing hormone analogues are frequently used in women with non-metastatic breast cancer. Such treatments may accelerate bone loss and increase fracture risk. In breast cancer patients with osteopenia, subcutaneous denosumab administration (twice yearly) produces significant increases in bone mineral density (BMD), both at trabecular and cortical bone, without adverse events [2]. Denosumab also increases BMD and reduces the incidence of new vertebral fractures among men under androgen-deprivation therapy for non-metastatic prostate cancer [3]. In these non-metastatic cancers, zoledronic acid has similar protective anti-osteoporotic effects as denosumab, although some related adverse effects have been reported with this bisphosphonate [4,5].

Bone metastases are frequent complications from malignant solid cancers and may be associated with pain, fracture risk, hypercalcemia and worsening of quality of life. SREs cause devastating clinical evolution that may require pharmacological treatments, surgical interventions or radiotherapy, repeated admissions and a large economic burden. Pharmacologic treatments include analgesics, glucocorticoids, chemotherapy and osteoclastic inhibitors. Intravenous bisphosphonates reduce SREs in patients with bone metastases. However, not all patients respond well and adverse effects are not infrequent. Bone-targeted agents are complementary to improve quality of life and reduce SREs [6]. The therapeutic objective is to palliate symptoms while disease is rarely cured.

Denosumab is a fully human monoclonal antibody (IgG2) that binds to the receptor activator of nuclear factor kappa-B ligand (RANKL), one of the mediators of osteoclast differentiation. Denosumab has been approved for osteoporosis and hormone-related bone loss. More recently, scientific evidence is accumulating for its use in bone metastases, giant cell tumor of the bone and multiple myeloma. It has the potential advantage, as compared to bisphosphonates, in not being excreted through the kidney, which is important in patients with chronic kidney disease. Subcutaneous denosumab treatment reduces bone turnover markers and the incidence of SREs, produces a significant delay in worsening of pain, is associated with a trend for better quality of life and for lesser number of adverse events in patients with bone metastases, as compared to intravenous bisphosphonates [7,8]. It seems that, although bisphosphonates (zoledronic acid, pamidronate, ibandronate) may be beneficial for bone metastases, denosumab has further clinical advantages. In addition, it seems that inhibition of RANKL by denosumab may be relevant in the control of malignant disease progression.

Patients with bone metastases included in the pooled analysis of Von Moos and colleagues [1] were randomized to subcutaneous administration of 120 mg of denosumab or intravenous administration of zoledronic acid 4 mg every 4 weeks (for patients with solid tumors). All patients also received vitamin D and calcium supplements. Denosumab delayed the median time to a clinically meaningful increase in pain by 0.3 months and reduced the risk of a clinically meaningful increase in pain severity by 8%, compared with bisphosphonate treatment. In addition, in subjects without pain at baseline, denosumab delayed by 1.5 months the onset of moderate or severe pain, as compared to bisphosphonate treatment. Denosumab-treated patients had less worsening of quality of life and less patients needed to shift to a strong opioid as compared to zoledronic acid-treated patients. Osteolytic resorption is related to the action of products produced by malignant cells in different bone areas. Metastatic cancer cells have increased expression of RANKL which stimulates bone destruction. Experimental studies suggest that RANKL inhibition reduces osteoclast number and activity as well as the attraction of malignant cells into the bone. Malignant cells have the ability to alter the bone micro-environment and to produce cytokines and growth factors that increase the production of RANKL, which then activates osteoclasts and alters the balance between bone resorption and formation. The lower bone resorption markers levels during denosumab point at a potential reduction in the risk for SREs, as compared to bisphosphonate treatments [9,10].

Denosumab has been approved by the US Food and Drug Administration to be used in patients with bone metastases secondary to solid cancers, and is under review by the European Medicine Agency and other health regulatory organisms. It seems that denosumab treatment is well tolerated in patients with solid cancer and metastatic disease and has less adverse events than zoledronic acid [1]. However, more data are needed on denosumab anti-fracture protection, calcium changes and the prevalence of jaw osteonecrosis in patients with bone metastases. The used dose (120 mg) is higher and the monthly administration more frequent than the conventional once in 6 months treatment (60 mg) in subjects with osteoporosis unrelated to cancer. The economic cost and the duration of clinical effects in patients with bone metastases warrant further studies.

Faustino R. Pérez-López
Professor of Obstetrics and Gynecology, University of Zaragoza Faculty of Medicine & Lozano Blesa University Hospital, Zaragoza, Spain

References

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http://www.ncbi.nlm.nih.gov/pubmed/23975226 
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http://www.ncbi.nlm.nih.gov/pubmed/18725648 
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http://www.ncbi.nlm.nih.gov/pubmed/22641239 
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http://www.ncbi.nlm.nih.gov/pubmed/24782453 
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http://www.ncbi.nlm.nih.gov/pubmed/24504100 
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http://www.ncbi.nlm.nih.gov/pubmed/22898302 
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http://www.ncbi.nlm.nih.gov/pubmed/24932278 
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http://www.ncbi.nlm.nih.gov/pubmed/15983391 
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http://www.ncbi.nlm.nih.gov/pubmed/23234632