The anti-resorptive effect of recombinant human OPG was reported two decades ago, after observations that its intravenous administration in normal rats increased bone mineral density and bone volume as a consequence of decreased active osteoclasts
[17]. This was in accordance with observations that OPG-deficient mice developed early osteopenia
[77]. However, despite its unequivocal physiological ability to impair bone resorption, very high subcutaneous doses (>10–30 mg/kg) of recombinant full-length OPG were required for in vivo efficacy, and its pharmacokinetic and pharmacodynamic profile was poor
[78]. The best protein was a recombinant protein comprising the a.a. 22–194 of human OPG fused with the human IgG1 Fc region, found to be over 200 times more active than full-length OPG in vivo and with prolonged half-life. Nonetheless, OPG-Fc and RANK-Fc were associated with autoimmune hypercalcemia, being discontinued in favor of an anti-RANK antibody and ultimately leading to AMG 16, currently known as denosumab
[19].
2.4.1. Bone Metastatic Disease
Although the treatment of BM from solid tumors and MM is rarely curative, it is possible to prevent disease progression and palliate symptoms for many years using systemic anticancer treatments
[20]. SREs reflect the burden of bone pain and structural damage caused by bone metastatic involvement, representing an important form of skeletal morbidity that impacts patients’ quality of life and results in significant healthcare costs
[79]. SREs comprise five major complications of tumor bone disease: pathological fracture, need for radiotherapy to relieve bone pain or reduce bone structural damage, need for bone surgery to prevent or repair fractures, spinal cord compression, and hypercalcemia
[20]. BTAs have been shown to improve bone structure and quality, minimizing the risk of SREs in patients with BM from solid tumors and MM
[75][79]. Therefore, in order to reduce morbidity and complement other cancer-specific treatments, current clinical guidelines recommend prescribing a BTA following the initial radiological diagnosis of BM in most patients
[80].
To understand the current clinical applications of RANKL inhibition in the context of BM, it is important to briefly review the role of BPs in the history of bone metastatic disease management. Several BPs have proven efficacious in preventing SREs in patients with BM from BCa or MM since the approval of clodronate in these indications in the early 1990s
[33][81]. Still, ZA remains the only BP approved for the treatment of metastatic castration-resistant PCa (CRPC) and BM from other solid tumors
[79]. The addition of a BTA in the treatment of endocrine-sensitive PCa showed no evidence of a survival improvement or SRE reduction compared with placebo and is hence not recommended outside treatment-induced bone loss prevention or pre-existing osteoporosis clinical settings
[80][82].
Since denosumab was first licensed for the treatment of BM from solid tumors in 2010, numerous head-to-head randomized controlled trials (RCTs) have compared denosumab with ZA in bone health settings in several human cancers (
Table 1)
[79].
Table 1. Head-to-head randomized controlled trials comparing denosumab with zoledronate for delay or prevention of skeletal-related events in bone metastatic solid tumors and multiple myeloma.
Cancer Type(s) |
First On-Study SREs (% of Patients; D vs. ZA) |
Time to First SRE |
Time to First and Subsequent SREs |
Ref. |
Breast (n = 2046) |
NE |
Denosumab superior (HR 0.82; 95% CI 0.71–0.95; p < 0.001 NI; p = 0.01 S) |
Denosumab superior (RR 0.77; 95% CI 0.66–0.89; p = 0.001 S) |
[32] |
CRPC (n = 1901) |
36 vs. 41 |
Denosumab superior (HR 0.82; 95% CI 0.71–0.95; p = 0.0002 NI; p = 0.008 S) |
Denosumab superior (RR 0.82; 95% CI 0.71–0.94; p = 0.008) |
[33] |
Solid tumors (excluding breast and prostate) and MM (n = 1779) |
NE |
Denosumab non-inferior, but not statistically superior (HR 0.84; 95% CI, 0.71 to 0.98; p = 0.0007 NI; p = 0.06 S) |
Denosumab not statically superior (RR 0.90; 95% CI 0.77–1.04; p = 0.14) |
[83] |
MM (n = 1718) |
44 vs. 45 |
Denosumab non-inferior, but not statistically superior (HR 0.98; 95% CI 0.85–1.14; p = 0.01 NI) |
Denosumab not statically superior (RR 1.01; 95% CI 0.89–1.15; p = 0.84) |
[83] |
CI, Confidence Interval; CRPC, Castration-Resistant PCa; D, Denosumab; HR, Hazard Ratio; MM, Multiple Myeloma; NE, Not Evaluable; NI, Non-Inferiority; RR, Rate Ratio; S, Superiority; SREs, Skeletal-Related Events; ZA, Zoledronate.
Denosumab was shown to be superior to ZA in delaying and preventing SREs in patients with bone metastatic BCa
[32] and metastatic CRPC
[33]. In an RCT including patients with BM from solid tumors and MM (excluding BCa and PCa), denosumab was non-inferior to ZA, but was not superior in delaying time to first and subsequent SREs
[34]. However, an ad hoc analysis of this trial excluding the MM cohort was able to demonstrate a significant advantage of denosumab in delaying SREs
[84]. There was no difference regarding OS or disease progression between patients treated with denosumab or ZA in each trial individually or in a combined analysis of the three trials (
Table 2).
Table 2. Randomized controlled trials of denosumab disease-modifying properties in advanced human cancer.
Cancer Type(s) |
Number of Patients |
Intervention |
Disease-Related Outcomes |
Trial Identifier/Reference |
Breast (advanced, all types, pre-and postmenopausal) |
2046 |
Denosumab vs. ZA |
Similar OS (HR 0.95; 95% CI 0.81–1.11; p = 0.49) and time to disease progression (HR 1.00; 95% CI 0.89–1.11; p = 0.93). |
NCT00321464 [32] |
CRPC |
1901 |
Denosumab vs. ZA |
Similar OS (HR 1.03; 95% CI 0.91–1.17; p = 0.65) and time to disease progression (HR 1.06; 95% CI 0.95–1.18; p = 0.30). |
NCT00321620 [33] |
Solid tumors (excluding breast and prostate) and MM |
1779 |
Denosumab vs. ZA |
Similar OS (HR 0.95; 95% CI 0.83–1.08; p = 0.43) and time to disease progression (HR 1.00; 95% CI 0.89–1.12; p = 1.00). Ad hoc analyses favored denosumab for NSCLC patients (HR 0.79; 95% CI 0.65–0.95) and ZA for MM patients (HR 2.26; 95% CI 1.13–4.50). |
NCT00330759 [34] |
NSCLC (stage IV) |
514 |
ChT + Denosumab vs. ChT |
Similar OS (HR 0.96; 95% CI 0.78–1.19; p = 0.36), PFS (HR 0.99; 95% CI 0.82–1.19; p = 0.46) and ORR (30.5% vs. 29.4%; p = 0.85). |
NCT02129699 (SPLENDOUR) [85] |
MM |
1718 |
Denosumab vs. ZA |
Denosumab improved PFS by 10.7 months (HR, 0.82; 95% CI 0.68–0.99; p = 0.036). Similar OS (HR, 0.90; 95% CI 0.70–1.16; p = 0.41). |
NCT01345019 [83] |
ChT, Chemotherapy; DFS, Disease-Free Survival; MM, Multiple Myeloma; NCT, National Clinical Trial; NSCLC, Non-Small Cell Lung Cancer; ORR, Objective Response Rate; OS, Overall Survival; PFS, Progression-Free Survival; ZA, Zoledronate.
An exploratory subgroup analysis of non-small cell lung cancer (NSCLC) patients from the phase 3 trial of denosumab versus ZA in the treatment of BM from solid tumors or MM suggested a significant OS advantage for denosumab
[86]. However, in the recently published SPLENDOUR trial (NCT02129699), denosumab failed to show a measurable impact in OS, progression-free survival (PFS), or objective response rate (ORR) when added to standard first-line platinum-based doublet chemotherapy in advanced NSCLC, irrespective of the presence of BM at diagnosis or histological subtype
[85].
In the case of MM, the Myeloma IX trial demonstrated that ZA has anti-myeloma effects beyond SRE prevention, evidencing a median PFS and OS improvement compared with clodronate
[87]. Contrarily to the observed in NSCLC, the ad hoc subgroup analysis of MM patients from the phase 3 RCT comparing denosumab with ZA in the treatment of non-breast, non-prostate bone metastatic solid tumors and MM suggested a survival advantage for ZA over denosumab. However, since this trial was considered potentially confounded by imbalances in patient characteristics, antitumor therapies, and early withdrawals and limited by the small proportion of the MM cohort (10%)
[88], a larger RCT focusing exclusively on MM patients was conducted
[83]. This trial evidenced that denosumab was statically non-inferior in preventing SREs and carried a PFS but not an OS advantage compared with ZA. These results led to the approval of denosumab for the prevention of SREs in patients with MM, currently representing a particularly useful alternative in patients with renal dysfunction, a common clinical consequence in MM for which BPs may be contraindicated.
In summary, a number of factors must be considered when selecting a BTA for bone health management in solid tumors or MM bone disease, namely drug availability, route of administration, and patient preference
[80]. Denosumab seems to have an advantage over other BTAs due to its efficacy, convenience, and renal health benefits. However, BPs may be more cost-effective.
Discontinuation is another important aspect to consider regarding BTAs. While BPs incorporate into the bone matrix, having a prolonged action duration, denosumab has a short half-life and bone turnover suppression is not maintained after discontinuation. This justifies that the frequency of ZA administration may be reduced during disease remission periods or even that ZA is interrupted to allow safer dental treatments without substantially influencing the risk of SREs. Denosumab discontinuation, on the other hand, can result in rebound osteolysis that may lead to rapid bone loss, increased bone pain, and increased risk of SREs
[89][90]. This supports the current recommendation to use BPs after stopping denosumab, as a way to minimize the clinical consequences of this rebound phenomenon
[80].