Denosumab is a fully human monoclonal IgG2 antibody against RANKL, a key mediator of osteoclast formation, function and survival.123
Denosumab inhibits bone resorption mediated by osteoclasts, with a mechanism of action different from that of bisphosphonates. By binding with high affinity and specificity to RANKL, denosumab prevents RANKL from activating its receptor RANK on the surface of osteoclasts and their precursors. Inhibition of RANK/RANKL interaction decreases bone resorption and increases bone strength ().
Figure 1 Denosumab in CTIBL: proposed mechanism of action.28
Denosumab, under the brand name Prolia® (60 mg every 6 months), is approved in the US, Canada, Mexico, Europe, Russia, and Australia for treatment of postmenopausal women with osteoporosis at increased risk for fracture; to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer; and to increase bone mass in women at increased risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. Check local product labeling for the wording of specific indications. Denosumab is also approved for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors in the US, Canada, the European Union, and several other countries under the brand name XGEVA® and in Japan under the brand name RANMARK®. Denosumab is not indicated for the prevention of SREs in patients with multiple myeloma except in Japan.
For the treatment of men or women receiving hormone ablation therapy, a 60 mg dose of denosumab is administered once every 6 months by subcutaneous injection in the upper arm, upper thigh, or abdomen.70
All patients receiving denosumab should also receive daily supplements of 1,000 mg of calcium and at least 400 IU of vitamin D. (Denosumab 120 mg is administered every 4 weeks to patients with bone metastases for the prevention of skeletal related events.124
Clinical studies in patients undergoing hormone ablation therapy
Denosumab was evaluated in patients with breast cancer or prostate cancer undergoing hormone ablation therapy in two placebo-controlled phase 3 studies that were similar in design (
). Differences included study duration and the fact that the prostate cancer study was much larger and included vertebral fracture reduction as a secondary endpoint.125,126
In both studies, patients received subcutaneous denosumab 60 mg or subcutaneous placebo every 6 months. All patients were urged to take ≥ 1,000 mg of calcium and ≥400 IU of vitamin D daily. Patients in the prostate cancer study received their last dose of study drug at month 30 and the study ended at month 36. Patients in the breast cancer study received their last dose at month 18 and completed the study at month 24. The primary endpoint in both studies was the percent change from baseline in lumbar spine BMD, assessed at 24 months in the prostate cancer study 126
and at 12 months in the breast cancer study.125
BMD was assessed with DXA scans, using Hologic or Lunar machines calibrated across study centers with a set of standard phantoms; scans were centrally monitored. These studies were placebo-controlled because no standard of care was defined and no medications were approved for the treatment of bone loss associated with hormone ablation therapy.125,126
Key demographic characteristics of prostate and breast cancer patients receiving hormone ablation therapy in these studies are summarized in .
Figure 2 Study designs: denosumab vs. placebo in men with prostate cancer and women with breast cancer receiving hormone ablation therapy.125,126
Prostate cancer study
The effects of denosumab treatment on the incidence of fractures, BMD, and bone turnover markers were assessed in the HALT study, a randomized, double-blind, placebo-controlled phase 3 study in 1,468 men with nonmetastatic prostate cancer receiving ADT.126
Eligible patients had histologically confirmed non-metastatic prostate cancer and were receiving ADT (bilateral orchiectomy or GnRH agonist with expected duration of on-study treatment ≥ 12 months). They had either a low baseline BMD (T-score < −1.0 at the lumbar spine, total hip, or femoral neck) or history of an osteoporotic fracture. Patients with very low BMD T-scores (<−4.0) at the lumbar spine, total hip, or femoral neck were excluded from the study. Randomization was stratified by age (<70 or ≥70 years) and duration of ADT (≤6 months or >6 months).
Denosumab was shown to reduce the risk of new vertebral fractures, increase BMD, and reduce markers of bone turnover among men with prostate cancer receiving ADT. The incidence of new vertebral fractures was reduced for the denosumab group after 1, 2, and 3 years. At 1 year, the percentage of new vertebral fractures was 0.3% with denosumab and 1.9% with placebo (relative risk, 0.15; P
= 0.004); at 24 months, 1.0% vs. 3.3% (relative risk, 0.31; P
= 0.004); and at 36 months, 1.5% with denosumab and 3.9% with placebo (relative risk, 0.38; P
= 0.006) (
Figure 3 Denosumab reduced the risk of vertebral fractures over 3 years in men with prostate cancer receiving ADT.126
In the same study, denosumab also significantly increased mean BMD at the lumbar spine, total hip, femoral neck, and distal third of the radius at 12, 24, and 36 months (P
≤ 0.001) (
At 24 months (the primary endpoint), the difference between denosumab and placebo was 6.7% at the lumbar spine, 4.8% at the total hip, 3.9% at the femoral neck, and 5.5% at the distal third of the radius. These significant increases in BMD were consistent in all patient subgroups, including older men and those with lower BMD, higher levels of bone turnover markers, or a history of vertebral fracture at baseline (
The BMD increase in the lumbar spine with denosumab at 36 months was 9.1% for men < 70 years of age and 7.7% for those ≥70 years of age. In men with BMD T-scores at baseline ≤−1.0, the BMD increase at the lumbar spine was 9.3%, versus 7.0% for men with baseline BMD T-scores > −1.0. In men with prevalent vertebral fractures, BMD increased 8.7% over the 36 months of the study, compared with 7.6% for men without a prevalent vertebral fracture. Likewise, the duration of ADT at baseline did not have a marked effect on BMD increases. Men who had been on ADT for ≤6 months experienced an LS mean gain of 9.1% in lumbar spine BMD, compared with 7.6% for men who had been on ADT for >6 months. Denosumab also increased BMD at the total hip and distal third of the radius in all patient subgroups.
Figure 4 Cumulative percent change in BMD from baseline, denosumab vs. placebo in men with prostate cancer receiving ADT.126
Figure 5 Mean difference in BMD from placebo at 36 months, denosumab vs. placebo, in men with prostate cancer receiving ADT: subgroup analyses.127
The effectiveness of denosumab in reducing bone resorption was also assessed in the HALT study using serum bone turnover markers.128
sCTX, TRACP-5b, and P1NP were assessed at baseline and 1 month postdose, and predose (denosumab trough level) at months 6, 12, 24, and 36. Denosumab treatment resulted in a rapid, sustained reduction of bone turnover markers from month 1 through the end of the last dosing interval at 36 months. As with BMD, denosumab’s effect on bone turnover was consistent across patients subgroups, including men aged ≥ 70 years, men with ADT duration at baseline > 6 months, and men with higher levels of bone turnover at baseline.128
The changes in bone turnover markers were associated with changes in BMD at 36 months.128
The effects of denosumab treatment on BMD and bone turnover markers were assessed in a randomized, double-blind, placebo-controlled phase 3 study in 252 women with nonmetastatic breast cancer receiving aromatase inhibitors.125
Eligible patients were women ≥ 18 years of age with histologically or cytologically confirmed, hormone-receptor positive breast cancer, who were undergoing adjuvant aromatase inhibitor therapy after completion of surgery and/or radiation at least 4 weeks before study entry. All patients had T-scores from −1.0 to −2.5 (osteopenia). Women were excluded if they had prior vertebral fractures, T-scores < −2.5, or current use of bisphosphonates or any anticancer therapy except aromatase inhibitors. Randomization was stratified by duration of prior aromatase inhibitor therapy (≤6 months or >6 months).
Over the 24 months of the study, denosumab treatment was associated with numerically fewer major nonvertebral fractures and significant increases in BMD compared with placebo. No vertebral fractures were reported in either treatment group during the study. Major nonvertebral fractures (defined as fractures in the pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm and hip) occurred in 3 patients (2%) in the denosumab group and 5 patients (4%) in the placebo group. Nonvertebral fractures of all types (excluding pathologic fractures, those resulting from severe trauma, and fractures of the skull, face, mandible, and digits) were reported in 8 patients (6%) in each treatment group.
At 12 months, BMD in the lumbar spine increased by 5.5% in the denosumab group compared with the placebo group (denosumab 4.8%, placebo −0.7%, P
< 0.0001) (
). At 24 months, the difference between groups was 7.6%, P
Patients in the denosumab group also experienced an increase in BMD after 12 and 24 months at other measured sites; the difference from placebo at 24 months was 4.7% at the total hip, 3.6% at the femoral neck, and 6.1% at the distal third of the radius at 24 months.125
Figure 6 Cumulative mean percent change in BMD from baseline, denosumab vs. placebo in women with breast cancer receiving aromatase inhibitors.129
Gains in BMD were consistent across various patient subgroups in this study.129
For example, patients who had been on aromatase inhibitor therapy for less than 6 months at baseline had a difference of 5.4% from placebo in lumbar spine BMD at 12 months, compared with 5.6% for patients on aromatase inhibitors for more than 6 months. Gains at the total hip, femoral neck, and distal third of the radius were also similar (
), and the treatment effect of denosumab on BMD was sustained through month 24. Denosumab was similarly effective at all BMD sites for patients regardless of type of AI therapy, prior use of tamoxifen, age, time since the onset of menopause, body mass index, and baseline T-score (). In the breast cancer study, 80% of patients treated with denosumab had a gain in BMD after 24 months of more than 3% at the lumbar spine, compared with 13% of patients receiving placebo; 50% of denosumab patients had a gain in BMD of more than 6%, compared with only 3% of placebo patients. Similar proportions of denosumab-treated patients had BMD gains at all measured sites.
Least squares mean difference in BMD from placebo at 12 months in women with breast cancer receiving aromatase inhibitors: subgroup analyses.
Safety and tolerability
In clinical studies of denosumab in patients with prostate or breast cancer receiving hormone ablation therapy, the overall rates of adverse events were similar between the denosumab and placebo treatment groups. A summary of adverse events in these two studies is presented in . The denosumab product labeling notes that, in patients treated with denosumab for CTIBL or osteoporosis, hypocalcemia may be exacerbated and that all patients treated with denosumab should receive calcium and vitamin D supplementation.70
Hypocalcemia was reported in one patient (0.1%) in the prostate cancer study of patients receiving hormone ablation therapy and no patients in the breast cancer study. In the FREEDOM trial of more than 7,800 women with postmenopausal osteoporosis, no patients in the denosumab group were reported to have hypocalcemia during the first 3 years of the study and 1 patient during the 2-year extension phase.130
In patients with bone metastases, who received a higher dose of denosumab than is given to cancer patients without bone metastases or for osteoporosis, adverse events of hypocalcemia were reported in the prostate cancer study in 6% of patients on zoledronic acid and 13% on denosumab, 131
and in the breast cancer study, in 3.4% of patients on zoledronic acid and 5.5% of patients on denosumab.132
Table 2 Summary of adverse events over 24 months in the breast cancer study and over 36 months in the prostate cancer study.125,126
Another potential risk of denosumab treatment mentioned in the denosumab product labeling is serious infection leading to hospitalization, which was reported more frequently with denosumab in the FREEDOM trial of more than 7,800 women with postmenopausal osteoporosis. Serious adverse events related to infection were reported in 5.9% of denosumab- treated patients and 4.6% of placebo-group patients in the prostate cancer study of men receiving hormone ablation therapy, and in 2% of denosumab-treated patients and 1% of placebo patients in the breast cancer hormone ablation study.
Osteonecrosis of the jaw (ONJ) has been reported in patients receiving either bisphosphonates or denosumab to prevent bone resorption. No cases of ONJ were reported in patients in the two studies described here of denosumab for patients with prostate or breast cancer receiving hormone ablation therapy.125,126
The product labeling for denosumab recommends that a routine oral examination be performed by the prescriber and that appropriate preventive dentistry be considered before initiation of denosumab treatment.70
In the HALT study of men receiving ADT, cataracts developed in 4.7% of patients receiving denosumab vs. 1.2% of those receiving placebo. Cataract formation was not observed in other studies of denosumab, in which annual doses 12 to 13 times higher were administered to patients with castrate-resistant prostate cancer, including study of men with bone metastases receiving denosumab or zoledronic acid131
and a placebo-controlled denosumab study in men at high risk for bone metastases.133
Likewise, cataract formation was not observed in studies of women with breast cancer treated with denosumab.125,129,132
Pharmacokinetics and metabolism
To profile the pharmacokinetics of denosumab, data were pooled from 11 clinical studies of varied doses of denosumab that included 22,944 samples from 495 healthy subjects and 1069 postmenopausal women with osteopenia or osteoporosis.134
The age of participants ranged from 18 to 80 years for healthy subjects (men and women) and from 18 to 85 for post- menopausal women with bone loss. The subcutaneous bioavailability of denosumab was 64%, and the first-order absorption rate constant (ka) was 0.00883 h−1
. The central volume of distribution was 2.49 L/66 kg; the linear clearance was 3.06 mL/h/66 kg. The variability between subjects was moderate. A fixed dose of 60 mg provided inhibition of RANKL similar to that achieved by equivalent body weight-based dosing. The effects of age and race were less than 15% on the area under the serum concentration-time curve of denosumab. Similar results were obtained in another study that included 581 subjects with advanced cancer.135
The antibody denosumab is metabolized through the reticuloendothelial system,136
without reliance on renal function, so potential renal impairment has no effect on the pharmacokinetics or pharmacodynamics of denosumab.70