Denosumab: A Review of Its Pharmacology and Clinical Implications

Publication
Article
Contemporary Oncology®Summer 2011
Volume 3
Issue 2

It is estimated that approximately 80% of all patients with diagnoses of breast cancer, prostate cancer, or multiple myeloma will develop bone metastases at some time during the course of their disease.

Background

Osteoporosis is characterized by low bone mass, deterioration of bone tissue and architecture, compromised bone strength, and an increase in fracture risk.1 The World Health Organization (WHO) defines osteoporosis as a bone mineral density (BMD) at the hip or spine ≤2.5 standard deviations below the young normal mean reference population. It affects nearly 10 million Americans and nearly 34 million are at risk, according to the National Osteoporosis Foundation. Although there is a greater incidence in women, men can also be affected.1 Postmenopausal women require special attention due to the decrease in estrogen levels, with an increase in the rate of bone remodeling causing an imbalance between osteoblasts and osteoclasts. Several measures are key techniques in both the prevention and treatment of osteoporosis, including but not limited to adequate intake of calcium and vitamin D, weight-bearing exercises, fall prevention techniques, bisphosphonate administration, nasal calcitonin, estrogen/hormonal replacement therapies, and parathyroid hormone supplementation.

In patients with bone metastases secondary to malignancy, there is an imbalance between osteoclast and osteoblast activity that results in local bone destruction. It is estimated that approximately 80% of all patients with diagnoses of breast cancer, prostate cancer, or multiple myeloma will develop bone metastases at some time during the course of their disease. The goal of treating these patients is to reduce the risk of developing a skeletal-related event (SRE), which is defined as spinal cord compression, a pathologic fracture, and a need for radiation therapy for skeletal stabilization or hypercalcemia.

Pharmacology

Denosumab is a human IgG2 monoclonal antibody that inhibits binding of the receptor activator of nuclear factor kappa-B ligand (RANKL, part of the tumor necrosis factor family) to RANK receptors located on the surface of osteoclasts and their precursors. This inactivation prevents the formation, function, and survival of osteoclasts, which then reduces bone resorption, allowing for growth in cortical and trabecular bone.2 Improvements in BMD have been demonstrated with the use of denosumab.

Serum type I C-telopeptide (CTx), a bone resorption marker, adequately reflects denosumab activity. Three days following a single injection, CTx levels were reduced by 83%. A maximum reduction was noted in 1 month, with ranges of 45% to 80% during the 6-month dosing interval. Bone formation markers such as osteocalcin and procollagen type I N-terminal peptide (PINP) were also observed to decrease, indicating the coupled action of bone remodeling.2 Unlike the bisphosphonates, dose reductions were not required in renal or hepatic impairment. Clearance occurred through the reticuloendothelial system, ending with renal filtration and excretion.3 Studies have shown that denosumab is not incorporated into bone; therefore, accumulation is not a factor.

Current Indications

Osteoporosis

In 2009, results were published for the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months) trial, a large international, randomized, placebo-controlled study.3 In this trial, patients were randomly assigned to either denosumab 60 mg subcutaneously (SC) or placebo every 6 months for 36 months. All patients received daily supplements containing at least 1000 mg of calcium and vitamin D supplementation as determined by the baseline labs. Patients were eligible for the trial if they were aged 60 to 90 years with a BMD T-score of <—2.5 at the lumbar spine or total hip. Patients who had previously used bisphosphonates for <3 years were eligible for the study if they had not received bisphosphonate therapy for the previous 12 months. Exclusion criteria for the study included previous oral bisphosphonate use for >3 years; intravenous (IV) bisphosphonate use within the previous 5 years; fluoride or strontium use within the previous 5 years; or a vitamin D level <12 ng/mL. The primary endpoint for the trial was the presence of new vertebral fractures, evaluated by annual lateral spine radiographs. Secondary endpoints were the time to the first nonvertebral fracture and time to the first hip fracture. The efficacy endpoints were evaluated based on the intention-to-treat analysis and safety analyses included all patients who had received ≥1 dose of a study drug. A total of 7868 women were enrolled in the study. The average age in both groups was 72.3 ± 5.2 years, and the groups were well matched in terms of baseline characteristics. At the end of the 36-month study period, 82% of patients had completed the study and 76% had completed all planned injections. The study’s end-point results are shown in Table 1. The risk reduction for vertebral fractures seen in the denosumab group is similar in magnitude to IV zoledronic acid and greater than the oral bisphosphonates. The denosumab group had a similar risk reduction to alendronate, risedronate, and zoledronic acid in regard to nonvertebral fractures. There were no significant differences between the denosumab and placebo groups in terms of adverse events (AEs), but there were significantly more patients in the denosumab group that developed eczema (3% vs 1.7%, respectively). The incidence of selected AEs is shown in Table 2.

Also in 2009, the results of a phase III randomized, double-blind study comparing 12 months of therapy with either denosumab (60 mg SC every 6 months) to alendronate (70 mg orally every week) was published.4 Eligible patients were postmenopausal women with a T-score ≤2.0 at the total hip or lumbar spine. Patients were excluded if they had previously received treatment with IV bisphosphonates, fluoride, or strontium. In addition to the study treatment, patients were instructed to take daily calcium supplements with ≥500 mg calcium and vitamin D supplements based on the baseline 25(OH)D levels. The primary endpoint of the study was the percentage change from baseline of the total hip BMD at month 12. Secondary endpoints included the percentage change from baseline in BMD at the femoral neck, trochanter, lumbar spine, and one-third radius at month 12. A total of 1189 subjects were enrolled in the study. The groups were similar in regards to baseline characteristics. The mean BMD percentage change at the total hip from baseline was significantly higher in the denosumab group (3.5%) compared to the alendronate group (2.6%; P <.0001) at month 12. Patients treated with denosumab had significantly greater increases in BMD compared to patients treated with alendronate at the trochanter (4.5% vs 3.4%; P <.0001) and one-third radius (1.1% vs 0.6%; P = .0001), in addition to the gains at the total hip. These results were consistent between the intention-to-treat analysis and per protocol populations. There were no significant differences in overall AEs between patients treated with denosumab and patients treated with alendronate (80.9% vs 82.3%, respectively; P = .60). The incidence of serious AEs was also similar between groups.

Bone Metastases

In addition to the current FDA-approved indication for denosumab use in the management of osteoporosis, Amgen, the manufacturer of denosumab, has also recently obtained FDA approval for an indication for the prevention of SREs in patients with breast and prostate cancers that have metastasized to the bones.5 Results of several phase II and III trials have recently been published, leading to these new approvals. A detailed discussion of those studies will follow under the appropriate indication.

Fizazi and colleagues performed a randomized phase II study in patients with bone metastases from prostate, breast, and other malignancies that had elevated urinary N-telopeptide levels (uNTx) despite receiving IV bisphosphonate therapy. Elevated NTx levels represent excessive bone resorption, and these are the patients at greatest risk for developing SREs, cancer progression, and cancer-associated death.6 The study was a randomized, open-label, multicenter trial conducted at 26 centers in Europe and North America. A total of 111 patients were randomized to 3 different treatment arms: continuation of an IV infusion of a bisphosphonate every 4 weeks (n = 37), denosumab 180 mg SC either every 4 weeks (n = 38) or every 12 weeks (n = 36). Patients were required to have a uNTx level >50 nmol/L/mM at screening despite having received IV bisphosphonate therapy for at least 8 weeks. The primary endpoint of the study was the proportion of patients with a uNTx level <50 nmol at week 13 (treatment phase). Secondary endpoints included a variety of other assessments of uNTx levels in terms of time to response and percentage change of this marker. Time to first on-study SRE and safety were also secondary endpoints of the study. Besides breast and prostate cancers, multiple myeloma was the next most common malignancy, with 8% of the patients having the diagnosis.

At week 13, the primary endpoint of a uNTx level <50 was achieved in 71% of the patients treated with denosumab, compared to 29% in the IV bisphosphonate arm. The median percentage reduction in uNTx levels at 13 weeks also favored denosumab, with a 78% reduction for denosumab compared to 33% for the bisphosphonate group. Finally, the estimated median time to obtaining a reduction in uNTx levels <50 was 9 days in the denosumab arm compared to 65 days for the IV bisphosphonate arm. All other measurements of marker activity favored the patients treated with denosumab.6

During the 25-week treatment period, the percentage of patients experiencing a first on-study SRE was 8% in the denosumab treatment arm compared to 17% for the bisphosphonate arm. Rates of AEs were similar between the study arms, with grade 3 to 5 AEs being reported in 55% of the patients treated with denosumab and 71% of the patients treated with bisphosphonate. The authors concluded that denosumab normalized elevated uNTx levels more frequently than bisphosphonate treatment in patients with bone metastases who have elevated uNTx levels despite bisphosphonate therapy. The ability of denosumab to further suppress markers of bone resorption despite previous bisphosphonate therapy indicates a different mechanism of action responsible for these effects.11

Metastatic Breast Cancer

To date there has been 1 large, randomized phase III study and several phase II trials that have evaluated the efficacy of denosumab in women with breast cancer that has metastasized to the bone. In these patients there is increased osteoclast activity at the site of bone metastases, resulting in local bone destruction and the potential for skeletal complications.

A multicenter, randomized, blinded phase II trial conducted by Lipton and associates evaluated the efficacy and safety of 5 different dosing levels of denosumab compared to IV bisphosphonates in patients with breast cancer and bone metastases that had not received prior IV bisphosphonate therapy.7,8 The primary endpoint of this study was the percentage change in uNTx (corrected for urine creatinine, uNTx/Cr), which is a marker for bone turnover, from baseline to week 13. Patients with elevated levels of NTx have been shown to be at an increased risk of developing SREs, disease progression, and death. In the trial, 255 patients were randomized to either denosumab 30 mg SC every 4 weeks (n = 42), 120 mg every 4 weeks (n = 42), 180 mg every 4 weeks (n = 43), 60 mg every 12 weeks (n = 42), or 180 mg every 12 weeks (n = 43); 43 patients were randomized to receive an IV bisphosphonate, zoledronic acid, pamidronate, or ibandronate, depending on site-specific labeling and commercial availability. Patients were also instructed to take 500 mg of oral calcium and 400 IU of vitamin D daily.7,8 Secondary endpoints of efficacy assessed at 25 weeks (end of treatment) included the percentage change from baseline in uNTx levels, the proportion of patients with a >65% reduction in uNTx from baseline, the median time to a >65% reduction in NTx from baseline, the percentage of patients with at least 1 on-study SRE, and the overall incidence of AEs and safety through the end of the follow-up period (57 weeks). The use of a 65% reduction in levels was chosen as the study endpoint because that number is the average decrease reported in the literature for patients with bone metastases treated with an IV bisphosphonate.

A total of 255 women with bone metastases secondary to advanced breast cancer were enrolled in the study. Demographics were generally well balanced, although the patients treated with denosumab were slightly older than the patients in the bisphosphonate group. The majority of patients had skeletal metastases at more than 2 separate sites. Suppression of NTx occurred at all doses of denosumab administered, but the 120 mg dose given every 4 weeks resulted in the greatest overall median suppression of NTx at 13 weeks, with computer estimations that approximately 95% of patients treated at a dose of 120 mg every 4 weeks would achieve >90% suppression of NTx. Overall, a >65% reduction in NTx/Cr occurred in 74% of all patients treated with denosumab, compared to 63% of those treated with an IV bisphosphonate. The median time from randomization to achievement of a >65% reduction in NTx/Cr was 13 days in the denosumab cohorts compared to 29 days for the bisphosphonate cohort. Time to first on-study SRE was similar between the 2 groups, with 9% of patients treated with denosumab and 16% of patients treated with bisphosphonate experiencing a first on-study SRE. The most commonly experienced SRE was fracture.7,8 The incidence and severity of reported AEs were similar between the groups, and there was no apparent relationship between the dose of denosumab administered and the development of AEs. Pyrexia, arthralgias, and asthenia more commonly reported in the bisphosphonate group, while nausea and fatigue were more common in the denosumab cohorts.

The authors concluded that denosumab and IV bisphosphonates appeared similar in regard to the suppression of uNTx/Cr. However, the 120 mg dose of denosumab administered every 4 weeks resulted in a numerically greater degree of suppression of uNTx/Cr than the other doses or dosing-interval combinations of denosumab. The authors also concluded that the 120 mg dose should be further studied in future phase III trials.

A randomized, double-blind phase III trial was conducted by Stopeck and colleagues in patients with advanced breast cancer and bone metastases to evaluate the impact of denosumab in preventing or delaying SREs.9,10 In this study an SRE was defined as either a pathological fracture, a need for radiation or surgery to the bone for an impending fracture, or spinal cord compression. The study was designed as a noninferiority trial comparing denosumab to zoledronic acid, with time to first SRE (on-study) as the primary endpoint. Secondary endpoints included a demonstration of superiority of denosumab over zoledronic acid with respect to time to first SRE (on-study) and time to first and subsequent SREs, and a safety and tolerability assessment. Patients were required to be naïve to previous treatments with IV bisphosphonates, and were encouraged to take a minimum of 500 mg of calcium and 400 IU of vitamin D daily.

A total of 1026 patients were randomized to the denosumab/zoledronic acid placebo arm, and 1020 were randomized to the zoledronic acid/denosumab placebo arm. Denosumab was administered every 4 weeks at a dose of 120 mg SC, while zoledronic acid was administered on the same 4-week dosing schedule at a dose of 4 mg. At an average follow-up period of 34 months, denosumab was found to be superior to zoledronic acid in preventing first on-study SREs (primary outcome), with an 18% reduction in their incidence (P = .01). In the zoledronic acid group, the median time to first on-study SRE was determined to be 26.5 months; in the denosumab arm, median time to first on-study SRE had not yet been reached at the time of the analysis. The secondary endpoint of time to first and subsequent SREs was also found to be superior in the patients treated with denosumab, with a 23% improvement in this study outcome favoring denosumab (P = .001). There were no differences noted in time to disease progression or overall survival (OS) between the 2 treatment arms.9,10

In terms of safety and tolerability, there were no differences in the overall reporting of AEs, with 96% of patients treated with denosumab and 97% of patients treated with zoledronic acid experiencing at least 1 on-study adverse event. There were also no differences in the rates of serious AEs reported (44% vs 46%), infection rates (46% vs 49%), or serious infections (7% vs 8%) in comparing denosumab with zoledronic acid, respectively. The reported incidence of osteonecrosis of the jaw (ONJ) was similar between the 2 arms, with a 2% incidence in the denosumab arm and a 1.4% incidence in the zoledronic acid arm (P = .39). Renal-related treatment complications slightly favored the patients treated with denosumab, with a 4.9% incidence compared to an 8.5% incidence in the zoledronic acid arm. The authors concluded that denosumab was superior to zoledronic acid in delaying the time to first on-study SRE and the time to both first and subsequent SREs. 9,10

Metastatic Prostate Cancer

Fizazi and colleagues conducted a phase III study in patients with metastatic prostate cancer and bone metastases that was identical in both design and outcome measures as the previously described Stopeck study of metastatic breast cancer. The Fizazi study was also a randomized, placebo-controlled, multicenter, double-blind, noninferiority trial comparing denosumab dosed at 120 mg SC monthly to zoledronic acid 4 mg IV piggyback (IVPB) monthly. The primary endpoint was to evaluate whether denosumab was noninferior to zoledronic acid with respect to time to first on-study SRE. The definition of SRE, along with additional secondary outcomes, was also identical to the Stopeck study.9-12

Use of denosumab resulted in an 18% decrease in the risk of first on-study SRE in this study (P = .008), with the median time to first on-study SRE being 20.7 months in the denosumab arm compared to 17.1 months in the zoledronic acid arm. Denosumab also demonstrated superiority in the time to first and subsequent SREs over zoledronic acid, an 18% risk reduction (P = .004). Time to disease progression and OS were similar in the 2 groups. This study also evaluated uNTx levels and found that greater suppression of this bone turnover marker occurred in the patients randomized to denosumab.

Similar to the Stopeck study, there were no significant differences in AEs experienced from the study drugs. AEs were reported in 97% of patients in both arms, with slightly more asymptomatic hypocalcemia in the denosumab arm (12.8% vs 5.8%) and more acute phase reactions in the zoledronic acid arm (17.8% vs 8.4%). There were also no significant differences in the incidence of ONJ in this study: 2.3% of patients treated with denosumab and 1.3% of patients treated with zoledronic acid developed ONJ.

Future Uses of Denosumab

Giant Cell Tumors

Giant cell tumors are tumors of the bone that are generally considered to be benign, but if treatment is ever warranted, traditionally it is in the form of surgery, radiation, or both. A recent phase II trial conducted by Thomas and associates evaluated the effects of monthly denosumab in 38 patients with giant cell tumors.13 Patients were initially treated with a “loading dose” of denosumab 120 mg administered SC on days 1, 8, and 15. Following the initial loading dose phase, patients received a monthly SC injection of 120 mg. Treatment was continued for a minimum of 25 weeks, or until ability to perform complete tumor resection, disease progression without clinical benefits, death, or patient discontinuation. The primary endpoint of this study was tumor response, which was defined as elimination of at least 90% of giant cells or no radiological progression of the target lesions up to week 25 of treatment. Thirty-five patients were assessable for response, with 30 of the 35 (86%) patients having had a tumor response. Treatments were well tolerated with only 5 serious AEs reported, none of which were felt to be treatment related. The most common AEs experienced in this trial were extremity and back pain and headache.13

Multiple Myeloma

Patients with multiple myeloma with bone metastases may benefit from RANKL inhibition. In theory, the same mechanisms and scientific premise behind the use of denosumab in patients with breast and prostate cancers that have metastasized to the bone would also apply to the management of patients with multiple myeloma who have demonstrated lytic lesions on their bones. This is based on the fact that RANK ligand is such a crucial regulator of osteoclast activity, the cycle of bone destruction, and the balance between osteoblast and osteoclast activity. Currently, denosumab is not indicated for prevention of SREs in patients with multiple myeloma.

The results from a large phase III trial evaluating denosumab in the prevention of SREs were recently published.14 Patients were included if they were diagnosed with either multiple myeloma or solid tumors and had at least 1 bone metastasis or osteolytic lesion. Patients who had previously received treatment with an IV bisphosphonate or had diagnoses of breast or prostate cancer were excluded. Of the patients enrolled in the trial, 10% had diagnoses of multiple myeloma. Patients were randomized to either denosumab 120 mg every 4 weeks or zoledronic acid every 4 weeks. The primary endpoint was time to first on-study SRE comparing denosumab with zoledronic acid for noninferiority. Secondary endpoints, which were only to be evaluated if noninferiority from the primary endpoint was demonstrated, were superiority assessments that included both time to first on-study SRE and time to first and subsequent SREs. The median time to first on-study SRE was 20.6 months for denosumab and 16.3 months for zoledronic acid. The results showed that denosumab was noninferior to zoledronic acid in delaying the time to first on-study SRE (P = .0007; 16% reduction in hazard). However, the 2 superiority analyses did not reach statistical significance. The time to first and subsequent SREs in the denosumab arm was longer (rate ratio = 0.90), but this did not reach statistical significance. There was no difference in OS and disease progression. Analyses of AEs are reported in Table 3. The results of this study show that denosumab provides a novel treatment option for patients with advanced cancer that has metastasized to the bone or multiple myeloma with osteolytic lesions.

Hypercalcemia of Malignancy

Trials have shown that denosumab lowers serum calcium, with its lowest point reached at approximately day 10. These reductions are usually temporary and seldom symptomatic. It is recommended that patients take supplements with calcium and vitamin D.15 Currently, IV bisphosphonates are used as the primary intervention to treat hypercalcemia associated with malignancy; denosumab does not carry the same indication.

One active phase II, single-arm, multicenter, proof-of-concept study is currently being completed. By lowering corrected serum calcium ≤11.5 mg/dl by day 10, the trial will determine if denosumab has the potential to treat malignant hypercalcemia in patients with elevated serum calcium who have not responded to recent treatment with IV bisphosphonates. Therapy consists of 120 mg of denosumab SC every 4 weeks after an initial loading dose of 120 mg on study days 1, 8, and 15. The primary outcome is the proportion of subjects with a response defined as a serum calcium ≤11.5 mg/dL by day 10. Several secondary options are being evaluated, including the proportion of patients with a response in 33 days, the proportion of patients with a complete response (serum calcium ≤10.8 mg/dL, time to response, and time to complete response. Trial completion is expected in September 2012.16

Safety

Denosumab is contraindicated in patients with preexisting hypocalcemia. It is recommended that calcium levels be corrected before initiation and monitored during therapy. Many precautions have been identified: suppression of bone remodeling, preexisting mineral abnormalities, infections, dermatologic reactions, and ONJ. Bone remodeling suppression can contribute to ONJ, atypical fractures, and delayed fracture healing. In patients with mineral metabolism disturbances such as hypoparathyroidism, malabsorption syndromes, and thyroid/parathyroid surgery, monitoring calcium and mineral levels is recommended. In clinical trials, the incidence of opportunistic infections was balanced between placebo and denosumab patients, and the overall incidence of infections was similar between the treatment groups. Patients undergoing concomitant immunosuppressant therapy and/or with impaired immune systems may be at greater risk. Clinical trials noted epidermal and dermal AEs such as dermatitis, eczema, and rashes. Injection site reactions were reported most often. A thorough dental examination prior to initiation and counseling on good oral hygiene to prevent ONJ is also recommended. Providers should utilize clinical judgment regarding continued therapy for patients requiring invasive dental procedures due to the risk of developing ONJ.2

The most common adverse reactions reported in clinical trials with denosumab were back pain, asthenia, extremity pain, musculoskeletal pain, upper respiratory infections, nasopharyngitis, fatigue, hypercholesterolemia, nausea/vomiting, and cystitis. Serious adverse reactions include endocarditis, cellulitis, dermatitis, rash, serious infections, pancreatitis, and hypocalcemia.2

Dosing and Availability

For osteoporosis, denosumab (under the brand name Prolia) is administered as a 60 mg SC injection, from a prefilled syringe, every 6 months in the upper arm, upper thigh, or abdomen. For the prevention of SREs in patients with metastatic (to bone) breast and prostate cancers, the approved dose is 120 mg administered SC monthly under the brand name Xgeva. Coadministration of calcium 1000 mg and vitamin D 400 to 800 IU daily is also recommended.

Conclusion

Denosumab provides a novel mechanism for treating osteoporosis in postmenopausal women based on the data that led to FDA approval. In addition to being an option for osteoporosis treatment, denosumab has shown benefits in treating bone metastases from a variety of cancers, and also carries an FDA indication in the prevention of SREs in these patients. Denosumab’s efficacy has equaled or surpassed the efficacy demonstrated by bisphosphonates when used for similar indications, depending on the bisphosphonate to which it was compared. To date, denosumab has been well tolerated in all clinical trials, so oncology professionals will likely see an increase in the use of denosumab for patients with bone metastases and/or osteoporosis.

Cost comparison

About the Authors

Affiliations:

Russell S. Crawford, BPharm, is a clinical oncology specialist at the Southern Arizona VA Health Care System in Tucson. Morgane C. Diven, PharmD, is a clinical oncology specialist at the Arizona Cancer Center in Tucson. Laura Yarbro, PharmD, is an oncology pharmacy resident at the Southern Arizona VA Health Care System in Tucson.

Disclosures:

Mr Crawford reports owning stock in Amgen Inc, the manufacturer of denosumab. The other authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Address correspondence to:

Russell S. Crawford, BPharm, Division of Hematology/Oncology, Southern Arizona VA Health Care System, 3601 S 6th Ave, Tucson, AZ 85723. E-mail: russel.crawford@va.gov.

References:

  1. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2010.
  2. Prolia. Amgen. 2010.
  3. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765.
  4. Brown JP, Prince RL, Deal C, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res. 2009;24(1):153-161.
  5. Amgen Website. Available at: http://www.amgen.com. Accessed October 5, 2010.
  6. Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009;27(10):1564-1571.
  7. Lipton A, Steger GG, Figueroa J, et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. J Clin Oncol. 2007;25(28):4431-4437.
  8. Lipton A, Steger GG, Figueroa J, et al. Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy. Clin Cancer Res. 2008;14(20):6690-6696.
  9. Stopeck AT, Body JJ, Fujiwara Y, et al. Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Eur J Can Suppl. 2009;7(3):2. Abstract 2LBA.
  10. Stopeck AT, JJ Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study [published online ahead of print November 8, 2010]. J Clin Oncol. 2010;28(35):5132-5139.
  11. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study [published online ahead of print February 25, 2011]. Lancet. 2011;377(9768):813-22.
  12. Fizazi K, Bosserman L, Gao G, Skacel T, Markus R. Denosumab treatment of prostate cancer with bone metastases and increased urine N-telopeptide levels after therapy with intravenous bisphosphonates: results of a randomized phase II trial. J Urol. 2009;182(2):509-516.
  13. Thomas D, Henshaw R, Skubitz K, et al. Denosumab in patients with giant-cell tumour of bone: an open-label, phase II study. Lancet Oncol. March 2010;11(3):275-280.
  14. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma [published online ahead of print February 22, 2011]. J Clin Oncol. 2011;29(9):1125-1132.
  15. Castellano D, Sepulveda JM, García-Escobar I, Rodriguez-Antolín A, Sundlöv A, Cortes-Funes H. The role of RANK-ligand inhibition in cancer: the story of denosumab. Oncologist. 2011;16(2):136-145.
  16. Study of denosumab in the treatment of hypercalcemia of malignancy in subjects with elevated serum calcium. Retrieved March 7, 2011, from http://clinicaltrials.gov/show.NCT00896454.
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