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Background
The National Osteoporosis Foundation Consensus Development Conference (2003) defined osteoporosis as a disease characterized by low bone mass and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and increased risk of hip, spine, and wrist fractures. Osteoporosis is the most common bone disease in humans. Approximately 10 million Americans (80 % of them women) suffer from osteoporosis. For post-menopausal women, age, Asian or Hispanic heritage, cortisone use, family or personal history of fracture, as well as smoking have been associated with significantly increased likelihood of osteoporosis; while African American heritage, estrogen or diuretic use, exercise, as well as higher body mass index (BMI) have been associated with significantly decreased likelihood of osteoporosis (Siris et al, 2001). Furthermore, Wu and colleagues (2002) reported that any fracture (unrelated to motor vehicle accidents) sustained between the ages of 20 and 50 years is associated with increased risk of fractures after the age of 50 years in women.
Bone mineral density (BMD) is useful in the diagnosis of osteoporosis. It is usually provided as the T score -- the number of standard deviations (SDs) the BMD falls below or above the mean value in a reference population (young, healthy adults). The World Health Organization (WHO) osteoporosis diagnostic classification assessment (1994) defines osteoporosis as a T score of 2.5 or more SDs below the mean (i.e., less than -2.5). Osteopenia is defined as a T score of -1.0 to -2.5; and a T score of -1.0 or higher is considered normal.
The North American Menopause Society's position statement on management of post-menopausal osteoporosis (2010) stated that management focuses first on non-pharmacological measures (e.g., adequate calcium and vitamin D intake, adequate exercise, avoidance of excessive alcohol intake, balanced diet, fall prevention, and smoking cessation). If pharmacotherapy is indicated, government-approved options are bisphosphonates (e.g., alendronate and risedronate), calcitonin-salmon, estrogens, parathyroid hormone (PTH), and selective estrogen-receptor modulators (SERMs) such as raloxifene. Lewiecki (2009) stated that available pharmacological agents for the management of post-menopausal osteoporosis include oral bisphosphonates, which are generally considered first-line therapy for patients with osteoporosis, but their use may be limited by gastrointestinal side effects. Other agents include calcitonin-salmon, hormone therapy, human recombinant PTH (teriparatide), raloxifene, and strontium ranelate. Emerging therapies for post-menopausal osteoporosis include novel SERMs (e.g., arzoxifene, bazedoxifene, lasofoxifene, ospemifene) and receptor activator of nuclear factor kappa beta ligand (RANKL) inhibitors (e.g., denosumab).
Denosumab is a fully human monoclonal antibody that inhibits osteoclastic bone resorption by binding to osteoblast-produced RANKL, a cytokine member of the tumor necrosis factor family. By reducing RANKL binding to the osteoclast receptor RANK, bone resorption and turnover decrease.
Post-Menopausal Osteoporosis:
On June 1, 2010, the Food and Drug Administration (FDA) approved denosumab (Prolia, Amgen Inc., Thousand Oaks, CA) for the treatment of post-menopausal women with osteoporosis who are at high risk for fractures (e.g., those who have had an osteoporotic fracture, or have multiple risk factors for fracture; or those who have failed or are intolerant to other available osteoporosis therapy). The recommended dosage is a 60-mg subcutaneous injection once every 6 months. The approval was based mainly on the study of Cummings et al (2009). The most common adverse events (AEs) reported with denosumab include back pain, high cholesterol levels, musculoskeletal pain, pain in the extremities, and urinary bladder infections. Serious AEs include hypocalcemia, serious infections, including infections of the skin, as well as dermatological reactions such as dermatitis, eczema, and rashes.
McClung et al (2006) evaluated the safety and effectiveness of denosumab over a period of 12 months in 412 post-menopausal women with low BMD: T score of -1.8 to -4.0 at the lumbar spine or -1.8 to -3.5 at the proximal femur. Subjects were randomly assigned to receive subcutaneous injection of denosumab either every 3 months (at a dose of 6, 14, or 30 mg) or every 6 months (at a dose of 14, 60, 100, or 210 mg), open-label oral alendronate once-weekly (at a dose of 70 mg), or placebo. The primary end point was the percentage change from baseline in BMD at the lumbar spine at 12 months. Changes in bone turnover were assessed by measurement of serum and urine telopeptides and bone-specific alkaline phosphatase. Denosumab treatment for 12 months resulted in an increase in BMD at the lumbar spine of 3.0 % to 6.7 % (as compared with an increase of 4.6 % with alendronate and a loss of 0.8 % with placebo), at the total hip of 1.9 % to 3.6 % (as compared with an increase of 2.1 % with alendronate and a loss of 0.6 % with placebo), and at the distal third of the radius of 0.4 % to 1.3 % (as compared with decreases of 0.5 % with alendronate and 2.0 % with placebo). Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident 3 days after the administration of denosumab. The duration of the suppression of bone turnover appeared to be dose-dependent. The authors concluded that in post-menopausal women with low bone mass, denosumab increased BMD and decreased bone resorption.
In a phase II study, Beck and co-workers (2008) compared the effects of denosumab with alendronate on the geometry of the proximal femur in post-menopausal women. Subjects were treated for up to 24 months with denosumab (60 mg once every 6 months; n = 39), placebo (n = 39), or open-label alendronate (70 mg once-weekly; n = 38). Hip scans were done by dual-energy X-ray absorptiometry (DEXA) at baseline, 12, and 24 months; these were analyzed with hip structural analysis software to evaluate BMD and cross-sectional geometry parameters at the narrowest segment of the femoral neck, the inter-trochanter, and the proximal shaft. Geometric parameters and derived strength indices included bone cross-sectional area, section modulus, and buckling ratio. At 12 and 24 months denosumab and alendronate improved these parameters compared with placebo. Denosumab effects were greater than alendronate at the inter-trochanteric and shaft sites. The magnitude and direction of the changes in structural geometry parameters observed in this study suggested that denosumab treatment may lead to improved bone mechanical properties.
In a 2-year randomized, double-blind, placebo-controlled study, Bone and colleagues (2008) evaluated the ability of denosumab to increase BMD and decrease bone turnover markers (BTMs) in early and later post-menopausal women with low BMD. Subjects included 332 post-menopausal women with lumbar spine BMD T-scores between -1.0 and -2.5. Patients were randomly assigned to receive denosumab subcutaneously, 60 mg every 6 months, or placebo. Randomization was stratified by time since onset of menopause (less than or equal to 5 years or greater than 5 years). The primary end point was the percent change in lumbar spine BMD by DEXA at 24 months. Additional end points were percent change in volumetric BMD of the distal radius by quantitative computed tomography; percent change in BMD by DEXA for the total hip, one-third radius, and total body; hip structural analysis; percent change in BTMs; and safety. Denosumab significantly increased lumbar spine BMD, compared with placebo at 24 months (6.5 versus -0.6 %; p < 0.0001) with similar results for both strata. Denosumab also produced significant increases in BMD at the total hip, one-third radius, and total body (p < 0.0001 versus placebo); increased distal radius volumetric BMD (p < 0.01); improved hip structural analysis parameters; and significantly suppressed serum C-telopeptide, tartrate-resistant acid phosphatase-5b, and intact N-terminal propeptide of type 1 pro-collagen. The overall incidence of adverse events (AEs) was similar between both study groups. The authors concluded that twice-yearly denosumab increased BMD and decreased BTMs in early and later post-menopausal women.
In a multi-center, double-blind, phase III study, Brown et al (2009) compared the safety and effectiveness of denosumab with alendronate in post-menopausal women with low bone mass. A total of 1,189 post-menopausal women with a T-score less than or equal to -2.0 at the lumbar spine or total hip were randomized 1:1 to receive subcutaneous denosumab injections (60 mg every 6 months [Q6M]) plus oral placebo weekly (n = 594) or oral alendronate weekly (70 mg) plus subcutaneous placebo injections Q6M (n = 595). Changes in BMD were assessed at the total hip, femoral neck, trochanter, lumbar spine, and one-third radius at 6 and 12 months and in BTMs at months 1, 3, 6, 9, and 12. Safety was evaluated by monitoring AEs and laboratory values. At the total hip, denosumab significantly increased BMD compared with alendronate at month 12 (3.5 % versus 2.6 %; p < 0.0001). Furthermore, significantly greater increases in BMD were observed with denosumab treatment at all measured skeletal sites (12-month treatment difference: 0.6 %, femoral neck; 1.0 %, trochanter; 1.1 %, lumbar spine; 0.6 %, one-third radius; p < or = 0.0002 all sites). Denosumab treatment led to significantly greater reduction of BTMs compared with alendronate therapy. Laboratory values and AEs were similar for denosumab- and alendronate-treated subjects. The authors concluded that denosumab showed significantly larger gains in BMD and greater reduction in BTMs compared with alendronate. The overall safety profile was similar for both treatments.
Cummings and colleagues (2009) examined the effectiveness of denosumab for prevention of fractures in post-menopausal women with osteoporosis. These investigators enrolled 7,868 women between the ages of 60 and 90 years who had a BMD T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included non-vertebral and hip fractures. As compared with placebo, denosumab reduced the risk of new radiographical vertebral fracture, with a cumulative incidence of 2.3 % in the denosumab group, versus 7.2 % in the placebo group (risk ratio, 0.32; 95 % confidence interval [CI]: 0.26 to 0.41; p < 0.001) -- a relative decrease of 68 %. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7 % in the denosumab group, versus 1.2 % in the placebo group (hazard ratio, 0.60; 95 % CI: 0.37 to 0.97; p = 0.04) -- a relative decrease of 40 %. Denosumab also reduced the risk of non-vertebral fracture, with a cumulative incidence of 6.5 % in the denosumab group, versus 8.0 % in the placebo group (hazard ratio, 0.80; 95 % CI: 0.67 to 0.95; p = 0.01) -- a relative decrease of 20 %. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. The authors concluded that denosumab given subcutaneously twice-yearly for 36 months was associated with a reduction in the risk of vertebral, non-vertebral, and hip fractures in women with post-menopausal osteoporosis.
Guidance from the National Institute for Health and Clinical Excellence (NICE, 2010) on denosumab for post-menopausal osteoporosis recommended denosumab as a treatment option for the primary prevention of osteoporotic fragility fractures only in elderly (70 or more years of age, or 65 or more years of age with clinical risk factors) post-menopausal women at increased risk of fractures: (i) who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments; and (ii) who exceed a threshold risk for osteoporotic factors, based on a combination of T-score, age and number of independent clinical risk factors for fracture (parental history of hip fracture, alcohol intake of 4 or more units per day, and rheumatoid arthritis), as described in the text of the NICE guidance. NICE also recommended denosumab a treatment option for the secondary prevention of osteoporotic fragility fractures only in post-menopausal women at increased risk of fractures who are unable to comply with the special instructions for administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments.
Bone Loss Associated with Aromatase Inhibitors:
Adjuvant aromatase inhibitor therapy (AIT) is effective in treating post-menopausal women with hormone receptor-positive breast cancer; however such therapy is complicated by accelerated bone loss and increased fracture risk. Ellis et al (2008) examined the ability of denosumab to protect against AIT-induced bone loss. Eligible women with hormone receptor-positive non-metastatic breast cancer treated with adjuvant AIT were stratified by duration of AIT (less than or equal to 6 months versus greater than 6 months), received supplemental calcium and vitamin D, and were randomly assigned to receive placebo (n = 125) or subcutaneous 60-mg denosumab (n = 127) every 6 months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary end point was percentage change from baseline at month 12 in lumbar spine BMD. At 12 and 24 months, lumbar spine BMD increased by 5.5 % and 7.6 %, respectively, in the denosumab group versus placebo (p < 0.0001 at both time points). Increases were observed as early as 1 month and were not influenced by duration of AIT. Increases in BMD were also observed at the total hip, total body, femoral neck, and the predominantly cortical one-third radius. Furthermore, BTMs decreased with denosumab treatment. Overall incidence of treatment-related AEs was similar between treatment groups. The authors concluded that in women with non-metastatic breast cancer and low bone mass who were receiving adjuvant AIT, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall AE rates similar to those of placebo.
In an editorial that accompanied the afore-mentioned study, Lonning (2008) stated that "While we may not ready to choose RANKL for clinical use outside of clinical trials, results are promising, and we may soon be there. The need for more research in this area cannot be overemphasized .... the article by Ellis, et al. in this issue represents an important step forward, demonstrating efficacy of denosumab in preventing bone loss induced by endocrine therapy. With more results from ongoing denosumab trials evaluating bone health on the way, the next generation of trials should be aiming at closing in the RANK(L) pathway, with the aim of preventing bone metastases (and possibly nonbone metastases) from breast cancer".
Michaud (2010) discussed trends in breast cancer prevalence and survival; risk factors for bone loss, osteoporosis, and fractures as well as the approach to risk assessment in these patients; established and investigational drug therapies for managing cancer treatment-induced bone loss and osteoporosis. Most patients with breast cancer should undergo assessment of risk for bone loss and osteoporosis that involves a bone-related history and physical examination, DEXA scanning, and the WHO fracture risk assessment tool. A National Comprehensive Cancer Network (NCCN) task force report on bone health in cancer care provided recommendations regarding the use of pharmacotherapy -- bisphosphonates are useful for slowing or preventing bone loss associated with hormone-ablation therapy in women with breast cancer, although fracture data are limited. The usefulness of other therapies (calcitonin salmon, estrogens, SERMs, and teriparatide) is limited by AEs, a lack of experience with the drugs in these patient populations, or both. Various drug therapies are in development for managing cancer treatment-induced bone loss and osteoporosis. Denosumab has been shown to improve BMD in women receiving hormone-ablation therapy for breast cancer, but additional data are needed to dispel safety concerns that could limit the use of this drug in these patients.
Bone Metastases from Solid Tumors (e.g., Breast and Prostate Cancer) and Multiple Myeloma:
Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab, a fully human monoclonal antibody to RANKL, suppresses bone resorption.
Lipton and Jun (2008) noted that bone metastases are common in patients with advanced malignancies and are associated with skeletal-related events (SREs), cancer progression, and death. Denosumab is being investigated in multiple clinical trials for the prevention and treatment of bone metastases. Burkiewicz et al (2009) stated that additional clinical trial data are needed to more completely establish the effectiveness of denosumab in the treatment of neoplastic disease as well as its cost-effectiveness and long-term safety.
Bartsch and Steger (2009) noted that in advanced breast cancer, denosumab reduced urinary-N-telopeptide:creatinine ratio with potentially fewer side effects compared with bisphosphonates. However, proof of direct anti-tumor activity is missing.
Body et al (2006) reported that a single-dose of denosumab resulted in a sustained reduction in bone resporption in persons with multiple myeloma or bone metastases from breast cancer. The investigators reported on a randomized, double-blind, active-controlled multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single-dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg) or pamidronate (90 mg IV). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Following a single subcutaneous dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well-tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. The investigators concluded that the decrease in bone turnover markers with denosumab was similar in magnitude but more sustained than with pamidronate.
Lipton et al (2007) found that subcutaneous denosumab had an effect similar to intravenous bisphosphonates in suppressing bone turnover in women with breast cancer-related bone metastases. The investigators evaluated the efficacy and safety of 5 dosing regimens of denosumab in patients with breast cancer-related bone metastases not previously treated with intravenous bisphosphonates. Eligible women (n = 255) with breast cancer-related bone metastases were stratified by type of anti-neoplastic therapy received and randomly assigned to 1 of 6 cohorts -- 5 denosumab cohorts, blinded to dose and frequency, and 1 open-label intravenous bisphosphonate cohort. Denosumab was administered subcutaneously every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg). The primary end point was percentage of change in the bone turnover marker urine N-telopeptide from baseline to study week 13. Secondary endpoints included the percentage of patients achieving more than 65 % urine N-telopeptide reduction, time to more than 65 % urine N-telopeptide reduction, patients experiencing one or more on-study skeletal-related events (SRE), and safety. At study week 13, the median percent reduction in urine N-telopeptide was 71 % for the pooled denosumab groups and 79 % for the intravenous bisphosphonate group. Overall, 74 % of denosumab-treated patients (157 of 211) achieved a more than 65 % reduction in urine N-telopeptide compared with 63 % of bisphosphonate-treated patients (27 of 43). On-study SREs were experienced by 9 % of denosumab-treated patients (20 of 211) versus 16 % of bisphosphonate-treated patients (seven of 43). No serious or fatal adverse events related to denosumab occurred. The investigators concluded that subcutaneous denosumab may be similar to intravenous bisphosphonates in suppressing bone turnover and reducing SRE risk.
On November 18, 2010, the FDA approved a new indication for denosumab (Xgeva, Amgen Inc., Thousand Oaks, CA) to help prevent SREs in patients with bone metastases from solid tumors. Skeletal-related events include bone fractures from cancer and bone pain requiring radiation. The FDA's approval of Xgeva was based on 3 randomized, double-blind clinical studies in 5,723 patients comparing Xgeva with Zometa. One study involved patients with breast cancer, another in patients with prostate cancer, and a third included patients with a variety of other cancers. The studies were designed to measure the time until occurrence of a fracture or spinal cord compression due to cancer or until radiation or surgery for control of bone pain was needed. In patients with breast or prostate cancers, Xgeva was superior to Zometa in delaying SREs. In men with prostate cancer, the median time to an SRE was 21 months with Xgeva compared to 17 months with Zometa. In patients with breast cancer, the median time to an SRE was 26 months with Zometa and has not yet been reached with Xgeva. In patients with other solid tumors, the time to development of an SRE was similar for both Xgeva and Zometa. The most serious side effects with Xgeva were hypocalcemia and osteonecrosis of the jaw. Xgeva is not FDA approved for the prevention of SREs in patients with multiple myeloma.
Xgeva and Prolia are both marketed by Amgen, Inc. Xgeva is administered using a higher dose and with more frequent dosing than Prolia. The recommended dosage is a 120 mg subcutaneous injection once every 4 weeks.
Vij and associates (2009) examined if RANKL inhibition with denosumab could reduce serum M-protein levels in relapsed or plateau-phase multiple myeloma (MM) subjects. All subjects received denosumab monthly, with loading doses on days 8 and 15 of month one, until disease progression or subject discontinuation. Results of this ongoing study demonstrated that no subjects in either cohort met the protocol-defined objective response criteria of complete response or partial response, but that denosumab effectively inhibited the RANKL pathway regardless of previous exposure to bisphosphonates, as evidenced by suppressed levels of the BTM, serum C-terminal telopeptide of type 1 collagen (sCTx). Eleven (21 %) subjects who relapsed within 3 months before study entry maintained stable disease for up to 16.5 months. Nineteen (46 %) subjects with plateau-phase MM maintained stable disease for up to 18.3 months. The AE profile for denosumab and its dosing schedule in these populations was consistent with that for advanced cancer patients receiving systemic therapy. The authors concluded that additional controlled clinical studies of denosumab in subjects with both relapsed and plateau-phase MM are warranted.
Bone Loss Associated with Androgen-Deprivation Therapy in Prostate Cancer:
Androgen-deprivation therapy (ADT) for patients with prostate cancer is associated with osteoporosis and fragility fractures. Several bisphosphonates have been shown to improve BMD in men receiving ADT. Egerdie and Saad (2010) stated that new agents such as denosumab and toremifene have shown promise in reducing fracture risk in these patients. A recent clinical trial reported that denosumab reduce the incidence of fragility fractures in patients with non-metastatic prostate cancer.
In a double-blind, multi-center, phase III study, Smith et al (2009) investigated the effects of denosumab on BMD and fractures in men receiving ADT for non-metastatic prostate cancer. These researchers randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (n = 734 in each group). The primary end point was percent change in BMD at the lumbar spine at 24 months. Key secondary end points included percent change in BMD at the femoral neck and total hip at 24 months and at all 3 sites at 36 months, as well as incidence of new vertebral fractures. At 24 months, BMD of the lumbar spine had increased by 5.6 % in the denosumab group as compared with a loss of 1.0 % in the placebo group (p < 0.001); significant differences between the 2 groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in BMD at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5 % versus 3.9 % with placebo) (relative risk, 0.38; 95 % CI: 0.19 to 0.78; p = 0.006). Rates of AEs were similar between the 2 groups. The authors concluded that denosumab was associated with increased BMD at all sites and a reduction in the incidence of new vertebral fractures among men receiving ADT for non-metastatic prostate cancer.
Michaud (2010) discussed trends in prostate cancer prevalence and survival; risk factors for bone loss, osteoporosis, and fractures as well as the approach to risk assessment in these patients; established and investigational drug therapies for managing cancer treatment-induced bone loss and osteoporosis. Most patients with prostate cancer should undergo assessment of risk for bone loss and osteoporosis that involves a bone-related history and physical examination, DEXA scanning, and the WHO fracture risk assessment tool. A NCCN task force report on bone health in cancer care provided recommendations for considering the use of pharmacotherapy -- bisphosphonates are useful for slowing or preventing bone loss associated with hormone-ablation therapy in men with prostate cancer, although fracture data are not available in men. The usefulness of other therapies (calcitonin salmon, estrogens, SERMs, and teriparatide) is limited by AEs, a lack of experience with the drugs in these patient populations, or both. Various drug therapies are in development for managing cancer treatment-induced bone loss and osteoporosis. Denosumab has been shown to improve BMD in men receiving hormone-ablation therapy for prostate cancer, but additional data are needed to dispel safety concerns that could limit the use of this drug in these patients.
The use of denosumab in the treatment of patients with metastatic prostate cancer is also being investigated. Albiges and colleagues (2010) noted that despite the advent of prostate cancer research that has led to the isolation of many new and promising targets, treatment of metastatic prostate cancer is still challenging. New agents targeting these molecules are currently under development in large randomized phase III trials, to improve overall survival and the quality of life of patients with metastatic castrate-resistant prostatic cancer. Cytotoxic chemotherapy (docetaxel-based chemotherapy) demonstrated clinical benefit on overall survival, but could be improved. Bone targeted therapies such as endothelin1 receptor A inhibitors, RANKL inhibitors (e.g., denosumab) as well as metabolic irradiation are in development in large phase III trials.
In a pre-specified exploratory analysis of a phase III, multi-center, double-blind study, Smith et al (2011) evaluated the effects of denosumab (60 mg subcutaneously every 6 months for 3 years) versus placebo (1,468 patients, 734 in each group) on BTM values. Bone turnover markers were measured at baseline, month 1, and pre-dose at months 6, 12, 24, and 36 in the overall population. Bone turnover markers at month 1 were also reported for subgroups based on age (less than 70 years versus greater than or equal to 70 years), prior duration of ADT (less than or equal to 6 months versus greater than 6 months), and baseline BTM (less than or equal to median versus greater than median BTM values). Patients had either a low BMD (T score at the lumbar spine, total hip, or femoral neck of less than −1.0) at baseline or a history of an osteoporotic fracture. Treatment with denosumab provided a rapid and sustained decrease of BTM values compared with placebo. The median change in serum type 1 C-telopeptide (sCTX) levels at month 1 was -90 % in the denosumab group and -3 % in the placebo group (p < 0.0001). The median change in TRAP-5b levels at month 1 was -55 % in the denosumab group and -3 % in the placebo group (p < 0.0001). The maximal median change in P1NP was -64 % in the denosumab group and -11 % in the placebo group, (p < 0.0001). Significantly greater decreases in BTM for denosumab were also seen in subgroup analyses based on age, prior ADT treatment, and baseline BTM values. Suppression of bone turnover markers was consistent with marked increases in bone mineral density reported previously.
In a phase III, randomized, double-blind study, Fizazi et al (2011) compared denosumab with zoledronic acid for prevention of skeletal-related events in men with bone metastases from castration-resistant prostate cancer (CRPC). Men with CRPC and no previous exposure to intravenous bisphosphonate were enrolled from 342 centers in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cut-off date. Randomization was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomization. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary end point was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary end point. Efficacy analysis was by intention-to-treat. A total of 1,904 patients were randomized, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cut-off date was 12.2 months (IQR 5.9 to 18.5) for patients on denosumab and 11.2 months (IQR 5.6 to 17.4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20.7 months (95 % CI: 18.8 to 24.9) with denosumab compared with 17.1 months (15.0 to 19.4) with zoledronic acid (hazard ratio 0.82, 95 % CI: 0.71 to 0.95; p = 0.0002 for non-inferiority; p = 0.008 for superiority). Adverse events were recorded in 916 patients (97 %) on denosumab and 918 patients (97 %) on zoledronic acid, and serious AEs were recorded in 594 patients (63 %) on denosumab and 568 patients (60 %) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 [13 %]) than in the zoledronic acid group (55 [6 %]; p < 0.0001). Osteonecrosis of the jaw occurred infrequently (22 [2 %] versus 12 [1 %]; p = 0.09). The authors concluded that denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from CRPC.
The European Association of Urology's guidelines on the treatment of advanced, relapsing, and CRPC (Mottet et al, 2011) states that zoledronic acid and denusomab can be used in men with CRPC and osseous metastases to prevent skeletal-related complications.
On September 16, 2011, the FDA approved denosumab (Prolia) as a treatment to increase bone mass in patients at high-risk for fracture receiving ADT for non-metastatic prostate cancer. In patients with non-metastatic prostate cancer, denosumab also reduced the incidence of vertebral fracture. The recommended dose and schedule for denosumab as a treatment to increase bone mass in patients at high-risk for fracture receiving ADT for non-metastatic prostate cancer is 60 mg subcutaneously every 6 months.
Other Indications:
Anderson et al (2008) reviewed investigational approaches and control paradigms for recurrent or metastatic primary bone tumors (Ewing's sarcoma [ES] and osteosarcoma [OS]). These researchers analyzed temozolomide plus irinotecan data and reviewed in the context of other newer approaches including anti-angiogenesis, anti-IGF-1R antibodies and bisphosphonates for ES. Some current state-of-the-art approaches for OS include L-MTP-PE, anti-IGF-1R inhibition, aerosol therapies and bone specific agents. The authors stated that bone-specific agents including denosumab and bisphosphonates may have benefit against ES, OS, and giant-cell tumor (GCT).
In an open-label, phase II study, Thomas et al (2010) examined the potential therapeutic effect of denosumab on tumor-cell survival and growth in patients with GCT. A total of 37 patients with recurrent or unresectable GCT were enrolled and received subcutaneous 120-mg denosumab monthly (every 28 days), with loading doses on days 8 and 15 of month 1. The primary end point was tumor response, defined as elimination of at least 90 % of giant cells or no radiological progression of the target lesion up to week 25. Study recruitment is closed; patient treatment and follow-up are ongoing. Two patients had insufficient histology or radiology data for efficacy assessment; 30 of 35 (86 %; 95 % CI: 70 to 95) of evaluable patients had a tumor response: 20 of 20 assessed by histology and 10 of 15 assessed by radiology. Adverse events were reported in 33 of 37 patients; the most common being back pain (n = 4), headache (n = 4), and pain in an extremity (n = 7). Five patients had grade 3 to 5 AEs, only 1 of which (grade 3 increase in human chorionic gonadotropin concentration not related to pregnancy) was deemed to be possibly treatment related. Five serious AEs were reported although none was deemed treatment related. The authors stated that further investigation of denosumab as a therapy for GCT is warranted.
Branstetter et al (2012) described histologic analyses of GCT of the bone (GCTB) tumor samples from a phase 2 study of denosumab in GCTB. Adult patients with recurrent or unresectable GCTB received subcutaneous denosumab 120 mg every 4 weeks (with additional doses on days 8 and 15). The primary histologic efficacy endpoint was the proportion of patients who had a greater than or equal to 90 % elimination of giant cells from their tumor. Baseline and on-study specimens were also evaluated for overall tumor morphology and expression of RANK and RANKL. Baseline tumor samples were typically composed of densely cellular proliferative RANKL-positive tumor stromal cells, RANK-positive rounded mononuclear cells, abundant RANK-positive tumor giant cells, and areas of scant de novo osteoid matrix and woven bone. In on-study samples from 20 of 20 patients (100 %), a decrease of greater than or equal to 90 % in tumor giant cells and a reduction in tumor stromal cells were observed. In these analyses, 13 patients (65 %) had an increased proportion of dense fibro-osseous tissue and/or new woven bone, replacing areas of proliferative RANKL positive stromal cells. The authors concluded that denosumab treatment of patients with GCTB significantly reduced or eliminated RANK-positive tumor giant cells. Denosumab also reduced the relative content of proliferative, densely cellular tumor stromal cells, replacing them with non-proliferative, differentiated, densely woven new bone. Denosumab continues to be studied as a potential treatment for GCTB.
An UpToDate review on “Giant cell tumor of bone” (Thomas and Desai, 2012) states that “Newer therapeutic agents hold promise for patients for whom local therapies are not suitable. The characterization of the role of the RANK/RANKL axis in mediating the recruitment and function of osteoclast-like cells has provided a strong rationale for the use of targeted therapies such as denosumab which affect this pathway. Although denosumab is not yet commercially available, participation in a clinical trial evaluating the use of denosumab for recurrent and/or unresectable disease is encouraged”.
Yamashita (2009) stated that cyclic intravenous pamidronate is now the standard treatment for moderate-to-severe forms of osteogenesis imperfecta (OI); however clinical studies are not yet sufficient to conclude appropriate annual dose and ideal duration of therapy at present time. Oral alendronate is also effective in milder forms of OI. Zoledronic acid has undergone international multi-center clinical trials to examine efficiency and long-term side effects including osteonecrosis of the jaw. Teriparatide and denosumab have the potential for management of OI.
Sharp and colleagues (2010) evaluated the effects of denosumab on cortical bone in rheumatoid arthritis (RA). Patients (n = 227) with active, erosive RA were randomized to receive subcutaneous 60-mg or 180-mg denosumab or placebo every 6 months. All patients received stable doses of methotrexate and daily calcium and vitamin D. For this blinded post hoc analysis (n = 218), cortical bone loss was determined by digital x-ray radiogrammetry using computer-assisted measurement of cortical thickness and shaft width at 21 mid-shaft levels of the 2nd through 4th metacarpal bones of both hands. At 12 months, patients receiving denosumab had significantly less metacarpal bone loss versus placebo (denosumab 60 mg: -0.0034, denosumab 180 mg: 0.0001 gain, placebo: -0.0108; p < or = 0.01 for both denosumab doses). Twelve-month decreases from baseline greater than the smallest detectable change occurred in 2 patients in the 180-mg denosumab group, 9 patients in the 60-mg denosumab group, and 12 patients in the placebo group. Negative correlation was significant between static cortical thickness ratios and static erosion scores (6 and 12 months), and for placebo, between changes in erosion scores and changes in cortical thickness ratio. The authors concluded that twice-yearly injections of denosumab with ongoing methotrexate treatment significantly reduced cortical bone loss in RA patients for up to 12 months. They stated that these findings add to the growing evidence supporting the clinical utility of digital x-ray radiogrammetry.
Morgans and colleagues (2011) noted that male osteoporosis is an increasingly recognized problem in aging men. A common cause of male osteoporosis is hypogonadism. Thousands of men with prostate cancer are treated with ADT. Men treated with ADT experience a decline in BMD and have an increased rate of fracture. These investigators described prostate cancer survivors as a model of hypogonadal osteoporosis and discussed the use of RANKL-targeted therapies in osteoporosis. Denosumab, the only RANKL-targeted therapy currently available, increases BMD and decreases fracture rate in men with prostate cancer. Denosumab is also associated with delayed time to first skeletal-related event and an increase in bone metastasis-free survival in these men. It is reasonable to investigate the use of RANKL-targeted therapy in male osteoporosis in the general population.
On September 12, 2012, the FDA approved a new indication for denusomab (Prolia) -- for the treatment of bone loss in men with osteoporosis at high-risk for fracture. This new approval was based on results from a multi-center, randomized, double-blind, placebo-controlled study (the ADAMO trial) that compared the safety and effectiveness of denosumab 60-mg every 6 months versus placebo in males with osteoporosis. A total of 242 men (aged 30 and 85 years with low BMD [T-score ≤ –2.0 and ≥ –3.5 at the lumbar spine or femoral neck] or who have experienced a prior major osteoporotic fracture and had a T-score ≤ –1.0 and ≥ –3.5) were enrolled in this phase III clinical trial. Patients were randomized (1:1) to receive either 60 mg of Prolia every 6 months or placebo. The primary study endpoint was the percent change from baseline in the lumbar spine BMD at month 12. Secondary efficacy endpoints included percent change in total hip and femoral neck BMD from baseline to 1 year. In the study, treatment with Prolia resulted in significantly greater gains at the lumbar spine when compared to placebo (5.7 % versus 0.9 %). Effects of Prolia on BMD were independent of age, baseline testosterone levels, BMD status and estimated fracture risk. Additional results showed that patients in the study who received treatment with Prolia experienced BMD increases at all other skeletal sites assessed compared to placebo, including at the total hip (2.4 % versus 0.3 %) and at the femoral neck (2.1 % versus 0.0 %). Safety findings were consistent with what have been observed in other studies of Prolia in post-menopausal women with osteoporosis. The most common adverse reactions reported (per patient incidence greater than 5 %) were arthralgia, back pain, and nasopharyngitis. All patients received daily calcium and vitamin D supplementation throughout the study.
Eriksen (2012) stated that the majority of osteoporotic fractures happen in individuals with BMD t-scores in the osteopenic range (-2, 5 < t-score < -1). However, widespread use of anti-osteoporotic medication in this group based on t-score alone is not advisable because: (i) the number needed to treat is much higher (NNT > 100) than in patients with fractured and t-score below -2,5 (NNT 10 to 20); (ii) while specific osteoporosis treatments have demonstrated significant reductions of the fracture risk in patients with t-score < -2, 5, the effectiveness in patients in the osteopenic range is less well-established. Thus, an osteopenic t-score does not in itself constitute a treatment imperative. Generally, osteopenia has to be associated with either low-energy fracture(s) or very high-risk for future fracture as assessed with risk calculators like FRAX to warrant specific osteoporosis therapy. Vertebral fractures are now conveniently assessed using lateral x-rays from DXA machines. In the vast majority of cases anti-resorptive treatments (mainly hormone replacement therapy and SERMS in younger and bisphosphonates or denosumab in older women) are the treatments of choice in this group of patients, only rarely is anabolic therapy indicated.
Camozzi et al (2012) noted that hyper-calcemia is a relatively frequent alteration, mostly associated to primary hyper-parathyroidism (PHPT) and malignancy-associated hyper-calcemia (MAH). Treatment first includes rehydration and loop diuretics, as general measures. Bisphosphonates are considered the drugs of choice due to their long-term management. Calcitonin is preferable in the short-term control of severe hyper-calcemia. The anti-reabsorptive action of bisphosphonates has been considered the most effective in the disorders characterized by an excessive bone resorption. Zoledronate is superior to both clodronate or pamidronate in the treatment of MAH. Calcimimetic agents has been recently introduced to control hyper-calcemia in selected cases of PHPT. They are used when surgery is not possible or patients do not meet surgical criteria. Malignancy-associate hyper-calcemia is broadly divided into 2 categories: (i) humoral MAH and (ii) osteolytic MAH. The first concerns the paraneoplastic release of humoral factors, mainly parathyroid hormone-related peptide (PTHrP). Recently a humanized monoclonal antibody against human PTHrP has been generated and is still under evaluation. The RANKL has a critical role in the etiology of malignancy skeletal complications. The fully humanized anti-RANKL antibody (denosumab) would seem to be even more effective than bisphosphonates to suppress bone resorption, as shown in preliminary results.
Khoury and colleagues (2012) reported a unique case of hyper-calcemia associated with post-essential thrombocythemia myelofibrosis and reviewed the clinical and laboratory features, pathogenesis, and responsiveness to treatment with denosumab. The patient was a 62-year old woman with essential thrombocythemia who presented with progression to myelofibrosis with lytic skull lesions and symptomatic hyper-calcemia. Other causes of hyper-calcemia were excluded. Her disturbance in calcium homeostasis was not PTH- or vitamin D-mediated, although this has been postulated in cases of hyper-calcemia with the related entity of primary myelofibrosis. Her hyper-calcemia was refractory to aggressive iv saline administration, furosemide, calcitonin, and pamidronate, but promptly improved after one 120-mg subcutaneous dose of denosumab, with sustained normo-calcemia for approximately 2 months. She died 6 months later from complications due to the leukemic transformation of her hematological disease. The authors concluded that the pathogenesis of myelofibrosis-related hyper-calcemia could be due to multiple factors, particularly changes in the RANK ligand-RANK-osteoprotegerin system that lead to increased osteoclast activity. Although the authors did not measure these factors, they stated that denosumab holds promise in the treatment of MAH and specifically that related to myelofibrosis.
UpToDate reviews on "Management of primary hyperparathyrodism" (Silverberg and Fuleihan, 2012), "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in adult predialysis patients with chronic kidney disease" (Quarles and Cronin, 2012a), and "Management of secondary hyperparathyroidism and mineral metabolism abnormalities in dialysis patients" (Quarles and Cronin, 2012b) do not mention the use of denosumab. Furthermore, the NCCN's Drugs & Biologics Compendium (2012) does not list hyper-calcemia/hyper-parathyroidism as an indication of denosumab.
In a review on “Current standards and future treatments of rheumatoid arthritis”, Onysko and Burch (2012) listed denosumab as an emerging therapy for RA.
Hageman et al (2013) evaluated the use of denosumab for the prevention of SREs in patients with osteolytic lesions associated with MM. MEDLINE/Ovid (1946 to Week 3 of April 2013), EMBASE (1980 to Week 16 of 2013), abstracts of the American Society of Clinical Oncology (1983 to April 22, 2013), American Society of Hematology (2004 to April 22, 2013), European Hematology Association (1994 to April 22, 2013), and the European Society for Medical Oncology (1990 to April 22, 2013) were searched using the terms denosumab and multiple myeloma. Clinical trials comparing the effectiveness of denosumab with that of bisphosphonates in preventing or delaying SREs in patients with MM were included. Trials solely evaluating bone turnover markers were excluded; 1 phase II trial, 1 phase III trial, and 1 post-hoc phase III analysis were included. A phase II trial compared denosumab to bisphosphonate continuation in patients with elevated urinary N-telopeptide levels (uNTX) despite bisphosphonate therapy. Denosumab patients experienced fewer SREs; however, this was not statistically significant. A phase III trial compared denosumab to zoledronic acid in patients with at least 1 osteolytic lesion. Denosumab delayed the time to a first SRE by 16 % (median of 20.6 versus 16.3 months; p = 0.0007 for non-inferiority). Superiority of denosumab was not reached. A post-hoc analysis revealed less favorable survival in MM patients treated with denosumab (HR 2.26; 95 % CI: 1.13 to 4.50). The incidence of overall adverse effects was similar between each group in both studies. The authors concluded that denosumab may be an alternative for the prevention of SREs in patients with MM with deteriorating renal function. Moreover, they stated that because of the high cost of the drug, low percentage of MM patients in the available studies, and the potential for their decreased survival, use of denosumab should be limited.
Grasemann et al (2013) stated that juvenile Paget's disease (JPD) is an extremely rare, yet painful and debilitating bone disease with onset occurring during early childhood. Juvenile Paget's disease can be caused by loss of function of osteoprotegerin (OPG), resulting in subsequent stimulation of osteoclasts via the RANK pathway. Increased bone turnover and lack of bone modeling lead to severe deformities, frequent fractures, short stature, and loss of hearing. The treatment for JPD is challenging and has previously been based on administration of either calcitonin or bisphosphonates. However, with the development of denosumab, a treatment targeting the pathophysiology of JPD may be available. These researchers reported the effects of denosumab treatment on an 8-year old girl with a severe form of JPD. Before starting the denosumab treatment regimen, the patient had been treated for 3.5 years with IV pamidronate. The administration of denosumab resulted in improved disease control compared with bisphosphonate, as assessed by monitoring markers of bone turnover. Alkaline phosphatase levels dropped within the normal range and remained at normal levels for 5 months after the final dose of denosumab. Additionally, bone pain was more efficiently controlled with denosumab. However, concomitant with the first injection, severe hypocalcemia developed, for which the patient was hospitalized and IV calcium supplementation was required for 13 days. The authors concluded that denosumab appears to be significantly effective for osteoclast inhibition for the treatment of JPD. However, in this patient, denosumab administration was associated with severe hypocalcemia, indicating that close monitoring of calcium levels is required during treatment.
Saki et al (2013) reported a 3-year old Iranian girl with JPD and craniosynostosis who had vitamin D deficiency in infancy. She presented with fractures during the 1st year of life followed by bone deformities, delayed development, failure-to-thrive, and pneumonias. At 1 year of age, biochemical studies of serum revealed marked hyper-phosphatasemia together with low-normal calcium and low inorganic phosphate and 25-hydroxyvitamin D levels. Several family members in previous generations of this consanguineous kindred may also have had JPD and vitamin D deficiency. Mutation analysis showed homozygosity for a unique missense change (c.130T>C, p.Cys44Arg) in TNFRSF11B that would compromise the cysteine-rich domain of OPG that binds RANKL. Both parents were heterozygous for this mutation. The patient's serum OPG level was extremely low and RANKL level markedly elevated. She responded well to rapid oral vitamin D repletion followed by pamidronate treatment given intravenously. The authors noted that this patient was the first Iranian reported with JPD. Her novel mutation in TNFRSF11B plus vitamin D deficiency in infancy was associated with severe JPD uniquely complicated by craniosynostosis. They noted that pamidronate treatment with vitamin D sufficiency can be effective therapy for the skeletal disease caused by the OPG deficiency form of JPD; denosumab was not mentioned as a therapeutic option.
Furthermore, an UpToDate review on “Treatment of Paget disease of bone” (Seton, 2013) does not list denosumab as a therapeutic option.
The European Association of Urology’s guidelines on “Muscle-invasive and metastatic bladder cancer” (Witjes et al, 2013) stated that “Zoledronic acid and denosumab have been approved for all cancer types including urothelial cancer, because they reduce and delay skeletal-related events in metastatic bone disease”.
Vardy and Agar (2014) reviewed the evidence for the use of non-opioid analgesic agents in patients with cancer and described the mode of action of the main drug classes. Evidence supports the use of anti-inflammatory drugs (e.g., acetaminophen/paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) for mild cancer pain. Adding an NSAID to an opioid for stronger cancer pain is effective, but the risk of long-term adverse effects has not been quantified. There is limited evidence to support using acetaminophen with stronger opioids. Corticosteroids have a specific role in spinal cord compression and brain metastases, where improved analgesia is a secondary benefit. There is limited evidence for adding corticosteroids to stronger opioids when pain control is the primary objective. Systematic reviews suggested a role for anti-depressant and anti-convulsant medications for neuropathic pain, but there are methodological issues with the available studies. The authors stated that bisphosphonates improve pain in patients with bony metastases in some tumor types; denosumab may delay worsening of pain compared with bisphosphonates. Moreover, they stated that larger studies of longer duration are needed to address outstanding questions concerning the use of non-opioid analgesia for stronger cancer pain.
Schreuder and colleagues (2014) noted that in the search for new pharmacotherapies for central giant cell granuloma (CGCG), proteins that are essential to osteoclastogenesis are intriguing potential targets. In the present case report, these researchers described a 25-year old patient with an aggressive CGCG of the maxilla, who was successfully treated with denosumab, after other pharmacotherapies had failed to achieve regression or stabilization of the tumor. The authors concluded that denosumab could be a promising alternative to potentially mutilating surgery for CGCG. However, they stated that more research is needed before definite conclusions can be drawn about the potential role of this agent in the treatment of CGCG.
Reagan et al (2014) stated that hypercalcemia is a common complication of malignancy and portends a worse prognosis. It causes a variety of symptoms in patients, which can range from confusion and polyuria to coma and death. There are 4 broad mechanistic categories to classify hypercalcemia of malignancy: (i) local osteolysis secondary to metastatic cancer or MM, (ii) excess parathyroid-related hormone, (iii) excess 1,25-dihydroxyvitamin D production, and (iv) ectopic parathyroid hormone production. Volume expansion with normal saline solution and treatment with intravenous bisphosphonates to decrease osteoclast-mediated bone destruction are effective initial therapies. Calcitonin, gallium nitrate, and corticosteroids can serve as adjunctive therapies. The author concluded that denosumab is an attractive therapeutic option for refractory cases of hypercalcemia, although more data are needed before this therapy can be recommended.
The FDA approved Xgeva or the treatment of hypercalcemia of malignancy (HCM) refractory to bisphosphonate therapy (Amgen, 2014). Xgeva was approved and granted Orphan Drug Designation by the FDA for this indication. Denosumab binds to RANK Ligand (RANKL), a protein essential for the formation, function and survival of osteoclasts, the cells responsible for bone resorption, thereby modulating calcium release from bone. Xgeva prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.
The approval of Xgeva was based on positive results from an open-label, single-arm study, which enrolled patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment (Amgen, 2014). The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) <11.5 mg/dL (2.9 mmol/L; Common Terminology for Adverse Events [CTCAE] grade <1) within 10 days after the first dose of Xgeva. Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC <10.8 mg/dL [2.7 mmol/L]) by day 10, time to response and response duration (defined as the number of days from the first occurrence of CSC <11.5 mg/dL). The study achieved its primary endpoint with a response rate at day 10 of 63.6 percent in the 33 patients evaluated. The overall complete response rate was 63.6 percent. The estimated median time to response (CSC <11.5 mg/dL) was nine days, and the median duration of response was 104 days.
The most common adverse reactions in patients receiving Xgeva for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation and diarrhea (Amgen, 2014).
For patients with HCM, Xgeva is administered as a subcutaneous injection (120 mg) every four weeks with additional doses of 120 mg on days eight and 15 of the first month of therapy (Amgen, 2014).
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