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Abstract

Denosumab is an investigational fully human monoclonal antibody to RANKL, a cytokine member of the tumor necrosis factor family that is the principal mediator of osteoclastic bone resorption. RANKL stimulates the differentiation, activity and survival of osteoclasts, and is implicated in the pathogenesis of postmenopausal osteoporosis and other skeletal disorders associated with high rates of bone remodeling. By inhibiting the action of RANKL, denosumab reduces the differentiation, activation and survival of osteoclasts and slows the rate of bone resorption. Postmenopausal women with low bone mineral density treated with denosumab have an increase in bone mineral density and a reduction of bone turnover markers that is rapid, sustained and reversible. In postmenopausal women with osteoporosis, denosumab reduces the risk of vertebral, hip and nonvertebral fractures. Denosumab is well tolerated with a favorable safety profile.

Keywords

AMG 162 denosumab FRAX osteoporosis prevention treatment

Osteoporosis is a skeletal disease characterized by low bone mineral density (BMD) and poor bone quality that reduces bone strength and increases the risk of fractures [1]. Osteoporosis is a major public health concern, affecting approximately 200 million individuals worldwide, including a third of women aged 60 to 70 years and two-thirds of women aged 80 years or older [101]. Fractures of the hip and spine are associated with increased morbidity and mortality [2]. Despite the high prevalence of osteoporosis and the availability of effective drugs to reduce fracture risk, it is underdiagnosed and undertreated. Patients with previous fractures, who are at very high risk of future fracture [3], are commonly not evaluated or treated for osteoporosis [4]. Even when treatment is started, patients often do not take medication correctly or continue to take it for long enough to benefit from a reduction in fracture risk [5]. Patients with good compliance to therapy have larger BMD increases [5], greater reduction in fracture risk [6] and lower healthcare costs than do patients who are poorly compliant [7]. Strategies to improve compliance to therapy include reducing the frequency of drug dosing and simplifying drug administration [8].

The WHO, in cooperation with many national and international medical societies, has developed a fracture risk assessment tool (FRAX) that provides an estimate of 10-year fracture probability based on BMD at the femoral neck and validated clinical risk factors for fracture [9]. When cost–effectiveness modeling is conducted using FRAX and country-specific economic assumptions (e.g., societal willingness to pay, consequences of fractures, costs of fracture care and treatment to prevent fractures), thresholds for intervention with pharmacological therapy can be determined. In the USA, such an analysis has been performed [10,11], resulting in recommendations for treatment with pharmacological agents that are partly based on 10-year probability of fracture [12]. This allows clinicians to make more informed decisions in the management of osteoporosis than with former guidelines that did not quantify the relationship between clinical risk factors and fracture risk [13].

Denosumab (previously AMG 162; Amgen Inc., Thousand Oaks, CA, USA) is an investigational drug that inhibits bone resorption through a novel mechanism of action, with long dosing intervals using a subcutaneous (sc.) injection method of administration. The 6-month interval between doses used for the management of osteoporosis may improve adherence to therapy compared with other osteoporosis treatments given more frequently, and the ease of sc. administration may expand the number of users compared with bisphosphonates that are given by intravenous infusion. Denosumab has been shown to suppress bone turnover in healthy postmenopausal women [14], increase BMD in postmenopausal women with low BMD [15 –18] and reduce the risk of fractures in women with postmenopausal osteoporosis (PMO) [19,102]. This is an update of evidence that has become available since a previous review in this journal suggesting the potential clinical use of denosumab in the management of PMO [20].

Overview of osteoporosis treatments

Drugs for the prevention and treatment of osteoporosis are classified as antiresorptive (anticatabolic) or anabolic (bone-forming) according to their effect on bone remodeling [21 –23]. Antiresorptive drugs include estrogens, bisphosphonates (alendronate, risedronate, ibandronate and zoledronic acid), raloxifene (an estrogen agonist/antagonist or selective estrogen-receptor modulator [SERM]) and salmon calcitonin. The anabolic drugs are teriparatide and recombinant human parathyroid hormone (1-84). Strontium rane-late (SR), which is approved in many countries (but not the USA) for the treatment of PMO, has both antiresorptive and anabolic properties [24].

Denosumab is an antiresorptive drug that acts directly on the RANKL/RANK/osteoprotegerin (OPG) signaling pathway that regulates bone resorption [14]. It is a fully human monoclonal antibody (IgG₂ immunoglobulin isotype) with a high affinity and specificity for human RANKL. By binding to RANKL, it prevents the interaction of RANKL with RANK and inhibits bone resorption.

RANKL/RANK/OPG regulation of osteoclastic bone resorption

The adult skeleton is continuously being broken down and reformed in a dynamic process termed bone remodeling, which occurs owing to the coordinated activity of osteoclasts and osteoblasts in discrete packets (bone-remodeling units) located on the surface of trabecular bone and in Haversian systems of cortical bone. When bone resorption exceeds bone formation, as is commonly seen in early postmenopausal women, bone loss occurs, with the consequences of skeletal fragility and an increased risk of fractures [25]. RANKL, a component of the RANKL/RANK/OPG signaling pathway, is the principal final mediator of bone resorption [26]. It is expressed on the surface of osteoblasts and has also been detected in soluble form after cleavage from the cell surface or secretion from T cells [27]. When RANKL binds to its RANK receptor, located on the cell surface of osteoclasts and preosteoclasts, it enhances osteoclast differentiation, activity and survival, thereby stimulating bone resorption. OPG is a naturally occurring soluble nonsignaling ‘decoy receptor’ that binds to RANKL, reducing the formation, activity and survival of osteoclasts, with inhibition of bone resorption [28]. An increase in the RANKL:OPG ratio has been implicated in the pathogenesis of PMO and other skeletal diseases associated with elevated bone resorption [29].

Pharmacokinetic properties of denosumab

The pharmacokinetics of denosumab are nonlinear with dose and similar to other fully human monoclonal antibodies. A Phase I dose-escalation trial in healthy postmenopausal women administered a single dose of sc. denosumab (0.01–3.0 mg/kg) showed three phases: (1) a prolonged absorption phase with maximum serum concentration (C_max) observed at 5–21 days postdose, increasing as dose increased; (2) a prolonged β-phase, with serum half-life as long as 32 days with the maximum dose; and (3) a rapid terminal phase when serum concentration dropped below 1000 ng/ml [14]. Postmenopausal women with low BMD given sc. denosumab 60 mg were found to have a median time to maximum concentration (T_max) after the first dose of 26 days (range 3–32 days) [30]. The duration of denosumab antiresorptive effect is likely to be a consequence of its long half-life and its effects on osteoclast recruitment, function and survival.

Phase I study of denosumab in healthy postmenopausal women

The findings of a Phase I single-dose, randomized, double-blind, placebo-controlled, dose-escalation study of denosumab in 49 healthy postmenopausal women administered variable doses of sc. denosumab or placebo [14] were previously reviewed in this journal [20]. The primary objectives of this study were to assess drug safety and tolerability, the effect on bone turnover markers and pharmacokinetics. The effect on suppression of bone resorption, as measured by urinary N-telopeptide (NTX), was dose-dependent, rapid (within 12 h, the earliest timepoint measured), profound (up to 84% decrease from baseline), sustained (up to 6 months) and reversible (rise in NTX at the end of the monitoring period). Suppression of serum bone-specific alkaline phosphatase (BSAP) occurred later and was less pronounced than was observed for NTX.

Phase II study of denosumab in postmenopausal women with low BMD

The efficacy and safety of denosumab were evaluated in a Phase II randomized, placebo-controlled, dose-ranging study in 412 postmenopausal women with low BMD (lumbar spine T-score −1.8 to −4.0, and total hip or femoral neck T-score −1.8 to −3.5) [16]. The subjects were randomized to nine groups (41–54 subjects per group) receiving sc. denosumab 6, 14 or 30 mg every 3 months; sc. denosumab 14, 60, 100 or 210 mg every 6 months; open-label alendronate 70 mg weekly; or placebo. The primary end point was percentage change in lumbar spine BMD at 12 months compared with baseline. Bone turnover was assessed by measurement of serum and urine telopeptides and BSAP.

Report of 12-month data

The findings at 12 months were previously reviewed in this journal [20]. Denosumab treatment for 12 months resulted in a BMD increase of 3.0–6.7% at the lumbar spine compared with baseline, while there was a 0.8% loss with placebo (p < 0.001). At the total hip, there was a BMD increase of 1.9–3.6% compared with baseline, with a 0.6% loss in the placebo group (p < 0.001). At the distal one-third radius, there was a BMD increase of 0.4–1.3% with denosumab, compared with a 2.0% loss with placebo (p < 0.001). In exploratory comparisons with alendronate, the BMD changes were at least as great with denosumab, with an apparently greater BMD increase at the total hip and distal one-third with denosumab 30 mg every 3 months and 60 mg every 6 months. Denosumab groups showed a decrease in serum C-telopeptide (CTX) compared with placebo (p < 0.001) as early as 3 days, the first scheduled time of CTX measurement. Serum CTX suppression reached a maximum mean decrease of 88% compared with 5% for placebo. The effects on urinary NTX were similar to those of serum CTX. The suppression of BSAP with denosumab was significant compared with placebo (p < 0.001), but was delayed by approximately 1 month compared with CTX. The suppression of bone turnover was dose-dependent, rapid, sustained and reversible.

Report of 24-month data

The efficacy and safety of denosumab after 24 months of treatment were evaluated in a prespecified exploratory analysis [15]. Outcome measures included BMD at the lumbar spine, total hip, distal one-third radius and total body; bone turnover markers; and safety. Of the original 412 women randomized, 337 (81.8%) completed the 24-month study. BMD increases at the lumbar spine at 24 months ranged from 4.13–8.89% with denosumab compared with a 1.18% decrease with placebo (p < 0.001 for all doses denosumab vs placebo). Compared to open-label alendronate, BMD increases with denosumab at all four skeletal sites were similar or greater, except with the denosumab dose of 14 mg every 6 months, for which the BMD change at the lumbar spine was less than with alendronate.

Report of 48-month data

The Phase II study was extended for an additional 24 months (total of 48 months), with blinded doses of sc. denosumab or placebo administered every 6 months (q6m) [17]. Denosumab-treated patients who continued the study were reassigned based on their randomization group at enrollment. Patients randomized to denosumab 6 and 14 mg every 3 months (q3m), and those receiving 14, 60 and 100 mg q6m, received denosumab 60 mg q6m. Patients randomized to the 210 mg q6m received placebo for the remainder of the study. Patients randomized to 30 mg q3m received placebo for 12 months then were subsequently re-treated with denosumab 60 mg q6m for 12 months. Open-label alendronate patients discontinued alendronate therapy after 24 months and received no additional drug therapy. The placebo group was maintained for the entire 48 months. Of patients initially randomized in the study, 64% (262 of 412) completed 48 months. Continuous, long-term denosumab treatment increased BMD at the lumbar spine (9.4–11.8%) and total hip (4.0–6.1%). Bone turnover markers were consistently suppressed over 48 months. Discontinuation of denosumab was associated with a BMD decrease of 6.6% at the lumbar spine and 5.3% at the total hip within the first 12 months of treatment discontinuation. Retreatment with denosumab increased lumbar spine BMD by 9.0% from original baseline values. Bone turnover marker levels increased with discontinuation of denosumab and decreased with retreatment.

Phase III trial of denosumab in women with postmenopausal osteoporosis

Denosumab for treatment of postmenopausal osteoporosis

The Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) trial was a 3-year, Phase III clinical trial in 7868 postmenopausal women with osteoporosis who were randomized to receive either sc. denosumab 60 mg (n = 3902) or placebo (n = 3906) q6m [19,102]. The primary efficacy end point was new vertebral fractures at 36 months, with secondary end points that included time to first hip and nonvertebral fractures. Study subjects were between the ages of 60 and 90 years (mean 72.3 years) with a baseline T-score at the lumbar spine or total hip less than −2.5 to greater than or equal to −4.0 (mean baseline T-score = −2.8 at the lumbar spine), approximately 23% of whom had at least one prevalent vertebral fracture at the time of entry into the study. All patients received elemental calcium 1000 mg and vitamin D 400–800 international units (IU) daily. Approximately 83% of subjects (denosumab n = 3272; placebo n = 3206) completed the 36-month study. Treatment with denosumab resulted in statistically significant reduction in the incidence of new vertebral fractures, new nonvertebral fractures, and hip fractures compared with placebo treatment. See Table 1 for a summary of the key findings with FREEDOM and other recent Phase III clinical trials of denosumab in the management of postmenopausal osteoporosis.

Table 1.

Summary of recent Phase III trials of denosumab for the management of postmenopausal osteoporosis.

Study	Description	Primary end point	No. randomized	Mean age (years)	Baseline T-score	Key efficacy finding	Key safety findings	Ref.
FREEDOM, Cummings et al. Amgen Inc.1	Treatment of PMO	New vertebral fractures at 36 months with denosumab compared with placebo	7868	72.3	<-2.5 to ≥-4.0 at LS or TH	Decreased risk of fracture (vertebral, hip and nonvertebral) with denosumab compared with placebo	Similar AEs and SAEs with denosumab compared with placebo	[19, 102]
DEFEND, Bone et al.	Prevention of PMO	Percent change in LS BMD at 24 months with denosumab compared with placebo	332	59.4	Between −1.0 and −2.5 at LS	Increased BMD with denosumab compared with placebo	Similar AEs and SAEs with denosumab compared with placebo	[18]
DECIDE, Brown et al.	Head-to-head comparison of denosumab and alendronate in patients starting treatment	Percent change in TH BMD at 12 months with denosumab compared with alendronate	1189	64.4	≤-2.0 at LS or TH	Increased BMD with denosumab compared with alendronate	Similar AEs and SAEs with denosumab compared with alendronate	[31]
STAND, Kendler et al.	Head-to-head comparison of denosumab and alendronate in patients previously treated with alendronate	Percent change in TH BMD at 12 months with denosumab compared with alendronate	504	68	≤-2.0 to ≥-4.0 at LS or TH	Increased BMD with denosumab compared with alendronate	Similar AEs and SAEs with denosumab compared with alendronate	[32]

AE: Adverse event; BMD: Bone mineral density; LS: Lumbar spine; PMO: Postmenopausal osteoporosis; SAE: Serious adverse event; TH: Total hip.

Phase III trial of denosumab in postmenopausal women with low bone mass (osteopenia)

Denosumab for prevention of postmenopausal osteoporosis

The Denosumab Fortifies Bone Density (DEFEND) trial was a 2-year Phase III trial in 332 postmenopausal women with lumbar spine T-scores between −1.0 and −2.5 who were randomized to receive sc. denosumab 60 mg q6m (n = 166) or placebo (n = 166) [18]. All subjects were instructed to take supplements of 1000 mg calcium per day, with variable vitamin D supplementation determined according to the baseline serum level of 25-hydroxyvitamin D. The primary efficacy end point was the percent change from baseline in lumbar spine BMD measured by dual x-ray absorptiometry at 24 months compared with placebo. Secondary end points included the percent change from baseline in BMD at the total hip, femoral neck, one-third radius and total body at 24 months; percent change from baseline in trabecular, cortical and total volumetric BMD measured by quantitative computed tomography and percent change from baseline in bone turnover markers. The mean baseline age of study subjects was 59.4 years, with a mean baseline lumbar spine T-score of −1.61. The study was completed by 86% of randomized subjects. Denosumab significantly increased BMD at the lumbar spine compared with placebo at 24 months (denosumab 6.5 vs placebo −0.6%; p < 0.0001), with significant BMD increases also reported at the total hip, one-third radius and total body (p < 0.0001 for each compared with placebo). There was also a significant decrease in markers of bone resorption and formation compared with placebo. It was concluded that sc. denosumab 60 mg q6m increased BMD and reduced bone turnover markers in postmenopausal women with osteopenia with an overall incidence of adverse events that was similar to placebo.

Phase III trials comparing denosumab with alendronate

Denosumab versus alendronate in patients starting treatment

The Determining Efficacy: Comparison of Initiating Denosumab versus Alendronate (DECIDE) trial was a 1-year Phase III double-blind, double-dummy, noninferiority trial in 1189 postmenopausal women with lumbar spine or total hip T-score of −2.0 or less who were randomized to receive sc. denosumab 60 mg q6m plus weekly oral placebo (n = 594) or oral alendronate 70 mg weekly plus sc. placebo injections q6m (n = 595) [31]. All subjects were instructed to take at least 500 mg supplemental calcium per day, with the dose of vitamin D supplementation adjusted according to baseline serum 25-hydroxyvitamin D. The primary end point was percent change from baseline of the total hip BMD at month 12 in subjects treated with denosumab compared with alendronate. Key secondary end points included the percent change from baseline in BMD at the femoral neck, trochanter, lumbar spine and one-third distal radius at month 12; and percent change in serum CTX-I and P1NP from baseline at months 1, 3, 6, 9 and 12. The mean baseline lumbar spine T-score was −2.6 and mean baseline age was 64 years, with 94% of subjects completing 12 months of study. At 12 months, there was a significantly greater BMD increase with denosumab compared with alendronate at the total hip (denosumab 3.5 vs alendronate 2.6%; p < 0.0001) and all other measured skeletal sites, with the treatment difference of 0.6% at the femoral neck, 1.0% at the trochanter, 1.1% at the lumbar spine and 0.6% at the distal one-third radius (p ≤ 0.0002 for all sites). There was a statistically significant greater reduction in bone-turnover markers (CTX-I and P1NP) with denosumab compared with placebo. This head-to-head blinded clinical trial of deno-sumab versus alendronate showed a significantly greater increase in BMD and greater suppression of bone turnover markers with denosumab, with a similar pattern and frequency of adverse events.

Denosumab versus alendronate in patients previously treated with alendronate

The Study of Transitioning from Alendronate to Denosumab (STAND) trial was a 1-year Phase III double-blind, active-controlled, double-dummy study in 504 postmenopausal women 55 years of age and older, previously treated with alendronate, with lumbar spine or total hip T-score of −2.0 to −4.0 [32]. Subjects were randomized to receive sc. denosumab 60 mg q6m or continuing oral alendronate 70 mg weekly. All subjects were given daily supplements of calcium 1000 mg and vitamin D at least 400 IU. The primary end point was percent change in BMD at the total hip at 12 months for denosumab compared with alendronate. The study design allowed testing of the primary end point for superiority if noninferiority was demonstrated. The mean age of subjects at the time of randomization was 68 ± 8 years and mean length of previous alendronate therapy was 44 ± 33 months. At 12 months, there was a statistically significant greater increase in BMD with denosumab compared with continuing alendronate at the total hip, lumbar spine and distal one-third radius. It was concluded that in postmenopausal women previously treated with alendronate, patients switched to denosumab increased BMD more than those continuing alendronate, with a similar incidence of adverse events.

Safety & tolerability of denosumab

Over the first 24 months of the Phase II trial of denosumab in postmenopausal women with low BMD, adverse events continued to be generally similar in the placebo, denosumab and alendronate groups [15]. There were six cases (1.9 %) of serious adverse events of infections in the denosumab group (two cases of diverticulitis, three cases of pneumonia and one case of labyrinthitis) compared with none in the placebo group or open label alendronate group. There was one death, caused by gastric cancer, in the denosumab group, and none in the placebo or alendronate groups. Discontinuation rates over the first 24 months were 2.2% for placebo, 2.9% for denosumab and 6.4% for alendronate. No neutralizing antibodies to denosumab were observed in the first 24 months of treatment.

At 48 months in the Phase II trial in postmenopausal women with low BMD, serious adverse events were 10.9% (5 of 46) in the placebo group, 17.8% (56 of 314) in the denosumab group and 17.4% (8 of 46) in the alendronate group. The incidence of malignant neoplasms was balanced among the treatment groups. The overall incidence of infections was similar in all treatment groups, while infections requiring hospitalization occurred in 3.2% (10 of 314) of denosumab-treated patients and none of those who received placebo or alendronate. All infections were common community-acquired infections that responded appropriately to standard antibiotic therapy, with no reports of opportunistic infections.

The incidence and types of adverse and serious adverse events observed in the 3-year FREEDOM trial in women with PMO were similar in the denosumab and placebo groups, including serious infections and neoplasms.

In DEFEND, adverse events were similar in both groups. Serious adverse events were reported numerically more often with denosumab compared with placebo, with the difference not statistically significant (denosumab 11% vs placebo 5.5%, p = 0.074), primarily owing to the greater number of subjects with infections treated as hospital inpatients (deno-sumab: 8 vs placebo: 1). The overall incidence of infections was balanced (denosumab: 60% vs placebo: 61%). In DECIDE, adverse events and serious adverse events, including infections and malignancies, were similar with both groups. In STAND, adverse events and serious adverse events, including infections and malignancies, were similar in both groups.

Conclusion

Denosumab is an investigational fully human monoclonal antibody to RANKL, the principal mediator of osteoclastic bone resorption. It suppresses bone resorption in a rapid, sustained and reversible manner. Treatment with sc. denosumab 60 mg q6m increases BMD and reduces bone turnover in postmenopausal women with low BMD. In women with PMO, sc. denosumab 60 mg q6m reduces the risk of vertebral, hip and nonvertebral fractures compared with placebo. In postmenopausal women with low BMD initiating treatment, denosumab increases BMD and decreases bone turnover markers more than alendronate. In postmenopausal women previously treated with alendronate, those switching to denosumab increased BMD more than those continuing alendronate. The safety and tolerability of denosumab is good compared with placebo and compared with alendronate. Denosumab is a promising agent for the management of women with PMO.

Future perspective

The evidence to date shows that denosumab is an effective and safe drug for the prevention and treatment of PMO. It may receive approval for clinical use by late 2009. The infrequent dosing interval offers the potential to improve compliance compared with more frequent dosing of oral medications, and the ease of sc. administration suggests that this drug may be more likely than intravenous bisphosphonates to be prescribed by primary care physicians. It is an attractive addition to current therapeutic agents for the management of PMO, especially for patients who are unable to benefit from oral bisphosphonates owing to a contraindication, intolerance, malabsorption or poor compliance.

Regulatory issues

Denosumab is an investigational drug that is not currently approved for clinical use.

Executive summary

Mechanism of action

Denosumab is a fully human monoclonal antibody to RANKL, the principal mediator of osteoclastic bone resorption.

Denosumab blocks the binding of RANKL to its RANK receptor, thereby inhibiting osteoclast differentiation, activity and survival.

Pharmacokinetic properties

The pharmacokinetics of denosumab are nonlinear with dose and similar to other fully human monoclonal antibodies of the IgG₂ class.

Serum levels in healthy postmenopausal women after single subcutaneous doses ranging from 0.01 to 3.0 mg/kg showed three phases: (1) a prolonged absorption phase with maximum serum concentration observed at 5 to 21 days postdose, increasing as dose increased; (2) a prolonged β-phase, with serum half-life as long as 32 days with the maximum dose; and (3) a rapid terminal phase when serum concentration dropped below 1000 ng/ml.

Denosumab does not bind to TNF-α, TNF-β, TRAIL or CD40L.

Clinical efficacy

Denosumab increases bone mineral density (BMD) and reduces bone turnover markers in postmenopausal women with low BMD and osteoporosis.

Effects on BMD and bone turnover markers are reversible with discontinuation, with a robust response to retreatment.

Denosumab reduces the risk of vertebral, hip and nonvertebral fractures in women with postmenopausal osteoporosis (PMO).

In women initiating treatment, those taking denosumab have a greater increase in BMD and a greater reduction in bone turnover markers than those taking alendronate.

In patients previously treated with alendronate, those switching to denosumab have a greater increase in BMD than those continuing alendronate.

Safety & tolerability

No significant differences in safety and tolerability end points were observed in the Phase III clinical trial in over 7800 women with PMO receiving denosumab or placebo.

Drug interactions

There are no known drug interactions with denosumab.

Dosage & administration

Denosumab of a dose of 60 mg subcutaneous every 6 months is the dose used in studies for the prevention and treatment of PMO.

Footnotes

E Michael Lewiecki has recieved financial support or has owned personal investments to the following categories in the past year: grant/research support as principal investigator for the New Mexico Clinical Research & Osteoporosis Center from Amgen, Eli Lilly, GSK, Novartis, Pfizer, Procter & Gamble, Roche, Sanofi aventis and Wyeth; other support as a member of the scientific advisory board or speaker' bureau from Amgen, Eli Lilly, Novartis, Roche/GSK, Upsher-Smith and Wyeth; and is a direct stock shareholder of Procter & Gamble and Teva. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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36.

Head-to-head trial of denosumab versus alendronate demonstrated a greater increase in BMD and a greater reduction of bone turnover markers with denosumab.

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Pending the publication of FREEDOM data in a peer-reviewed journal, this is the most detailed authoritative document on fracture risk reduction and safety end points with denosumab versus placebo in women with PMO.

Denosumab for the Treatment of Postmenopausal Osteoporosis

Abstract

Keywords

Overview of osteoporosis treatments

RANKL/RANK/OPG regulation of osteoclastic bone resorption

Pharmacokinetic properties of denosumab

Phase I study of denosumab in healthy postmenopausal women

Phase II study of denosumab in postmenopausal women with low BMD

Report of 12-month data

Report of 24-month data

Report of 48-month data

Phase III trial of denosumab in women with postmenopausal osteoporosis

Denosumab for treatment of postmenopausal osteoporosis

Phase III trial of denosumab in postmenopausal women with low bone mass (osteopenia)

Denosumab for prevention of postmenopausal osteoporosis

Phase III trials comparing denosumab with alendronate

Denosumab versus alendronate in patients starting treatment

Denosumab versus alendronate in patients previously treated with alendronate

Safety & tolerability of denosumab

Conclusion

Future perspective

Regulatory issues

Footnotes

References