A Review on the Role of Denosumab in Fracture Prevention

Introduction

Osteoporosis is a metabolic disease of the skeletal system with insidious onset and affects bone mineral density (BMD) adversely.¹ According to World Health Organization, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young adult (T-score ≤ −2.5).² Fragility fractures are the ultimate consequence of osteoporosis. An estimate showed that 75% of all vertebral and non-vertebral fractures occur in individuals aged ≥65 years, and more than 75% of hip fractures affect individuals aged ≥75 years.³ Fragility fractures are traumatic events for the octogenarians and geriatric patients because their overall health and functioning status will be severely impaired.^4,5 Vertebral fractures were linked with increased comorbidity and admission events, as well as prolonged duration of hospitalization.⁶ Elderly men have higher chances of suffering from these complications, particularly pneumonia and musculoskeletal diseases, compared to their female counterparts.^7,8 Patients with fragility fracture suffer from higher morbidity, higher risk for subsequent fracture and greater mortality risk after discharge.⁹ Patients with refracture possess a mortality rate of 1.2 times higher than patients without refracture patients 3 years.¹⁰

Both pharmacological and non-pharmacological strategies are required in constructing better fracture prevention care for the elderly. The National Osteoporosis Foundation Guidelines for Pharmacologic Treatment of Osteoporosis recommends pharmacological treatments to postmenopausal women and men aged ≥50 years with a history of hip/vertebral fracture, presenting with BMD T-score between −1.0 and −2.5 at the femoral neck/spine or those with a T-score ≤ −2.5 at the femoral neck/spine.¹¹ These populations have a 10-year risk of hip fracture ≥3% or 10-year risk of major osteoporosis-related fracture ≥20% by Fracture Risk Assessment Tool (FRAX) calculation.¹² Anti-osteoporotic therapy has been demonstrated to reduce mortality in patients with osteoporosis who have been reported to be at risk of high mortality.^13–15 Given the higher chance of refracture among the fracture population, post-fracture anti-osteoporosis treatment is important in reducing the burden of fragility fracture.

Denosumab is a human recombinant monoclonal antibody that prevents the binding of receptor activator of nuclear factor kappa-Β (RANK) ligand (RANKL) to RANK on osteoclasts, thereby suppressing bone resorption.^16,17 It is one of the most commonly prescribed antiresorptive drugs in clinical practice for the management of osteoporosis in postmenopausal women.¹⁸ Denosumab is reported to increase BMD, inhibit high bone turnover and reduce fracture risk in postmenopausal women with osteoporosis.^19,20 A potential rise in the risk of multiple vertebral fractures follows discontinuation of denosumab.²¹ Several reviews on the effects of denosumab on BMD have been published.^22–24 In this article, the effects of denosumab alone or in comparison with other anti-resorptive drugs in fracture/refracture risk reduction among the elderly are reviewed. We also addressed the mortality rate and safety of denosumab use in patients with osteoporosis.

Overview of the Human Studies

A total of 22 original research articles reporting the anti-fracture effects of denosumab from human retrospective cohort and clinical trials were included in this review. Human studies that did not report the fracture incidence or risk are not included. There are two retrospective cohort studies utilizing national data;^25,26 seven articles from Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) clinical trial and FREEDOM extension;^27–33 nine articles on post hoc analysis of FREEDOM data^31,39 (wherein 2 articles reporting both post hoc analysis and FREEDOM extension);^32,33 one article from Austrian Breast Cancer Study Group study (ABCSG-18);⁴⁰ one article from Denosumab fracture Intervention RandomizEd placebo Controlled Trial (DIRECT);⁴¹ two articles from FRActure study in postmenopausal woMen with ostEoporosis study (FRAME)^42,43 and two articles from a randomized controlled trial (RCT) by Saag et al.^44,45 The denosumab was administrated at 60 mg subcutaneously once in every 6 months in these clinical trials. However, the treatment period, dose and compliance of denosumab are not known for retrospective cohort studies.^25,26

Two retrospective cohort studies compared the anti-fracture effects of denosumab with bisphosphonates.^25,26 Behavona et al analyzed the national data (98% coverage; n=47,139) in Austria among patients aged ≥50 years, who experienced a hip fracture between January 2012 and December 2016, and then either left untreated or treated with denosumab or bisphosphonates (oral or intravenous).²⁵ They were tracked up to 60 months for any incidence of subsequent hip fracture and all-cause mortality as study outcomes.²⁵ Pederson et al performed a similar nationwide, population-based, historical cohort study from Danish health registries or database.²⁶ A total of 92,355 subjects aged ≥50 years and received the first dispensing of denosumab or alendronate from May 2010 to December 2017 without any antiosteoporosis medication within 1 year were included in the retrospective analysis.²⁶ These subjects were follow-up up to 7.5 years for any hip or other fracture as study outcomes.²⁶ The data were analyzed by treatment condition and then further with subgroup analysis by sex, age, and prior history of hip or any fracture.²⁶

To date, more than 6 completed clinical trials related to denosumab had been reported. FREEDOM trial is an international Phase 3 randomized, placebo-controlled trial designed to investigate the effect of denosumab on fracture risk in postmenopausal women aged 60–90 years with a BMD T-score of less than −2.5 at the lumbar spine or total hip in a 3-year follow-up period.^28,46,47 It was started in August 2004 and completed in June 2008, and involved 7808 postmenopausal women as either placebo (N=3902) or denosumab groups (N=3906).^28,47 Placebo or 60 mg denosumab was administered subcutaneously once every 6 months for 3 years.^28,47 The new vertebral, non-vertebral or hip fracture incidence were recorded as primary outcomes.^28,47 A continuation of FREEDOM trial (also known as FREEDOM extension) was conducted, wherein all subjects (both placebo and denosumab groups) who did not miss more than 1 dose of the investigational product were recruited to receive the denosumab up to an additional 7 years.^27,29–33 The placebo of FREEDOM trial was noted as “cross-over group” because they received denosumab in the FREEDOM extension while denosumab group continued to receive denosumab up to 10 years and was named the “long-term group”.^27,29–33

ABCSG-18 study is a prospective, double-blind, placebo-controlled, multicentre phase 3 trial on 3420 postmenopausal women with hormone receptor-positive breast cancer and underwent aromatase inhibitor as treatment.⁴⁰ All subjects were randomly assigned to receive either denosumab (N=1274) or placebo (N=1188) up to 7 years with a median time of study of 38 months.⁴⁰

DIRECT was a randomized, double-blind, placebo-controlled trial that evaluates the anti-fracture effects of denosumab on both Japanese postmenopausal women and men with osteoporosis.⁴¹ A total of 1034 Japanese postmenopausal women and men, aged ≥50 years, with BMD T-score <-1.7 (lumbar spine) or <-1.6 (total hip) with 1–4 prevalent vertebral fractures were randomly assigned in a 2:2:1 ratio to receive either placebo (N=416), denosumab (N=414), or 35 mg oral alendronate weekly (N=204) for 24 months.⁴¹

FRAME trial is an international, randomized, double-blind, placebo-controlled, phase 3 trial on postmenopausal women with osteoporosis.^42,43 A total of 7180 postmenopausal women, aged 55–90 years and with a total hip or femoral neck BMD T-score of −3.5 to −2.5 were randomly assigned to receive either placebo or romosozumab (at a dose of 210 mg) monthly for the first 12 months; and subsequently subcutaneous administration of denosumab up to 24 months.^42,43 Miyauchi et al performed a subgroup analysis on the Japanese subjects (with romosozumab (N=247) and placebo (N=245)).⁴³

Lastly, Saag et al had conducted a phase 3, international, randomized, double-blind, double-dummy, active-controlled, non-inferiority clinical trial on patients with glucocorticoid-induced osteoporosis (N=590) with the lumbar spine, total hip or femoral neck BMD T-score ≤ −2.0 or ≤ −1.0 with fracture history or past osteoporosis-related fracture history.^44,45 Subjects receiving glucocorticoid therapy for less than 3 months before screening was grouped as “glucocorticoid-initiating group” (n=253) while those with more than 3 months therapy were grouped as “glucocorticoid-continuing group” (n=438).^44,45 All subjects were randomly assigned either subcutaneous denosumab and oral placebo daily for 24 months, or oral risedronate 5 mg daily with subcutaneous placebo every 6 months for 24 months.^44,45

Figure 1 provides an overview of the human retrospective cohorts and clinical trials included in this review.

Figure 1 An overview of the human retrospective cohorts and clinical trials included in this review.

The Effect of Denosumab on Vertebral Fracture Risk Reduction

In the FREEDOM trial, 36-month denosumab treatment significantly reduced the risk of new vertebral fracture, new clinical vertebral fracture, multiple new vertebral fractures, new or worsening vertebral fracture, clinical osteoporotic fractures (vertebral and non-vertebral fractures) and primary or secondary fragility fracture (new vertebral and low-trauma non-vertebral fracture).^{28,30,31,33–38,48} Parallelly, in ABCSG-18 trial, 36-month denosumab treatment also significantly reduced the new vertebral fracture, new or worsening vertebral fracture incidences, as well as the first clinical fracture among breast cancer patients treated with an aromatase inhibitor.⁴⁰ Similar fracture risk reduction was also reported as early as 12-month denosumab treatment during FREEDOM and DIRECT study.^{28,30,34,35,41} Denosumab was also as effective as risedronate in reducing the fracture incidences, including any osteoporosis-related fracture and new or worsening vertebral fractures upon 24-month treatment.⁴⁵ The efficacy of denosumab and risedronate were similar regardless of sex and menopause status in women.^44,45

Additionally, denosumab also reduced new vertebral fracture incidence during the 2–7 years of FREEDOM extension.^27,30,31 New vertebral fracture incidence was initially high in the placebo group during the FREEDOM study,^30,31 but decreased sharply during the first 2 years of denosumab treatment³⁰ and remained low throughout the 7 years of FREEDOM extension.²⁷ The trend of fracture risk reduction in the cross-over group was similar to the FREEDOM denosumab group in the first 2 years of denosumab treatment.³⁰ Additionally, the cumulative new vertebral fracture incidence of the long-term group was also significantly reduced in both FREEDOM study and the 7-year FREEDOM extension.²⁷ Moreover, denosumab reduced the exposure-adjusted subsequent osteoporotic fracture rate during FREEDOM trial as well as on all subjects receiving denosumab during the 7-year FREEDOM extension.³³

FREEDOM post hoc analyses demonstrated a greater anti-fracture effect of denosumab in certain subgroups.^{33–35,37,41} Denosumab significantly reduced the new vertebral fracture incidences in the high-risk subgroup with prevalent vertebral fracture and/or vertebral deformity or those with baseline femoral neck BMD T-score of ≤−2.5 or those with all above risk factors after 24 and 36 months.³⁵ McCloskey et al also reported that the efficacy of denosumab was better on patients with moderate to high fracture risk and low body mass index.³⁷ Additionally, 24-month denosumab reduced the risk of new or worsening vertebral fracture among Japanese postmenopausal women but not men during the DIRECT study.⁴¹ Recently, Kendler et al also reported a higher fracture risk reduction among subjects with a history of osteoporotic fracture with denosumab treatment.³³

On the other hand, McClung et al reported the efficacy of denosumab in new vertebral fracture risk reduction was independent of age, race, region, body mass index, estimated creatinine clearance, femoral neck BMD, prevalent vertebral fracture, prior non-vertebral fracture and prior use of osteoporosis medications upon a post-hoc analysis on FREEDOM data.³⁸ A similar finding by Palacios et al also reported that the anti-fracture effects of denosumab were independent of age, prior fragility fracture history, fracture site, previous osteoporotic treatment history as well as those presented with both risk factors of age and prior fragility fracture.⁴⁸ Similarly, denosumab reduced the osteoporotic fracture regardless of age, femoral neck BMD value, prior fracture, parental history of hip fracture, secondary causes of osteoporosis, smoking or alcohol intake in another FREEDOM post-hoc analysis.³⁷ Similarly, prevalent vertebral fracture, femoral neck BMD and the functionality of the kidney also did not affect the efficacy of denosumab on fracture risk reduction.^35,36,40

The Effect of Denosumab on Hip Fracture Risk Reduction

Two retrospective cohort studies were conducted to evaluate the effects of denosumab in reducing bone fracture.^25,26 Behavona et al reported no significant difference in subsequent hip fracture risk between denosumab and bisphosphonate groups.²⁵ Surprisingly, patients treated with bisphosphonates and denosumab experienced a higher risk and cumulative incidence of subsequent hip fracture compared to patients without antiresorptive treatment.²⁵ The increase in subsequent hip fracture risk was more prominent among women receiving denosumab.²⁵ The increase of subsequent hip fracture risk with denosumab treatment might be due to a short follow-up time or confounders, such as alcohol consumption, physical activity, nutrition and/or medication adherence.²⁵ Sample size for the denosumab group was relatively small (N=555) as compared with untreated patients (N=42,795).²⁵ A recent retrospective cohort study by Pederson et al identified that hip fracture risk was similar between patients treated with denosumab and alendronate within 3 years of follow-up, regardless of sex, age, previous history of hip fracture or any fracture.²⁶ Subgroup analysis revealed a marginally lower risk among women, subjects <80 years old, those with or without a history of any fracture and those without previous hip fracture compared to alendronate.²⁶

In FREEDOM study, 36-month denosumab treatment significantly reduced the risk of hip fractures compared to placebo.^28,30,35,36 Prolonged (>3 years) denosumab treatment reduced the hip fracture incidence during the first 3 years of FREEDOM trial, then further reduced and maintained it throughout the 7 years of FREEDOM extension.^29–31 A similar trend was detected in the cross-over group, where the hip fracture incidence was significantly reduced, reaching a level comparable to the long-term group at the end of FREEDOM extension.^27,29-31 Boonen et al reported that denosumab could significantly reduce the risk of hip fractures in the entire FREEDOM population as well as high-risk subgroups, for example, subjects aged ≥75 years; baseline femoral neck BMD T-score of ≤ −2.5 or those with both risk factors.³⁵ There was no significant difference in hip fracture risk reduction between denosumab and placebo for low-risk subgroups due to the low baseline hip fracture risk.³⁵ Parallelly, in the FREEDOM post-hoc subgroup analysis, denosumab did not reduce hip fractures after adjusting for age and major osteoporotic fracture probability calculated by FRAX.³⁷

The Effect of Denosumab on Non-Vertebral Fracture Risk Reduction

In FREEDOM study, 36-month denosumab treatment significantly reduced the risk of non-vertebral fractures compared to placebo.^{28,30,35,36,38} The anti-fracture effects of denosumab in the non-vertebral or other minor fractures are heterogeneous, especially with shorter treatment time. Saag et al reported that the efficacy of denosumab in reducing low-trauma non-vertebral fractures was similar to risedronate during a 24-month treatment frame.^44,45 However, marginal non-vertebral fracture risk reduction was reported after 12- and 24-month denosumab treatment.^34,41 Additionally, Nakamura et al also reported that 24-month denosumab increased the risk of non-major non-vertebral fracture to 2.5% as compared to 0.4% among placebo.⁴¹ Thus, the efficacy of denosumab in reducing non-vertebral fracture risk needs to be investigated further.

Prolonged (>3 years) denosumab treatment resulted in a similar or even better fracture risk reduction compared with shorter treatment. Denosumab reduced the non-vertebral fracture incidence during the first 3 years of FREEDOM trial, then further reduced and maintained it throughout the 7 years of FREEDOM extension.^27,29–31 A similar trend was detected in the cross-over group, where the non-vertebral fracture incidence was significantly reduced, reaching a comparable level as the long-term group at the end of FREEDOM extension.^27,29–31 The non-vertebral fracture incidence was significantly higher among FREEDOM placebo and the twin-estimated placebo in FREEDOM extension.³⁰ It can be concluded that the anti-fracture effect of denosumab is only significant after ≥3 years of treatment.

In the FREEDOM post-hoc subgroup analysis, denosumab significantly reduced the clinical osteoporotic fractures after adjusting for age and FRAX major osteoporotic fracture probability.³⁷ Denosumab only significantly reduced the non-vertebral fracture risk in those subgroups with BMI <25 kg/m², femoral neck BMD T-score ≤-2.5 or without a prevalent vertebral fracture.³⁸ Additionally, the efficacy of denosumab on non-vertebral fracture was independent of age groups, kidney function, total hip BMD, and prior history of non-vertebral fracture.^34,36,38 Subgroup analysis revealed that denosumab-induced non-vertebral fracture risk reduction was more prominent among subjects with the lower hip (T-score between −1.0 and −2.5) or femoral neck BMD (T-score ≤-2.5) during FREEDOM extension.²⁹ In other words, the risk reduction effects of denosumab in a specific subgroup may be marginal and only become prominent upon a longer treatment time. Additionally, the selection of inclusion and exclusion criteria and subgrouping definition may also affect the outcome in subgroup analysis.

The Effect of Denosumab on Wrist and Other Fracture Risk Reduction

The effects of denosumab on wrist and other fractures, including forearm and humerus fractures, were also reported. However, the effects might not be as significant as major fractures.^32,39 Denosumab significantly reduced the wrist fracture incidence for FREEDOM subgroup with a femoral neck T-score ≤ −2.5, but not for the entire FREEDOM population.³⁹ Bilezikian et al also reported the beneficial effects of denosumab on upper limb fractures during the 7-year FREEDOM extension.³² Denosumab significantly reduced the humerus but not wrist and forearm fracture rate among the extension group during the 1st–3rd year of FREEDOM extension.³² The overall fracture rate for upper limbs, including wrist, forearm and humerus fractures, was significantly lower in the extension group during the 4th–7th year of FREEDOM extension.³² Parallel with vertebral and non-vertebral fracture, this observation also suggested that a longer denosumab treatment is necessary to optimize its anti-fracture effects for the upper limbs.

Figure 2 summarizes the effects of denosumab on vertebral, non-vertebral, hip, wrist and other fractures risk reduction.

Figure 2 The anti-fracture effects of denosumab in vertebral, non-vertebral, hip, wrist and other fractures. Notes: ↓Increase; ↑Decrease.Abbreviations: BMI, body mass index; BMD, bone mass density; NS, non-significant; RANKL, receptor activator of nuclear factor kappa-Β ligand.

Comparison of the Fracture Risk Reduction Between Denosumab and Other Anti-Osteoporotic Drugs

The retrospective cohort study by Pedersen et al compared the risk of hip and any fracture between patients treated with denosumab and alendronate.²⁶ The hazard ratios of hip fractures for both denosumab and alendronate were similar regardless of sex, age, or fracture history.²⁶ On the other hand, denosumab was more potent than risedronate in improving BMD as evidenced in an RCT study.^44,45 Denosumab, as compared to risedronate, significantly increased the percentage change of BMDs at the lumbar spine, total hip, femoral neck and 1/3 radius among those glucocorticoid-treated subjects.^44,45 There was an early downregulation of serum BTM levels prior to the increase of BMDs upon denosumab treatment.^44,45

On the other hand, the anti-osteoporotic effects of combined denosumab and romosozumab among postmenopausal women were studied in the FRAME trial.^42,43 Subjects with 1 year of romosozumab followed by another year of denosumab showed a similar incidence of non-vertebral and clinical fracture.⁴² With the continuation of an extra 1 year of denosumab treatment, no significant reduction in new vertebral, clinical, non-vertebral, major non-vertebral, major osteoporotic, clinical new or worsening vertebral and hip fractures was observed compared to subjects with the first year of placebo and subsequent 2 years of denosumab.⁴³ Denosumab did increase the BMDs in both groups. However, the pre-treatment of romosozumab significantly increased patients’ BMD from the baseline values.^42,43 The anti-fracture effects of romosozumab-denosumab combination need to be further confirmed via a larger sample size and/or longer treatment time.

Teriparatide is the first approved anabolic agent that stimulates osteoblastic bone formation.^49,50 The anti-osteoporotic effects of teriparatide, denosumab and other anti-osteoporotic agents have been examined in systematical review and meta-analysis recently.⁵¹ Both teriparatide (daily dose of 20–40 μg) and denosumab were effective in reducing vertebral fracture risk by 86% and 68%, respectively.⁵¹ However, the between-groups comparison was not performed by the authors. In the Denosumab and Teriparatide Administration randomized trial (DATA), 12-month denosumab was superior to teriparatide based on the increment of BMDs at femoral neck, total hip and distal 1/3 of radial shaft.⁵² In the DATA extension study, 24-month teriparatide was as effective as denosumab in increasing the BMDs at the lumbar spine, femoral neck and total hip.⁵³ Denosumab, but not teriparatide, significantly increased the BMD at the 1/3 distal radius.⁵³

Short-term teriparatide treatment is preferable given its potential carcinogenic effect, based on the osteosarcoma induction in rats upon long-term exposure (2-year).^54,55 A shorter (3 to 6 months) but cyclic approach of teriparatide could exert a similar or slightly weaker anti-osteoporotic effect compared to standard daily teriparatide treatment.⁵⁶ Moreover, the cyclic teriparatide treatment with three cycles of teriparatide (6 months) to denosumab (6 months) was similar to standard sequential teriparatide (18 months) to denosumab (18 months) treatment in increasing the BMDs at spine, total femur, femoral neck and 1/3 radius.⁵⁷ On the other hand, in DATA-Switch study, co-treatment of teriparatide and denosumab for 24 months, followed by 24-month denosumab alone was more potent in increasing the BMDs at total hip, femoral neck and radius bone (but not lumbar spine) than sequential treatments with teriparatide (24 months) to denosumab (24 months) or vice versa.^58,59 Similar findings were obtained in the DATA and DATA extension study, whereby the co-treatment of teriparatide and denosumab induced a greater increase in BMDs.^52,53

A summary of the anti-fracture effects of denosumab is presented in Table 1.

Table 1 The Anti-Fracture Effects of Denosumab in the Retrospective Cohort and Clinical Trials

Discontinuation of Denosumab and Fracture Risk

The effect of denosumab discontinuation on fracture risk has been reviewed extensively.^21,60,61 Denosumab discontinuation is closely associated with a rebound effect, indicated increased BTM levels and the parallel loss of gained BMD within 6–24 months of discontinuation, as reported in several case reports, observational study, RCTs and post-hoc analysis of FREEDOM data.^62–67 Additionally, denosumab discontinuation also resulted in a higher risk of rebound-associated vertebral fracture, including multiple vertebral fractures.^68–72 The simultaneous reactivation of all dormant osteoclasts at once after denosumab discontinuation, which subsequently leads to excessive bone resorption, is suggested to be the mechanism of rebound effect.⁷³ As evidence, an early 5- to 7-fold increase of CTX and P1NP levels after the 3-month discontinuation of denosumab was observed. This effect was accompanied by an increase in RANKL level and a gradual decrease in Dickkopf-1 and sclerostin level.⁷⁴ A recent histomorphological analysis on bone biopsies from fracture patients also confirmed that denosumab discontinuation caused a higher bone turnover activity and bone structures and hardness reduction, which may explain the rebound-associated fracture.⁷⁵ Moreover, there is a downregulation of miR-503 and miR-222-2 (miRNAs that downregulate osteoclastogenesis) upon denosumab discontinuation, which leads to the subsequent upregulation of RANK and cathepsin K mRNAs.⁷³ The optimum treatment after discontinuation of denosumab is not yet established. The re-initiation of denosumab was reported to increase the BMDs again, but a very recent case report from Niimi et al showed that re-initiation of denosumab did not eliminate the risk of rebound-associated vertebral fractures.^70,76 A pre-treatment or follow-up course of bisphosphonates upon denosumab discontinuation was found to be protective by maintaining BMDs and CTX levels, possibly via the reduction of the dormant osteoclasts.^74,77-80 Further investigation is required to elucidate the underlying mechanisms of denosumab discontinuation and establish a proper strategy to overcome fractures associated with it.

Mortality Rate and Safety of Denosumab in Patients

Subcutaneous administration of denosumab (60 mg every 6 months) is safe for human as the mortality rate is reduced or maintained at the same level as the placebo.^25,27,35 A retrospective cohort study by Behanova et al reported that denosumab treatment (as well as bisphosphonate) significantly reduced the risk of mortality as compared to untreated patients.²⁵ Subgroup analysis also identified that the mortality-reducing effect of denosumab was more prominent in men than women.²⁵ Additionally, denosumab also significantly reduced the mortality rate among high-risk subjects based on prevalent vertebral fracture status with or without a low femoral neck BMD.³⁵ Comparing with risedronate, there was a 1% increase in mortality rate upon denosumab treatment.^44,45 However, statistical analysis was not performed.

In terms of the adverse reaction, denosumab did not significantly increase the total incidence of adverse effects including infection, cancer, hypocalcaemia, cardiovascular and peripheral vascular diseases, stroke, heart diseases. No cases of study discontinuation due to adverse events were reported.²⁸ All and serious adverse events remained stable over time in both denosumab and placebo groups during DIRECT, FREEDOM and FREEDOM extension studies.^27,30,31,41 Additionally, denosumab is also safe regardless of age groups, kidney function, fragility fracture history, as well as in patients with breast cancer treated with an aromatase inhibitor.^{30,35,36,40,48} No event of osteonecrosis or neutralising anti-denosumab antibodies was identified.^27,28,40,81 Histological examination of 22 samples from the 10-year denosumab-treated group revealed that all lamellar bones were normally mineralized with no pathological changes and low remodelling activation.²⁷

Denosumab, however, did slightly increase the incidence of certain adverse events including hypocalcaemia, bacterial cellulitis, infection, cardiovascular disorder, bone pain, pain in extremity, hot flush, hypertension, osteoarthritis and nervous system disorders in some subjects.^40,41 Denosumab was also associated with a marginally higher incidence of eczema, flatulence and cellulitis among some FREEDOM subjects.²⁸ These adverse events, however, became insignificant during the 10-year FREEDOM extension study.²⁷ The adverse events and serious adverse events were found similar between denosumab and risedronate groups among glucocorticoid-treated subjects up to 24 months of treatment.^44,45 Denosumab did marginally (~1%) increase the incidence of adverse events including back pain, hypertension, osteoporosis-related fractures and non-vertebral fractures compared to risedronate, but the statistical analysis was not performed.⁴⁴

Conclusion

Denosumab prevents the binding of RANKL to RANK on osteoclasts, thereby preventing bone loss through resorption and lowering the fracture risk. Through the clinical trials conducted, especially FREEDOM and its extension, denosumab demonstrates efficacy in preventing vertebral and non-vertebral fractures even with 10 years of continuous treatment. The performance of denosumab is on par with other treatment agents for osteoporosis like bisphosphonates. It is also safe to be used among vulnerable patients with chronic kidney disease and breast cancer treated with an aromatase inhibitor. Its hypocalcemic effects may require the physicians to assess the calcium status of the patients before initiating treatment. Rebound bone loss and fracture risk after discontinuation is a concern, but this can be overcome by subsequent treatment with other agents like bisphosphonates. Since the efficacy of denosumab in preventing fracture is only assessed in limited studies, more comprehensive trials involving patients of diverse genetics and environmental exposure background are warranted.