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Guideline

Pharmacologic approaches to prevention and treatment

Denosumab

Denosumab

Recommendation 24

Grade

Denosumab is recommended for the treatment of osteoporosis in postmenopausal women at high risk of minimal trauma fracture.

A

Recommendation 25

Grade

Denosumab should be considered as an alternative to bisphosphonates for the treatment of men at increased risk of minimal trauma fracture.

B

Recommendation 26

Grade

Denosumab therapy should not be interrupted. If denosumab therapy needs to be ceased, patients should be transitioned to bisphosphonate therapy for a minimum of 12 months.

C

Denosumab is a fully human, high-specificity and high-affinity monoclonal antibody against receptor activator of nuclear factor kappa B ligand (RANKL), an important regulator of osteoclast development and activity. Denosumab prevents RANKL binding to its receptor (RANK) on the osteoclast surface. Consequently, osteoclast formation, function, and survival are disrupted, resulting in decreased bone resorption and increased mass and strength of both cortical and trabecular bone. Denosumab significantly reduces the risk of vertebral, non-vertebral, and hip fractures in postmenopausal women.1–4 Trials in men with low BMD demonstrated similarly significant gains in BMD (8.0% lumbar spine, 3.4% total hip) after two years of denosumab treatment.5,6

One RCT showed a decreased incidence of new vertebral fractures in men being treated with ADT for prostate cancer.7 A meta-analysis of published RCTs found denosumab improved BMD more than bisphosphonate treatment at the lumbar spine, total hip, and FN.8 This is due to a combination of guaranteed bioavailability from parenteral administration and denosumab’s potent antiresorptive effect.

Denosumab has been registered for the treatment of osteoporosis in Australia since 2010 and is subsidised by the PBS for men and women aged >70 years with a T-score of –2.5 or less, and for men and women with a minimal trauma fracture. Denosumab is given as a subcutaneous injection of 60 mg every six months.

Denosumab used for the treatment of osteoporosis is generally well tolerated. The subcutaneous mode of administration avoids the gastrointestinal side effects associated with oral bisphosphonates and ensures excellent bioavailability. RCT data indicate no significant increase in adverse events with long-term denosumab treatment, including infection, malignancy, pancreatitis, cardiovascular disease, peripheral vascular disease, MRONJ and AFFs.2,3 Cellulitis has been more frequently reported with denosumab compared with placebo, although the incidence remains low (<0.2 events per 100 subject-years for long-term denosumab).1 Hypocalcaemia following denosumab administration is a significant risk in patients with severe renal impairment (chronic kidney disease Stage 4 or 5) or in patients receiving dialysis.

The development of multiple vertebral fractures following discontinuation of denosumab therapy due to rebound bone resorption is now well recognised,9 especially in those with previous vertebral fractures.10 In the 1001 participants who discontinued denosumab during the FREEDOM study or its extension, the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1 per 100 participant-years following denosumab cessation.10 The odds of developing multiple vertebral fractures after stopping denosumab were 3.9 (95% CI: 2.1–7.2)-fold higher in those with than without prior vertebral fractures.10 The mechanism for this remains uncertain, but may be due to a pool of osteoclasts that are activated following loss of the inhibitory effect of denosumab.11

A delay in denosumab administration of more than six months was associated with increased risk of rebound fracture.12 Although definitive measures to minimise the risk of rebound vertebral fractures remain unclear at the time of writing, denosumab should either be continued long-term or cessation should be followed by another antiresorptive medication (i.e., 12 months of oral bisphosphonate or one or more infusions of zoledronate).13,14

Evidence Statement

The first randomised placebo-controlled trial of denosumab with fracture as a primary outcome was the FREEDOM trial, published in 2009.1 In that trial, 7668 women aged 60–90 years with a DXA T-score at the hip or spine of –2.5 to –4.0 were randomised to either 60 mg denosumab or placebo subcutaneously every six months for 36 months. Relative to placebo, denosumab reduced the risk of new radiographic vertebral fractures by 68% (cumulative incidence in treatment and placebo groups 2.3% and 7.2%, respectively; RR 0.32; 95% CI 0.26–0.41; P<0.001), hip fractures by 40% (cumulative incidence in treatment and placebo groups 0.7% and 1.2%, respectively; HR 0.60; 95% CI: 0.37–0.97; P=0.04) and non-vertebral, non-hip fractures by 20% (cumulative incidence in treatment and placebo groups 6.5% and 8.0%, respectively; HR 0.80; 95% CI: 0.67–0.95; P=0.01).1 The FREEDOM trial was extended for a further seven years (total trial length 10 years), and outcomes of the first two,2 three,3 four, and five4 years of the extension have been reported. The FREEDOM extension used a crossover design. Women who completed three years of denosumab treatment in the original trial were eligible to continue denosumab treatment, whereas those in the placebo group ‘crossed over’ to receive denosumab for the duration of the extension. After five years of the extension (1542 long-term subjects completing eight years of denosumab treatment and 1462 subjects crossing over to receive five years of denosumab treatment), the respective annual incidence of new vertebral fractures in long-term subjects was 1.5%, 1.3% and 1.3% during extension years 4–5, 6 and 7–8 and the respective annual incidence in crossover subjects was 0.9%, 1.6% and 1.8%.4 The annual incidence of non-vertebral fractures also remained low in both the long-term and crossover groups during the extension years, varying between 0.7% and 1.8%, and 1.2% and 2.6%, respectively. The cumulative incidence of hip fractures over the five-year extension was 0.7% in the long-term group and 1.1% in the crossover group (mean age 79 years at year 8 of extension).4

The two-year Denosumab Fracture Intervention Randomised Placebo Controlled Trial (DIRECT)15 measured fracture incidence with denosumab treatment versus placebo in Japanese men and women aged >50 years with 1–4 prevalent fractures and mean DXA T-scores of –2.8 at the lumbar spine and –2.0 at the hip. Over 24 months, the incidence of new or worsening vertebral fracture was 3.6% in the denosumab group, compared with 10.3% in the placebo group, a risk reduction of 65.7% (P=0.0001). Subgroup analysis of female subjects showed that the risk of new or worsening vertebral fracture at 24 months was reduced by 63.2% in the denosumab compared with placebo group (HR 0.37; 95% CI: 0.21–0.65; P=0.0004). The incidence of new vertebral fracture was reduced by 74% (P<0.0001). Subgroup analysis of male subjects showed a new or worsening vertebral fracture incidence at 24 months of 0% in denosumab-treated men, compared with 12.5% in men treated with placebo. However, this difference did not reach statistical significance (P=0.07) due to the small sample size (23 men in the denosumab arm and 24 in the placebo arm).15 A one-year crossover extension (n=775) of the DIRECT trial showed maintenance of low-fracture rates, with no difference in annualised fracture incidence between two and three years of treatment in the long-term group.16 As expected, the incidence of new and worsening vertebral fractures was reduced in the crossover group after commencement of denosumab treatment; the RaRs comparing years 2 and 1 and years 3 and 1 were 2.87 (P=0.003) and 0.23 (P=0.0003), respectively.16 These results suggested that the magnitude of effect on fracture risk reduction by denosumab depended on treatment duration. Overall, in men with low BMD treated with denosumab, increases in BMD were similar to those seen in postmenopausal women.5

Safety

The original three-year FREEDOM trial showed no significant increase in the incidence of cancer or infection compared with placebo.1 There was no increase in serious adverse events, including coronary heart disease and stroke, compared with placebo, but a significant increase in cellulitis requiring hospitalisation was reported (0.3% in the denosumab group compared with <0.1% in the placebo group; P=0.002). No cases of MRONJ or AFFs were reported. In the five-year extension study, adverse events for the duration of the FREEDOM extension, including cellulitis and other serious infection, were similar to those in the denosumab group in the original FREEDOM trial, with no increases over time.3 A total of two cases of AFF occurred in year 3 (in the crossover group) and year 7 (long-term group) of denosumab treatment, and a total of eight cases of MRONJ occurred in years 2 and 4 (in the crossover group) and years 6 and 7 (long-term group) of denosumab treatment. The cumulative incidence rates during the FREEDOM extension were 4.2 per 10,000 subject-years for MRONJ and 1.0 per 10,000 subject-years for AFF.4 Adverse event rates were similarly low in the two-year DIRECT trial and one-year DIRECT extension, with no significant difference between treatment and placebo groups.15,16 One case of MRONJ occurred during the extension in a crossover subject (one year of denosumab treatment).15,16 Although no head-to-head trials have been published, a systematic review of nine RCTs (n=4890) comparing the safety and efficacy of denosumab with bisphosphonate treatment for up to two years found no statistically significant difference between groups in terms of fracture risk or adverse events.17

Definitive measures to minimise the risk of rebound vertebral fractures remain unclear at the time of writing. To avoid this phenomenon, denosumab could be continued long term. However, if denosumab cessation is required, an observational study suggested that after 2–5 years of denosumab, 5 mg IV zoledronate administered six months following the last denosumab injection protected against the occurrence of multiple vertebral fractures.13 Zoledronate also appeared to retain 66% of the BMD gained with denosumab at the lumbar spine and 49% at the total hip.13 However, a recent randomised open-label study found that IV zoledronate did not fully prevent the increased bone turnover and bone loss observed following denosumab cessation, even when IV zoledronate was readministered following a rise in bone turnover markers or a fall in BMD.14 More evidence is required to guide therapy in this area.

  • Hypocalcaemia is an identified risk of denosumab treatment, particularly in patients with severe renal impairment (creatinine clearance <30 mL per minute or receiving dialysis). Hypocalcaemia must be corrected prior to treatment initiation, and calcium levels monitored during treatment of such high-risk patients, especially in the first two weeks of initiating therapy.
  • Dietary calcium intake and serum 25(OH)D levels should be optimised, using supplements if required, prior to commencing denosumab therapy.
  • Patients should be advised to seek prompt medical attention if they develop signs or symptoms of cellulitis.
  • Unlike bisphosphonates, which are sequestered in bone, the effects of denosumab on bone resorption do not persist after treatment has stopped. Therefore, regular six-monthly administration is required for continued reduction of fracture risk.
  • Strict six-monthly dosing of denosumab is important to minimise the risk of rebound vertebral fractures.
  • Cessation of denosumab should be followed by antiresorptive therapy. Specialist review may be required, particularly in patients with high fracture risk.
  1. Cummings SR Sr, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361(8):756–65.
  2. Papapoulos S, Chapurlat R, Libanati C, et al. Five years of denosumab exposure in women with postmenopausal osteoporosis: Results from the first two years of the FREEDOM extension. J Bone Miner Res 2012;27(3):694–701.
  3. Bone HG, Chapurlat R, Brandi ML, et al. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: Results from the FREEDOM extension. J Clin Endocrinol Metab 2013;98(11):4483–92.
  4. Papapoulos S, Lippuner K, Roux C, et al. The effect of 8 or 5 years of denosumab treatment in postmenopausal women with osteoporosis: Results from the FREEDOM Extension study. Osteoporos Int 2015;26(12):2773–83.
  5. Orwoll E, Teglbjærg CS, Langdahl BL, et al. A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab 2012;97(9):3161–69.
  6. Langdahl BL, Teglbjærg CS, Ho PR, et al. A 24-month study evaluating the efficacy and safety of denosumab for the treatment of men with low bone mineral density: Results from the ADAMO trial. J Clin Endocrinol Metab 2015;100(4):1335–42.
  7. Smith MREB, Egerdie B, Hernández Toriz N, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361(8):745–55.
  8. Lyu H, Jundi B, Xu C, et al. Comparison of denosumab and bisphosphonates in patients with osteoporosis: A meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 2019;104(5):1753–65.
  9. Tsourdi E, Langdahl B, Cohen-Solal M, et al. Discontinuation of denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Bone 2017;105:11–17.
  10. Cummings SR, Ferrari S, Eastell R, et al. Vertebral fractures after discontinuation of denosumab: A post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 2018;33(2):190–98.
  11. McDonald MM, Khoo WH, Ng PY, et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell 2021;184(5):1330–1347.e13.
  12. Lyu H, Yoshida K, Zhao SS, et al. Delayed denosumab injections and fracture risk among patients with osteoporosis: A population-based cohort study. Ann Intern Med 2020;173(7):516–26.
  13. Everts-Graber J, Reichenbach S, Ziswiler HR, Studer U, Lehmann T. A single infusion of zoledronate in postmenopausal women following denosumab discontinuation results in partial conservation of bone mass gains. J Bone Miner Res 2020;35(7):1207–15.
  14. Sølling AS, Harsløf T, Langdahl B. Treatment with zoledronate subsequent to denosumab in osteoporosis: A 2-year randomized study. J Bone Miner Res 2021;36(7):1245–54.
  15. Nakamura T, Matsumoto T, Sugimoto T, et al. Clinical trials express: Fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT). J Clin Endocrinol Metab 2014;99(7):2599–607.
  16. Sugimoto T, Matsumoto T, Hosoi T, et al. Three-year denosumab treatment in postmenopausal Japanese women and men with osteoporosis: Results from a 1-year open-label extension of the Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT). Osteoporos Int 2015;26(2):765–74.
  17. Beaudoin C, Jean S, Bessette L, Ste-Marie LG, Moore L, Brown JP. Denosumab compared to other treatments to prevent or treat osteoporosis in individuals at risk of fracture: A systematic review and meta-analysis. Osteoporos Int 2016;27(9):2835–44.
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