Osteoporosis prevention, diagnosis and management in postmenopausal women and men over 50 years of age

Recommendations

Denosumab

Evidence statement

The first randomised, placebo-controlled trial of denosumab with fracture as a primary outcome was the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every Six Months (FREEDOM) trial, published in 2009.3 Seven thousand six hundred and sixty-eight women aged 60 to 90 with a T-score at the hip or spine of –2.5 to –4.0 were randomised to receive 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; relative risk [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; hazard ratio [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).3 The FREEDOM trial has been extended for a further seven years (total trial length 10 years), and outcomes of the first two,4 three,5 four and five6 years of the extension have been reported. The FREEDOM extension employs a crossover design. Women who completed three years of denosumab treatment in the original trial were eligible to continue denosumab treatment, while 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 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 respectively, and the annual incidence in crossover subjects was 0.9%, 1.6% and 1.8%. The annual incidence of nonvertebral 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).6

The two-year Denosumab Fracture Intervention Randomised Placebo Controlled Trial (DIRECT)7 measured fracture incidence with denosumab treatment versus placebo in Japanese men and women older than 50 years of age with 1–4 prevalent fractures and mean 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 versus 10.3% in the placebo group, a risk reduction of 65.7% (P = 0.0001). Sub-group 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 group compared with placebo (HR: 0.368, 95% CI: 0.207–0.653, P = 0.0004). New vertebral fracture incidence was reduced by 74.0% (P <0.0001). Sub-group 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).7 A one-year crossover extension (n = 775) of the DIRECT trial8 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. The rate ratio of new vertebral fractures in this group in year 2 compared with year 1 was 0.89 (P = 0.83), and year 3 compared with year 1 was 0.19 (P = 0.13). As expected, the incidence of new and worsening vertebral fractures was reduced in the crossover group after commencement of denosumab treatment; the rate ratios comparing years 2 and 1 and years 3 and 1 were 2.87 (P = 0.003) and 0.23 (P = 0.0003), respectively.8 These results suggest that the magnitude of effect on fracture risk reduction by denosumab depends on treatment duration. Results reported in the DIRECT extension were not stratified by sex. To date, no further denosumab trial data in men with fracture as an outcome measure have been published. However, in men with low BMD treated with denosumab, increases in BMD are similar to those seen in postmenopausal women.1

Safety

The original three-year FREEDOM trial showed no significant increase in the incidence of cancer or infection compared with placebo.3 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.1 In the five-year extension study, the yearly exposure-adjusted subject incidence for
all adverse events for the duration of the FREEDOM extension, including cellulitis and other serious infection, are similar to those in the denosumab group in the original FREEDOM trial, with no increases over time.6 A total of two cases of AFF occurred in years 3 (in the crossover group) and 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), 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.7,8 One case of MRONJ occurred during the extension in a crossover subject (one year of denosumab treatment).7,8
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 statistical difference between groups in terms of fracture risk or adverse events.9

Grade: A

Recommendation 18
Denosumab is recommended for the treatment of osteoporosis in postmenopausal women at increased risk of minimal trauma fracture.

Grade: B

Recommendation 19
Denosumab should be considered as an alternative to bisphosphonates for the treatment of men at increased risk of minimal trauma fracture.

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. As a consequence, osteoclast formation, function and survival is 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. At the time of writing, few data on fracture incidence in men treated with denosumab were available. However, the results of two recent trials in men with low bone mineral density (BMD) demonstrate similarly significant gains in BMD (8.0% lumbar spine, 3.4% total hip) after two years of denosumab treatment.1,2

Denosumab has been registered for the treatment of osteoporosis in Australia since 2010, and is subsidised by the Pharmaceutical Benefits Scheme for men and women over the age of 70 years with a T-score –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 in the treatment of osteoporosis is generally well tolerated. Its subcutaneous mode of administration avoids the gastrointestinal side effects associated with oral bisphosphonate treatment. Randomised controlled trial (RCT) data to date indicate no significant increase in adverse events with long-term denosumab treatment, including infection, malignancy, pancreatitis, cardiovascular disease, peripheral vascular disease, medication-related osteonecrosis of the jaw (MRONJ) and atypical fractures of the femur (AFFs). Cellulitis has been more frequently reported with denosumab compared with placebo, although the incidence remains low (less than 0.2 events per 100 subject-years for long-term denosumab). 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.

  • 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.
  1. 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.
  2. 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.
  3. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361(8):756–65.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Beaudoin C, Jean S, Bessette L, Ste-Marie LG, 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. doi:10.1007/s00198-016-3607-6.

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