|Pharmacotherapeutic group: Drugs for the treatment of bone diseases Other drugs affecting bone structure and mineralization, ATC code: M05BX04|
Mechanism of actionDenosumab is a human monoclonal antibody (IgG2) that targets and binds with high affinity and specificity to RANKL, preventing activation of its receptor, RANK, on the surface of osteoclast precursors and osteoclasts. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function and survival, thereby decreasing bone resorption in cortical and trabecular bone.
Pharmacodynamic effectsProlia treatment rapidly reduced the rate of bone turnover, reaching a nadir for the bone resorption marker serum type 1 C-telopeptides (CTX) (85% reduction) by 3 days, with reductions maintained over the dosing interval. At the end of each dosing interval, CTX reductions were partially attenuated from maximal reduction of ≥ 87% to approximately ≥ 45% (range 45-80%), reflecting the reversibility of Prolia's effects on bone remodelling once serum levels diminish. These effects were sustained with continued treatment. Bone turnover markers generally reached pre-treatment levels within 9 months after the last dose. Upon re-initiation, reductions in CTX by denosumab were similar to those observed in patients initiating primary denosumab treatment.
ImmunogenicityIn clinical studies, neutralising antibodies have not been observed for Prolia. Using a sensitive immunoassay < 1% of patients treated with denosumab for up to 5 years tested positive for non neutralising binding antibodies with no evidence of altered pharmacokinetics, toxicity, or clinical response.
Treatment of osteoporosis in postmenopausal womenEfficacy and safety of Prolia administered once every 6 months for 3 years were investigated in post-menopausal women (7,808 women aged 60-91 years, of which 23.6% had prevalent vertebral fractures) with baseline bone mineral density (BMD) T-scores at the lumbar spine or total hip between 2.5 and 4.0 and a mean absolute 10-year fracture probability of 18.60% (deciles: 7.9-32.4%) for major osteoporotic fracture and 7.22% (deciles: 1.4-14.9%) for hip fracture. Women with other diseases or on therapies that may affect bone were excluded from this study. Women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily.
Effect on vertebral fracturesProlia significantly reduced the risk of new vertebral fractures at 1, 2 and 3 years (p < 0.0001) (see table 2).
Table 2 The effect of Prolia on the risk of new vertebral fractures
*p < 0.0001, **p < 0.0001 exploratory analysis
| ||Proportion of women with fracture (%)
||Absolute risk reduction (%)
||Relative risk reduction (%)
n = 3,906
n = 3,902
||1.4 (0.8, 1.9)
||61 (42, 74)**
||3.5 (2.7, 4.3)
||4.8 (3.9, 5.8)
||68 (59, 74)*
Effect on hip fracturesProlia demonstrated a 40% relative reduction (0.5% absolute risk reduction) in the risk of hip fracture over 3 years (p < 0.05). The incidence of hip fracture was 1.2% in the placebo group compared to 0.7% in the Prolia group at 3 years. In a post-hoc analysis in women > 75 years, a 62% relative risk reduction was observed with Prolia (1.4% absolute risk reduction, p < 0.01).
Effect on all clinical fracturesProlia significantly reduced fractures across all fracture types/groups (see table 3).
Table 3 The effect of Prolia on the risk of clinical fractures over 3 years
*p ≤ 0.05; **p = 0.0106 (secondary endpoint included in multiplicity adjustment), ***p ≤ 0.0001 + Event rates based on Kaplan-Meier estimates at 3 years.(1) Includes clinical vertebral fractures and non-vertebral fractures.(2) Excludes those of the vertebrae, skull, facial, mandible, metacarpus, and finger and toe phalanges.(3) Includes pelvis, distal femur, proximal tibia, ribs, proximal humerus, forearm, and hip.(4) Includes clinical vertebral, hip, forearm, and humerus fractures, as defined by the WHO.In women with baseline femoral neck BMD ≤ -2.5, Prolia reduced the risk of non-vertebral fracture (35% relative risk reduction, 4.1% absolute risk reduction, p < 0.001, exploratory analysis). The reduction in the incidence of new vertebral fractures, hip fractures and non-vertebral fractures by Prolia over 3 years were consistent regardless of the 10-year baseline fracture risk.
| ||Proportion of women with fracture (%)+||Absolute risk reduction (%)
||Relative risk reduction (%)
n = 3,906
n = 3,902
|Any clinical fracture1||10.2
||2.9 (1.6, 4.2)
||30 (19, 41)***
|Clinical vertebral fracture
||1.8 (1.2, 2.4)
||69 (53, 80)***
||1.5 (0.3, 2.7)
||20 (5, 33)**
|Major non-vertebral fracture3||6.4
||1.2 (0.1, 2.2)
||20 (3, 34)*
|Major osteoporotic fracture4||8.0
||2.7 (1.6, 3.9)
||35 (22, 45)***
Effect on bone mineral densityProlia significantly increased BMD at all clinical sites measured, versus placebo at 1, 2 and 3 years. Prolia increased BMD by 9.2% at the lumbar spine, 6.0% at the total hip, 4.8% at the femoral neck, 7.9% at the hip trochanter, 3.5% at the distal 1/3 radius and 4.1% at the total body over 3 years (all p < 0.0001). In clinical studies examining the effects of discontinuation of Prolia, BMD returned to approximately pre-treatment levels and remained above placebo within 18 months of the last dose. These data indicate that continued treatment with Prolia is required to maintain the effect of the medicinal product. Re-initiation of Prolia resulted in gains in BMD similar to those when Prolia was first administered.
Open-label Extension Study in the Treatment of Postmenopausal OsteoporosisA total of 4550 patients (2343 Prolia & 2207 placebo) who missed no more than one dose of investigational product in the pivotal study described above and completed all study visits agreed to enroll in a 7-year, multinational, multicenter, open label, single-arm extension study to evaluate the long-term safety and efficacy of Prolia. At month 24 of the extension study, after 5 years of denosumab treatment, the long-term group increased BMD by 13.8% at the lumbar spine, 7.0% at the total hip, 6.2% at the femoral neck and 9.7% at the trochanter from the original pivotal study baseline. Fracture incidence was evaluated as a safety endpoint: continued Prolia treatment maintained a low incidence of new vertebral and non-vertebral fractures in years 4 and 5 (annualised rate of new vertebral fracture was 1.4% in both years 4 and 5, while 1.4% and 1.1% of patients had a nonvertebral fracture in years 4 and 5 respectively). Three cases of osteonecrosis of the jaw (ONJ) occurred during the first 25 months in the study, two cases in the de novo treatment group and one case in the long term treatment group, all cases resolved.
Bone histologyBone histology was evaluated in 62 postmenopausal women with osteoporosis or with low bone mass who were either naïve to osteoporosis therapies or had transitioned from previous alendronate therapy following 1-3 years treatment with Prolia. Bone biopsy results from both studies showed bone of normal architecture and quality with no evidence of mineralisation defects, woven bone or marrow fibrosis.
Treatment of bone loss associated with androgen deprivationEfficacy and safety of Prolia once every 6 months for 3 years were investigated in men with histologically confirmed non-metastatic prostate cancer receiving ADT (1,468 men aged 48-97 years) who were at increased risk of fracture (defined as > 70 years, or < 70 years with a BMD T-score at the lumbar spine, total hip, or femoral neck < -1.0 or a history of an osteoporotic fracture.) All men received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily. Prolia significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 3 years: 7.9% at the lumbar spine, 5.7% at the total hip, 4.9% at the femoral neck, 6.9% at the hip trochanter, 6.9% at the distal 1/3 radius and 4.7% at the total body (all p < 0.0001). In a prospectively planned exploratory analysis, significant increases in BMD were observed at the lumbar spine, total hip, femoral neck and the hip trochanter 1 month after the initial dose.Prolia demonstrated a significant relative risk reduction of new vertebral fractures: 85% (1.6% absolute risk reduction) at 1 year, 69% (2.2% absolute risk reduction) at 2 years and 62% (2.4% absolute risk reduction) at 3 years (all p < 0.01).
Treatment of bone loss associated with adjuvant aromatase inhibitor therapyEfficacy and safety of Prolia once every 6 months for 2 years was investigated in women with non-metastatic breast cancer (252 women aged 35-84 years) and baseline BMD T-scores between -1.0 to -2.5 at the lumbar spine, total hip or femoral neck. All women received calcium (at least 1,000 mg) and vitamin D (at least 400 IU) supplementation daily. The primary efficacy variable was percent change in lumbar spine BMD, fracture efficacy was not evaluated. Prolia significantly increased BMD at all clinical sites measured, relative to treatment with placebo at 2 years: 7.6% at lumbar spine, 4.7% at total hip, 3.6% at femoral neck, 5.9% at hip trochanter, 6.1% at distal 1/3 radius and 4.2% at total body (all p < 0.0001).
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with Prolia in all subsets of the paediatric population in the treatment of menopausal and other perimenopausal disorders, and in the treatment of bone loss associated with sex hormone ablative therapy. See section 4.2 for information on paediatric use.