Can Prolia (denosumab) be initiated for osteopenia prophylaxis concurrently with an aromatase inhibitor?

Can Prolia (denosumab) be initiated for osteopenia prophylaxis concurrently with an aromatase inhibitor?

Comment by InpharmD Researcher

According to a joint position statement from various organizations, including the International Osteoporosis Foundation, antiresorptive therapy with agents such as denosumab is recommended once patients present with two of the following risk factors: T-score <-1.5, age > 65 years, low BMI (<20), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use of > 6 months, or current/history of smoking. However, any patient initiating or receiving aromatase inhibitor therapy with a T-score <-2 should receive antiresorptive therapy irrespective of the presence of other risk factors. In a phase 3 trial denosumab (Prolia) as an adjunct to aromatase inhibitor therapy decreased occurence of fractures (see table 1).

Background

A 2017 position statement from various professional organizations discusses the use of denosumab for the management of aromatase inhibitor-associated bone loss (AIBL) for postmenopausal women with breast cancer. While denosumab has reported successful use for the prevention and treatment of AIBL, its recommended use is primarily in patients presenting with bone loss or risk factors for fracture. Patients who begin AI treatment without bisphosphonate with a T-score > 2.0 and no other fracture risk factor are recommended to have their bone mineral density (BMD) and risk status assessed after 12 months. Antiresorptive therapy is only recommended once patients present with two of the following risk factors: T-score <-1.5, age > 65 years, low BMI (<20 kg/m2), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use of > 6 months, or current/history of smoking. Additionally, any patient initiating or receiving AI therapy with a T-score <-2 should receive antiresporptive therapy irrespective of the presence of other risk factors.[1]

A 2020 review provided general evidence of how AIs in women with breast cancer impact bone health as well as potential management strategies to preserve bone strength. The authors reported results from a randomized trial studying the efficacy of denosumab in preventing AI-induced bone loss. This study revealed increased lumbar spine bone mineral density after 12 and 24 months with denosumab 60 mg every 6 months (p<0.0001 for both). However, this study included patients with existing evidence of bone loss upon the start of the trial. An additional study also reported successful outcomes when denosumab was used as an adjunct to AI treatment for reducing clinical fractures in postmenopausal women with hormone receptor-positive, early-stage breast cancer (see Table 1).[2]

Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

Can Prolia (denosumab) be initiated for osteopenia prophylaxis concurrently with an aromatase inhibitor?

Please see Table 1 for your response.

Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial
Design	Prospective, double-blind, placebo-controlled, phase 3 trial N= 3,420
Objective	To investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer.
Study Groups	Placebo (n= 1,709) Denosumab (n= 1,711)
Inclusion Criteria	Postmenopausal women; histologically confirmed non-metastatic estrogen receptor-positive breast cancer; receiving adjuvant non-steroidal aromatase inhibitors
Exclusion Criteria	Aromatase inhibitor therapy > 24 months prior to trial inclusion; use of selective estrogen receptor modulators; metastatic disease; intravenous bisphosphonate administration; oral bisphosphonate if taking for 3 years or longer continuously or taken between 3 months and 3 years (unless there was a 1 year washout period prior to randomization); oral bisphosphonate use 3 months before randomization, previous denosumab use; Paget's disease; Cushing's disease; hyperprolactinaemia; active metabolic bone disease; hyper/hypocalcemia
Methods	Patients were randomized (1:1) to receive either denosumab 60 mg SubQ or matching placebo every 6 months. Patients did not require a certain T-score to be enrolled and one of the randomization stratifications was based on if T-score was < -1.0 versus > -1.0. Follow-up assessment of fracture was performed at least every 6 months until the cut-off day.
Duration	Enrollment period: December 18, 2006 to July 22, 2013 Follow-up cutoff date: March 26, 2014
Outcome Measures	Primary: Time from randomization until radiograph confirming first clinical fracture (clinically evident fractures in areas aside from the skull, face, fingers, and toes) Secondary: Primary outcome in all randomized patients separated by their T-score; disease-free survival
Baseline Characteristics		Placebo (n= 1,709)	Denosumab (n= 1,711)
	Age, years < 50 50 to 59 60 to 69 70 to 79 > 80	2% 26% 44% 24% 4%	2% 28% 46% 22% 3%
	White	99%	99%
	Chemotherapy before randomization None Adjuvant Neoadjuvant	75% 19% 5%	75% 20% 5%
	Start of aromatase inhibitor treatment With denosumab/placebo Before denosumab/placebo	16% 84%	16% 84%
	Total lumbar spine bone mineral density T-score < -1.0 T-score > 1.0	45% 55%	45% 55%
Results	Endpoint	Placebo (n= 1,709)	Denosumab (n= 1,711)	Hazard ratio (95% confidence interval [CI]; p-Value)
	Occurrence of clinical fractures overall	176	92	0.50 (0.39 to 0.65; p<0.0001)
	Occurrence of clinical fractures in the subgroup T-score < -1 T-score > -1	49/773 43/938	84/775 92/934	0.57 (0.40 to 0.82; 0.002) 0.44 (0.31 to 0.64; p<0.0001)
	Disease-free survival events	16.8%	14%	0.82 (0.69 to 0.98)
Adverse Events	No additional toxicity from denosumab was reported
Study Author Conclusions	Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice.
InpharmD Researcher Critique	The subanalysis results indicate patients with normal mineral bone density receiving aromatase inhibitor may also benefit from a reduced risk of clinical fractures. Yet these findings are exploratory until a subsequent follow-up study is performed. The ethnicity of patients was predominantly white, limiting the generalizability of the study.

References:

[1] Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, et al. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015;386:433–43.
[2] Gnant M, Pfeiler G, Steger GG, et al. Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):339-351. doi:10.1016/S1470-2045(18)30862-3