Introduction

Denosumab is a fully humanized monoclonal antibody that inhibits osteoclastogenesis by preventing the binding of receptor activator of nuclear factor kappa B ligand (RANKL) to its receptor, leading to increased bone mineral density (BMD) and reduced incidence of vertebral and non-vertebral fractures, making it a widely used treatment for osteoporosis.

Denosumab does not incorporate into the bone matrix therefore, unlike bisphosphonates that bind to the bone matrix and maintain their effects. The effects of denosumab are reversible. Its effects on bone remodelling rapidly disappear once its administration is discontinued.

Aim

To assess the relationship between delayed dosing of denosumab and the extent of elevated fracture risk.

Patient Profile

Women aged 45 to 89 years who were started on denosumab for osteoporosis

Methods

• Population-Based Retrospective Study
• The analysis included 149,199 patients, accounting for 218,823 denosumab administrations
• Participants were divided into the following groups according to when they received their subsequent denosumab dose (after 6 months of prior denosumab)

• Early dosing (ED30): within 30 days before the recommended dosing day (180th day after earlier denosumab dosing)
• Standard dosing (Referent): between 180-210 days
• Delayed dosing (DD90): 30-90 days later than planned
• Delayed dosing (DD180): 90-180 days later than planned
• Severely delayed dosing (DD181+): more than 181 days later than planned

• The primary outcome was the incidence of all clinical fractures

Results

• The incidence of all fractures was significantly higher in the DD90 compared to reference group
  • 2.06/100 case-year in the reference group
  • 2.06/100 case-year in ED 30 group
  • 2.55/100 case-year in the DD90 group
  • 3.92/100 case-year in the DD180 group
  • 3.83/100 case-year in the DD181+group
• The risk of all fractures was even higher in the longer delayed DD180 group

• HR of 1.24 (P=0.002) in the DD90 group
• HR of 1.89 (P<0.001) in the DD180 group
• HR of 1.83(P<0.001) in the DD181+group

• The risk of fracture increased nearly two-fold in the longer-delayed groups (180 and 181+ delay) as compared to the reference group.
• The risk of vertebral fractures was significantly higher in the delayed dosing groups compared to the reference group, with HR of 1.35 in the DD90 group, 2.18 in the DD180 group, and 2.41 in the DD181+ group, indicating consistently increased risks associated with delayed dosing

Table 1: Risk of All Clinical Fractures & Vertebral Fractures based on the Timing of the Subsequent Denosumab Injections

ED, early dosing; DD, delayed dosing; HR, hazard ratio.

• In patientswho received bisphosphonate treatment within 1 year of denosumab initiation, delayed dosing of denosumab was associated with an increased risk of clinical & vertebral fractures in DD180 and DD181+ groups, but not the DD90 group.

  Table 2 : Risk of all clinical fractures or vertebral fractures based on the timing of subsequent denosumab injections in patients with a history of bisphosphonate use.

  		Subsequent denosumab injection time
  Variable	150–180 days (ED30)	181–210 days (Reference)	211–270 days (DD90)	271–360 days (DD180)	361 days or more (DD181+)
  Cases	9,430	54,639	6,728	2,737	3,284
  All clinical fractures
  Fracture	109	563	84	54	31
  Case-year	4,687	27,111	3,223	1,089	847
  Incidence, /100 case-yr	2.33	2.08	2.61	4.96	3.66
  HR	1.12	Reference	1.26	2.38	1.74
  P value	0.28		0.052	<0.001	0.003
  Vertebral fractures
  Fracture	49	290	44	30	18
  Case-year	4,704	27,179	3,233	1,094	851
  Incidence, /100 case-yr	1.04	1.07	1.36	2.74	2.12
  HR	0.98	Reference	1.28	2.55	1.95
  P value	0.876		0.133	<0.001	0.006

   

• In patients without a prior history of fractures, delayed denosumab treatment was associated with increased risks of both all clinical and vertebral fractures.
• The risk of non-vertebral fractures significantly increased in the DD180 group (HR, 1.55; P=0.002), while the increase in the DD181+ group was not statistically significant.

Conclusion

• Delayed denosumab dosing, even by 1 to 3 months, is significantly associated with an increased risk of all clinical and vertebral fractures, while short delays of less than 30 days do not have a significant impact on fracture risk.
• Timely dosing at 6-month intervals is crucial for effective management of osteoporosis in denosumab-treated patients, as delays may elevate fracture risk.

Reference

Endocrinol Metab 2024; 39:946-955