PROOF Study: Effectiveness of Salmon Calcitonin Nasal Spray in Reducing Risk of New Vertebral Fractures in Osteoporotic Postmenopausal Women

19 Jul, 22

Introduction

Calcitonin is a physiologic endogenous inhibitor of bone resorption, decreases osteoclast formation, osteoclast attachment. The treatment with calcitonin may be beneficial in diseases associated with increased bone resorption, such as postmenopausal osteoporosis.

Aim

The Prevent Recurrence of Osteoporotic Fractures (PROOF) study determined whether salmon calcitonin nasal spray reduced the risk of new vertebral fractures in postmenopausal women with osteoporosis

Patient Profile

Postmenopausal women with osteoporosis

Methods

5-year, double-blind, randomized, placebo-controlled study
N= 1,255 postmenopausal women

The primary analysis for the incident vertebral fracture endpoint was an intention-to-treat analysis among all participants with at least one follow-up radiograph.
Secondary analyses were performed among participants with one to five prevalent vertebral fractures at enrolment (as per protocol) and among those who received the study drug for at least 3 years or who had a fracture during the first 3 years of treatment (3-year valid completer analysis)

Results

200-IU dose of salmon calcitonin nasal spray was associated with significant reduction in risk of new vertebral fractures by 33%. [200 IU: 51 of 287, placebo: 70 of 270, relative risk (RR): 0.67, P = 0.03]

Figure 1: Vertebral Fracture Analyses for Entire Study Cohort

The number of new vertebral fractures per 1,000 participant radiograph years was reduced by 40% (P = 0.02) in the 200-IU group compared with the placebo group
New vertebral fractures/1000 participant radiograph years was
- Placebo =131
- 100 IU=129
- 200 IU= 78
- 400 IU=111
In the 817 women with one to five prevalent vertebral fractures at enrollment, the risk was reduced by 36% (RR=0.64, P = 0.03).

Table 1: Vertebral Fracture Analyses for Subgroup with One to Five Prevalent Vertebral Fractures, and for 3-Year Completers

		Treatment Groups
	Placebo	100 IU	200 IU	400 IU
Participants with 1-5 prevalent fractures	n =203	n = 201	n = 207	n =206
Participants with >1 new vertebral fractures (%)	30	26	19	23
Relative risk		0.94	0.64	0.78
Participants with >2 new vertebral fractures (%)	15	16	9	11
Odds ratio		1.09	0.55	0.73
Three-year completers	n = 162	n = 152	n = 157	n = 155
Participants with >1 new vertebral fractures (%)	36	32	26	27
Relative risk		0.91	0.66	0.71

The reductions in vertebral fractures in the 100-IU (RR = 0.85,) and the 400-IU (RR =0.84) groups were not significantly different from placebo.
In participants receiving 100 IU salmon calcitonin nasal spray, there was a significant 64% reduction in the risk of fractures of the arm (RR=0.36, P=0.03), but the reductions in risk in the 200-IU and 400-IU groups were not statistically significant

Table 2: Nonvertebral Fracture Analyses

		Treatment Group
	Placebo	Nasal Spray Salmon Calcitonin
	Placebo	100 IU	200 IU	400 IU
Number of participants at risk	(n=305)	(n = 313)	(n =315)	(n = 312)
All nonvertebral fractures
Participants %	16	10	15	13
Relative risk		0.64^*	0.88	0.81
Hip or femoral fractures
Participants %	3	0.3	2	2
Relative risk	-	0.1^*	0.5	0.8
Arm fractures^#
Participants %	5	2	4	5
Relative risk	-	0.4	0.75	0.84

^*P <0.05 versus placebo.

^#Fractures of the humerus, radius, ulna, or wrist.

Significant increase in lumbar spine bone mineral density was reported in all active treatment groups (1% to 1.5%, P<0.01)
Bone turnover was inhibited, as shown by suppression of serum type-I collagen cross-linked telopeptide (C-telopeptide) by 12% in the 200-IU group (P <0.01) and by 14% in the 400-IU group (P<0.01) as compared with placebo

Salmon calcitonin nasal spray was well tolerated in study population
The rate and reasons for discontinuation were distributed equally among treatment groups
- Intolerance to the nasal spray did not contribute significantly to study discontinuation; less than 5% of participants discontinued for this reason

Conclusion

Salmon calcitonin nasal spray at a dose of 200 IU daily demonstrated significant reduction in the risk of new vertebral fractures in postmenopausal women with osteoporosis
The findings showed it as safe and effective treatment option for postmenopausal women with established spinal osteoporosis

Reference

Am J Med. 2000; 109:267–276.