A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study

doi:10.1016/S0002-9343(00)00490-3

The American Journal of Medicine

Volume 109, Issue 4, September 2000, Pages 267-276

https://doi.org/10.1016/S0002-9343(00)00490-3 Get rights and content

Abstract

PURPOSE: We conducted a 5-year, double-blind, randomized, placebo-controlled study to determine whether salmon calcitonin nasal spray reduced the risk of new vertebral fractures in postmenopausal women with osteoporosis.

SUBJECTS AND METHODS: A total of 1,255 postmenopausal women with established osteoporosis were randomly assigned to receive salmon calcitonin nasal spray (100, 200, or 400 IU) or placebo daily. All participants received elemental calcium (1,000 mg) and vitamin D (400 IU) daily. Vertebral fractures were assessed with lateral radiographs of the spine. The primary efficacy endpoint was the risk of new vertebral fractures in the salmon calcitonin nasal spray 200-IU group compared with the placebo group.

RESULTS: During 5 years, 1,108 participants had at least one follow-up radiograph. A total of 783 women completed 3 years of treatment, and 511 completed 5 years. The 200-IU dose of salmon calcitonin nasal spray significantly reduced the risk of new vertebral fractures by 33% compared with placebo [200 IU: 51 of 287, placebo: 70 of 270, relative risk (RR) = 0.67, 95% confidence interval (CI): 0.47– to 0.97, P = 0.03]. In the 817 women with one to five prevalent vertebral fractures at enrollment, the risk was reduced by 36% (RR = 0.64, 95% CI: 0.43– to 0.96, P = 0.03). The reductions in vertebral fractures in the 100-IU (RR = 0.85, 95% CI: 0.60– to 1.21) and the 400-IU (RR = 0.84, 95% CI: 0.59– to 1.18) groups were not significantly different from placebo. Lumbar spine bone mineral density increased significantly from baseline (1% to 1.5%, P <0.01) in all active treatment groups. 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.

CONCLUSION: Salmon calcitonin nasal spray at a dose of 200 IU daily significantly reduces the risk of new vertebral fractures in postmenopausal women with osteoporosis.

Section snippets

Material and methods

This double-blind, placebo-controlled trial was conducted in 42 centers in the United States and five centers in the United Kingdom. A total of 1,255 women were enrolled between February 1991 and July 1993.

Results

More than 3,500 women were screened for study participation, of whom 1,255 were randomly assigned to either placebo (n = 311), salmon calcitonin nasal spray 100 IU (n = 316), 200 IU (n = 316), or 400 IU (n = 312) (Table 1). After adjudication of baseline spine radiographs, 910 women had one to five prevalent vertebral fractures (as specified by the protocol), 269 had no vertebral fractures, and 65 had more than five fractures. Spinal radiographs could not be evaluated in 11 women, who were

Discussion

The results of this 5-year clinical trial show that 200 IU of salmon calcitonin nasal spray per day significantly reduces the risk of new vertebral fractures by 33% to 36% in postmenopausal women with low bone mass or prevalent vertebral fractures. Among women with one to five vertebral fractures at baseline, 11 needed to be treated for 3 years to prevent a new vertebral fracture. The effect on vertebral fractures was accompanied by a modest increase in lumbar spine bone mineral density and a

Acknowledgements

This article is dedicated to the late John H. Carstens, Jr., MD (1945 to 1992), whose foresight and leadership made this clinical program possible, and to Janet Partridge, who was responsible for coordinating and managing the study. We are grateful to Moı̈se Azria, PhD, for his help with the literature search.

PROOF STUDY GROUP:

Jeffrey Miller, Jane Sherman, (Tampa, FL); Douglas Kiel, Jeannette Szaro (Providence, RI); Suthin Songcharoen, Susan Williams (Jackson, MS); Robert Bing-You, Donna

References (53)

D.M. Kallio et al.
Ultrastructural effects of calcitonin on osteoclasts in tissue culture
J Ultrastruct Res
(1972)
K. Overgaard et al.
Discontinuous calcitonin treatment of established osteoporosis —effects of withdrawal of treatment
Am J Med
(1990)
J.Y. Reginster et al.
1-Year controlled randomized trial of prevention of early postmenopausal bone loss by intranasal calcitonin
Lancet
(1987)
J.Y. Reginster et al.
A double-blind, placebo-controlled, dose-finding trial of intermittent nasal salmon calcitonin for prevention of postmenopausal lumbar spine bone loss
Am J Med
(1995)
G. Thamsborg et al.
Effect of nasal salmon calcitonin on bone remodeling and bone mass in postmenopausal osteoporosis
Bone
(1996)
H.E. Gruber et al.
Long-term calcitonin therapy in postmenopausal osteoporosis
Metabolism
(1984)
D.M. Black et al.
Randomized trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group
Lancet
(1996)
C.H. Chesnut et al.
Alendronate treatment of the postmenopausal osteoporotic womaneffect of multiple dosages on bone mass and bone remodeling
Am J Med
(1995)
M. Azria
The CalcitoninsPhysiology and Pharmacology
(1989)
B. Baron et al.
Behavior of osteoclasts during a rapid change in their number induced by high doses of parathyroid hormone or calcitonin in intact rats
Metab Bone Dis Relat Res
(1981)

P. Geusens et al.

Effect of salmon calcitonin on femoral bone quality in adult ovariectomized ewes

Calcif Tissue Int

(1996)

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Puntos para una lectura rápida
- •
  La disminución de la densidad mineral ósea es un factor de riesgo de fractura más, no un criterio de enfermedad. La edad es el factor de riesgo más importante (siete veces más que el descenso de la DMO en fractura de cadera).
- •
  La estrategia de realizar un cribado poblacional en mayores de 50 años no se sustenta. La mayoría de las sociedades científicas asumen la estrategia de valorar el riesgo de fractura en los próximos 10 años con escalas validadas y calibradas. La escala FRAX es la más ampliamente utilizada.
- •
  Una estrategia para calibrar el riesgo y determinar los umbrales de intervención y tratamiento válida para nuestro entorno es la propuesta en 2015 por la DGFCM (diseñada con datos de fractura de cadera de la Comunidad de Madrid). El modelo propone valorar el riesgo de fractura de cadera en los próximos 10 años en función de la edad y de la puntuación de riesgo individual de la paciente. En mujeres con riesgo > 10% recomiendan tratamiento sin necesidad de densitometría y en mujeres con riesgo < 3% desaconsejan hacer ninguna intervención. En mujeres de riesgo intermedio (10-3%), recomiendan solicitar densitometría como prueba discriminante, valorando la indicación de tratamiento según la Z-score obtenida en la misma.
- •
  No hay evidencia de eficacia de los tratamientos antifractura ni en prevención primaria ni en mujeres con densitometría en rango osteopénico: las poblaciones de los estudios de los distintos fármacos eran mujeres con AP de fracturas o <-2DS de T-score. Los fármacos han demostrado eficacia en fractura vertebral, pero hay escasa evidencia de su eficacia en fractura de cadera.
- •
  No existen estudios en prevención primaria en mujeres < 65 años, por lo que en ellas el riesgo debe ser individualizado. Asimismo, la decisión de tratar a mujeres > 80 años debe ser también individualizada por su situación de pluripatología y polifarmacia.
- •
  Los fármacos de primera elección son el alendronato (10 mg/día o 70 mg/semana VO) o risedronato (5 mg/día, 35 mg/s o 75 mg/mes VO), que deben administrarse con suplementos de vitamina D (400-800 UI/día) y calcio (0,5-1,2 g/día). El tratamiento no debe superar los 5 años de duración y el seguimiento de las pacientes ha de ser anual mediante la reevaluación clínica de las mismas (presencia de nuevos factores de riesgo o de nuevas fracturas osteoporóticas).
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Clinical studyA randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study

Abstract

Section snippets

Material and methods

Results

Discussion

Acknowledgements

J Ultrastruct Res

Am J Med

Lancet

Am J Med

Bone

Metabolism

Lancet

Am J Med

The CalcitoninsPhysiology and Pharmacology

Behavior of osteoclasts during a rapid change in their number induced by high doses of parathyroid hormone or calcitonin in intact rats

Metab Bone Dis Relat Res

The effects of parathyroid hormone, colchicine, and calcitonin on the ultrastructure and the activity of osteoclasts in organ culture

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The effect on vertebral bone mass and strength of long term treatment with antiresorptive agents (estrogen and calcitonin), human parathyroid hormone-(1–38), and combination therapy, assessed in aged ovariectomized rats

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Clinical study
A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study