A four-year randomized controlled trial of hormone replacement and bisphosphonate, alone or in combination, in women with postmenopausal osteoporosis

Am J Med. 1998 Mar;104(3):219-26. doi: 10.1016/s0002-9343(98)00029-1.


Purpose: Hormone replacement therapy (HRT) with estrogen and treatment with bisphosphonates have been shown to increase bone mineral density (BMD) in postmenopausal women. This 4-year prospective randomized study was carried out to assess the effectiveness of the combined HRT plus etidronate on BMD in postmenopausal women with established osteoporosis.

Patients and methods: Seventy-two postmenopausal women (mean age 64.9+/-0.5 years) attending metabolic bone disease outpatient clinics with established osteoporosis were randomly allocated into one of four treatment groups and monitored for 4 years. All patients enrolled in this study including the control group (n=18) received 1.0 g elemental calcium and 400 units vitamin D per day. The HRT group (n=18) received cyclical estrogen and progesterone; the etidronate group (n=17) received intermittent cyclical etidronate; and the combined therapy group (n=19) received both HRT and etidronate. BMD was measured in the lumbar spine and the hip before treatment and at 2 and 4 years after treatment. Changes in height were recorded, and the occurrence of new vertebral fractures were documented in comparison with the baseline radiographic evaluation. In 40 patients (10 patients per group), analysis of bone histomorphometry was carried out after 4 years of treatment.

Results: In patients who received the combined therapy, BMD increased in the lumbar spine by 10.4% (P <0.001) and in the hip by 7.0% (P <0.001) at 4 years. For patients treated with ICE, these increases were 7.3% (P <0.001) and 0.9% (P <0.05), and with HRT, the increases were 7.0% (P <0.001) and 4.8% (P <0.01) in the vertebrae and femora, respectively. The group treated with calcium and vitamin D lost 2.5% (P <0.05) and 4.4% (P <0.01) of BMD in the vertebrae and femora, respectively, after 4 years. Patients who received combined therapy had significantly higher BMD in both the vertebrae and in the femora (P <0.05) in comparison with patients who were treated with HRT or etidronate alone after 4 years. In comparison with patients in the control group, there was a trend toward a lower rate of new vertebral fractures in the treatment groups. Height loss was significantly less in all three active treatment groups (HRT [P <0.001], etidronate [P <0.02], and combined therapy group [P <0.0001]), in comparison with the control group. The combined therapy group did not have a significant height loss, in comparison with the HRT (P <0.02) and the etidronate (P <0.001) groups. None of the patients had histomorphometric evidence of osteomalacia.

Conclusion: This 4-year randomized study showed an additive effect of etidronate and HRT on hip and spine BMD in postmenopausal women with established osteoporosis.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Bone Density / drug effects*
  • Drug Administration Schedule
  • Drug Therapy, Combination
  • Estrogen Replacement Therapy*
  • Etidronic Acid / therapeutic use*
  • Female
  • Femur Neck / drug effects
  • Femur Neck / physiopathology
  • Humans
  • Lumbar Vertebrae / drug effects
  • Lumbar Vertebrae / physiopathology
  • Middle Aged
  • Osteoporosis, Postmenopausal / drug therapy*
  • Osteoporosis, Postmenopausal / physiopathology
  • Treatment Outcome


  • Etidronic Acid