Combined therapy with estrogen and etidronate has an additive effect on bone mineral density in the hip and vertebrae: four-year randomized study

Am J Med. 1995 Jul;99(1):36-42. doi: 10.1016/s0002-9343(99)80102-8.


Background: Administration of estrogen or etidronate has been shown to increase bone mineral density in postmenopausal women. This 4-year, prospective, randomized study was carried out to monitor any added beneficial effect on bone mineral density when hormone-replacement therapy (HRT) was combined with etidronate.

Patients and methods: Fifty-eight early postmenopausal women attending metabolic bone disease outpatient clinics were randomly allocated into four treatment groups and monitored for up to 4 years. All patients received 1.0 g/d of elemental calcium. In addition, group 1 received percutaneously administered HRT (n = 15); group 2, intermittent cyclical etidronate (ICE) (n = 14); group 3, HRT and ICE (n = 15); and group 4, calcium alone (n = 14). The bone mineral density (measured by dual-energy x-ray absorptiometry), biochemical variables of bone turnover, including bone-specific alkaline phosphatase, and urinary hydroxyproline:creatinine ratios were measured before treatment and at 2 and 4 years after treatment.

Results: In patients who received the combined therapy, bone mineral density was increased in the vertebrae by 10.9% (P < 0.001) and in the femora by 7.25% (P < 0.001) at 4 years. For patients treated with ICE, the increase was 6.79% (P < 0.001) and 1.20% (P < 0.05), and with HRT, 6.78% (P < 0.001) and 4.01% (P < 0.01) in the vertebrae and femora, respectively. The group treated with calcium alone lost 3.81% (P < 0.01) and 4.96% (P < 0.01) of bone mineral density in vertebrae and femora. Patients who received no specific therapy lost 8.58% (P < 0.01) from vertebrae, and 7.83% (P < 0.01) from the femora over 4 years. Patients who received combined therapy had significantly higher bone mineral density in both vertebrae (P < 0.05) and femora (P < 0.01), in comparison to patients who were treated with HRT, or ICE, alone. Three of 9 patients (33%) in the ICE group developed osteomalacia, as shown by bone histomorphometry, whereas in women who received combined HRT and ICE therapies, none of the 11 patients tested had evidence of bone mineralization defects.

Conclusion: This 4-year, prospective, randomized study in early postmenopausal women showed an additive effect of ICE and HRT on the bone mineral density in both vertebrae and the hip. Furthermore, the combined therapy prevented the occurrence of osteomalacia associated with etidronate. This is the first study to demonstrate the effects of etidronate in early postmenopausal women, and the additive beneficial effects of HRT and ICE on bone mineral density.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Absorptiometry, Photon
  • Analysis of Variance
  • Bone Density / drug effects*
  • Drug Administration Schedule
  • Drug Synergism
  • Drug Therapy, Combination
  • Estrogen Replacement Therapy*
  • Estrogens / administration & dosage
  • Estrogens / pharmacology*
  • Etidronic Acid / administration & dosage
  • Etidronic Acid / adverse effects
  • Etidronic Acid / pharmacology*
  • Female
  • Hip
  • Humans
  • Middle Aged
  • Prospective Studies
  • Spine


  • Estrogens
  • Etidronic Acid