A randomized double blind placebo controlled trial of the effects on bone metabolism of the combination of nafarelin acetate and norethisterone

Abstract

Objective: We observed the effects on bone metabolism of the addition of different doses of oral norethisterone during treatment with the GnRH agonist nafarelin (Synarel, Syntex).

Patients: Ninety-four women with a subjective complaint of heavy menstrual blood loss or objective evidence of endometriosis received intra-nasal nafarelin 400 micrograms daily for 6 months and also received, in a randomized, double blind manner, either 0.7 mg (n = 24), 1.4 mg (n = 23) or 2.45 mg (n = 23) of oral norethisterone or placebo (n = 24) daily. Follow-up was continued for a further 6 months after treatment.

Results: Thirty-one patients (33%) left the study prematurely and three patients were non-compliant with the study drug. By 6 months significant increases in urinary calcium/creatinine ratio were seen, compared to baseline, in the nafareline and placebo (P = 0.001, n = 14), 0.7 mg (P = 0.04, n = 13) and 1.4 mg norethisterone groups (P = 0.009, n = 17) but not in the nafarelin or 2.45 mg norethisterone groups (P = 0.72, n = 16). Densitometry of the spine, however, showed decreases at 6 months in all groups: 6.14% (P = 0.0004, n = 11), 5.46% n = 0.0006, n = 13), 3.93% (P = 0.008, n = 14) and 4.04% (P = 0.004, n = 16) for the groups receiving nafarelin and placebo, nafarelin and norethisterone 0.7, 1.4 and 2.45 mg respectively. Six months after stopping nafarelin, with or without norethisterone, bone mass was not different from baseline.

Conclusion: The concomitant daily use of up to 2.45 mg of norethisterone does not eliminate the bone demineralization seen during GnRH agonist therapy with nafarelin in premenopausal women.