Objective: To assess the efficacy of a continuous-combined transdermal patch (estradiol/ norethisterone acetate [E2/NETA] 25/125; Estragest TTS, Novartis, Basel, Switzerland) in the reduction of bone loss in postmenopausal women.
Design: In a 96-week, double-blind, randomized, multicenter, parallel study, 124 healthy women with an intact uterus more than 4 years after menopause received either transdermal continuous-combined E2/NETA (0.025/0.125 mg/day) or placebo patch for 24 treatment cycles; diet was normalized for calcium intake. Lumbar spine bone mineral density (BMD) ranged from 0.969 to 0.805 g/cm2 with a mean annual BMD decrement ranging from 3% to 8% within the last 24 months. BMD at lumbar spine L2-L4 (postero-anterior) and femur were assessed by dual energy x-ray absorptiometry after 6, 12, and 24 cycles. Efficacy variables included measurement of biochemical markers of bone turnover (3, 6, 12, and 24 months).
Results: BMD at lumbar spine was significantly higher at all time points in the E2/NETA group than in the placebo group (P < 0.0001). Significant increases in BMD (P < 0.0008) from baseline were observed at all sites after 24 months in the E2/NETA group compared with placebo, which demonstrated a decrease from baseline. At endpoint, statistically significant decrements in the values of bone remodeling markers were observed (P < 0.05) with E2/NETA.
Conclusions: E2/NETA 25/125 Estragest TTS was more effective than placebo in reducing the activation frequency of bone remodeling and in preventing bone loss at the spine and hip. Effects on the hip were similar to those observed for higher doses of estrogen.
Estrogen deficiency, which follows the progressive loss of ovarian function at menopause, plays a major role in the pathogenesis of bone loss in postmenopausal women. 1,2 Bone loss occurs as a result of an increased skeletal turnover with a greater increase in bone resorption than in bone formation, inducing a mass deficit at each remodeling site. 3 Most bone loss occurs during the first 3 to 6 years after menopause, with a subsequent slower decline thereafter. 4 As a result, millions of women worldwide suffer from osteoporosis, characterized by low bone mass and structural deterioration of bone tissue, leading to bone fragility with a subsequent increased risk of fracture. 5
Research has shown that hormone replacement therapy (HRT) is effective in the treatment of menopausal symptoms, 6 and it can reduce or even revert bone loss, irrespective of age, menopausal age, or route of administration. 7–12 Considerable epidemiological data exist that show that an inverse association exists between estrogen use and reduction of osteoporotic fractures, with an approximate 50% reduction in overall fracture incidence for primary prevention with current or recent use of estrogens. 13,14 It has been found, however, that for significant skeletal benefit, HRT should be given continuously for more than 5 years 8 and that the fracture risk reduction resulting from HRT use decreased to 25% after 5 or more years without HRT. 15
The strategy for the secondary prevention of postmenopausal osteoporosis should consider the smallest dose of estrogen that will prevent bone loss but cause the least side effects. Previous studies have suggested that a minimal dose of 0.05 mg transdermal estradiol (E2) is required to prevent bone loss in perimenopausal women and women in the early years after menopause. 9,16 Recent studies have shown that in this group of women, low doses of estrogens (ie, 0.3 mg conjugated equine estrogen or 0.025 mg transdermal E2) are also effective in the prevention of bone loss. 17–24 Unopposed estrogen treatment in women with an intact uterus can lead to excessive endometrial stimulation and an increased risk of hyperplasia, 25–27 but this can be prevented by the use of cyclical progestogens for at least 10 to 12 days each month. 28 Besides their protective effect on the uterus, progestogens might also exert an anabolic action on bone, particularly norethisterone acetate. 29,30
The return of monthly bleeding associated with such combination HRT regimens is unacceptable to many postmenopausal women and is a common reason for noncompliance and cessation of therapy. 31 Continuous-combined estrogen and progestogen regimens have, therefore, been developed that, in a significant percentage of women, result in an atrophic endometrium and amenorrhea. These have been shown to be effective, safe, and well-tolerated in women who are 1 to 2 years postmenopause. 32–35
A transdermal patch has been developed for the continuous administration of combined estrogen/ progestogen (Estragest TTS, Novartis, Basel, Switzerland), which delivers 0.025 mg/day of E2 and 0.125 mg/day of norethisterone acetate (NETA) simultaneously. This patch has been approved for treatment of mild to moderate postmenopausal symptoms in women at least 2 years postmenopause and has been marketed since 1998. Previous phase III studies have shown that this regimen provides adequate endometrial protection and produces high rates of amenorrhea and low rates of hyperplasia, in both cases being at least as good as established oral continuous-combined regimens. 36 In addition, the patch was tolerated better than products providing higher doses of estrogen.
The aim of this study was to evaluate the efficacy of this continuous-combined transdermal E2/NETA system, in terms of the reduction of postmenopausal bone loss in healthy women younger than 70 years of age and at least 4 years past physiological menopause, in comparison with placebo, in a 2-year trial.
From the 1Bone Metabolic Unit, Scientific Institute, San Raffaele Hospital, Milan, Italy, 2Novartis Farma S.p.A, Origgio, Italy, 3Clinica Ostetrico Ginecologica, Ospedale Maggiore di Parma Universitàdegli Studi Azenda Ospedaliera, Parma, Italy, 4Centro di Fisiopatologia della Menopausa Div. di Ostetricia e Ginecologia, Ospedale Bellaria Maggiore, Azienda USL, Bologna, Italy, 5Divisione di Ostetricia Ginecologia, Presidio Ospedaliero di Fidenza, Fidenza, Italy, 6Centro Menopausa Clinica Ostetrico-Ginecologica, Università degli Studi, Siena, Italy, 7Clinica Ostetrica e Ginecologica, Az. Osp.Arcispedale S. Anna Università degli Studi, Ferrara, Italy, 8Novartis Pharma AG, Basel, Switzerland.
Received June 10, 2002; revised and accepted September 18, 2002.
This study was supported by Novartis Pharma AG.
Address reprint requests to Alessandro Rubinacci, MD, Bone Metabolic Unit, Scientific Institute, San Raffaele Hospital, Via Olgettina 60, 20132 Milano, Italy. E-mail: email@example.com.