Laura Piaggesi

Effects of combined low dose of the isoflavone derivative ipriflavone and estrogen replacement on bone mineral density and metabolism in postmenopausal women

OBJECTIVES To assess the pattern of biochemical markers of bone metabolism and vertebral bone mineral density in early postmenopausal women treated with combined ipriflavone and low dose conjugated estrogens. METHODS Bone biochemical markers and vertebral bone density were evaluated in a longitudinal, comparative, 2 year study conducted in postmenopausal women treated with sole calcium supplementation (500 mg/day), or with either ipriflavone (IP) at the standard dose (600 mg/day) plus the same calcium dose, low dose conjugated estrogens (CE) (0.3 mg/day) plus calcium, or low dose IP (400 mg/day) plus low dose CE (0.3 mg/day) plus calcium. The results were analyzed by repeated measures analysis of variance, as appropriate. RESULTS No modifications of both urinary excretion of hydroxyproline and plasma osteocalcin levels were observed in calcium and in CE-treated women, while vertebral bone density significantly decreased (P < 0.0001) in both groups. In IP or IP + CE-treated women, plasma osteocalcin did not show any modification, while urinary hydroxyproline showed a significant (P < 0.05) decrease, that paralleled a significant (P < 0.05) increase in vertebral bone density. CONCLUSION Postmenopausal IP administration, at the standard dose of 600 mg/day, can prevent the increase in bone turnover and the decrease in bone density that follow ovarian failure. The same effect can be obtained with the combined administration of low dose (400 mg/day) IP with low dose (0.3 mg/day) CE.

Hormone replacement therapy in perimenopausal women with a low dose oral contraceptive preparation: effects on bone mineral density and metabolism.

In a 2-year longitudinal, calcium-controlled study we evaluated bone density and metabolism in perimenopausal women with initial ovarian failure, and the effects of hormone replacement with a low dose oral contraceptive preparation (OC). In perimenopausal oligomenorrhoic women (n = 16) a significant (P < 0.01) increase in cycle length and plasma FSH levels as well as a parallel decrease in plasma estradiol levels (P < 0.01) were evident. In this group, despite the calcium supplementation (500 mg/day), a significant (P < 0.001) increase in the biochemical markers of bone remodelling paralleled a significant (P < 0.001) decrease (-3.4% after 24 months) in bone density. Conversely, in premenopausal oligomenorrhoic women treated with a low dose oral contraceptive (OC) formulation (30 mcg ethinyl estradiol plus 75 mcg gestodene, n = 16), bone markers showed a significant (P < 0.01) decrease, that paralleled a slight but significant (P < 0.01) increase (+1.71%) in bone density. These data suggest that premenopausal administration of OC can prevent the acceleration of bone turnover and reverse the decrease in bone density that follows the premenopausal impairment of ovarian function.

Bone loss in perimenopausal women: a longitudinal study

A longitudinal evaluation of bone mineral density (BMD) and metabolism was performed in premenopausal women. During the 2-year observation period, the menstrual pattern, plasma estradiol and FSH levels as well as the values of bone markers and BMD did not show any significant modification in a group of eumenorrhoic women (n = 37). Conversely, in age-matched oligomenorrhoic women (n = 37) a significant (P < 0.05) increase in the cycle length with a concomitant significant (P < 0.05) increase in circulating plasma FSH and parallel decrease of plasma estradiol levels (P < 0.05) was evident. In this group a significant (P < 0.05) increase in both urinary excretion of OH-P/Cr and plasma BGP levels paralleled a significant (P < 0.05) decrease in radial BMD. These data suggest that premenopausal impairment of ovarian function can lead to a bone loss in a significant proportion of women in which prevention should be considered before menopause.

Ipriflavone prevents the bone mass reduction in premenopausal women treated with gonadotropin hormone-releasing hormone agonists.

In the present study we assessed the effects of ipriflavone in the prevention of increased bone turnover and the rapid bone loss that follows medical induced hypogonadism caused by the administration of a gonadotropin hormone-releasing hormone agonist (GnRH-A). In a double blind, placebo-controlled study, ipriflavone (600 mg/day, tdd (three divided doses)) or identical placebo tablets were given with 500 mg/day of calcium to patients treated with 3.75 mg leuproreline acetate every 30 days, for 6 months. In placebo-treated subjects (n = 39), urinary hydroxyproline excretion and plasma bone GLA protein levels showed a substantial (P < 0.01) increase, while spine bone density and total body bone density significantly (P < 0.01) decreased after 3 and 6 months of GnRH-A administration. Conversely, in ipriflavone treated group (n = 39), no significant difference in bone markers and bone density was evidenced. These data indicate that ipriflavone can restrain the bone remodeling processes and prevent the rapid bone loss that follows medical induced hypogonadism. Thus, ipriflavone administration can be of value in the prevention of osteopenia in women treated with GnRH-A.

Treatment of postmenopausal vertebral osteopenia with monofluorophospate: A long-term calcium-controlled study

The aim of the present study was to assess the effects of the new fluorine pro-drug monofluorophos-phate (MFP) in postmenopausal women with vertebral osteopenia and high bone turnover. We enrolled postmenopausal women (PMW, 43–59 years) who had had a natural menopause 2–5 years before the study, had vertebral bone mineral density (BMD) <13 SD from the premenopausal mean, and had at least one of the biochemical markers of bone remodeling >1 SD over the mean for premenopausal women. Patients were randomly divided into two treatment groups (group 1, 500 mg/day of oral calcium; group 2, MFP at the dose of 20 mg F-equivalents + 600 mg calcium/day) for 2 years (n=21 in each group). The lumbar vertebral (L2–4) BMD and total body bone mineral (TBBM) were measured by dual-energy X-ray absorptiometry (Lunar DPX, Lunar Corporation, USA). Urinary hydroxyproline excretion (OH-P/Cr), plasma bone Gla protein (BGP) and serum alkaline phosphatase (AP) were assayed. In group 1 the markers of bone turnover and vertebral BMD did not show any significant modification, while TBBM showed a significant (p<0.05) decrease after 24 months. In group 2 a significant (p<0.05) decrease in OH-P/Cr (−23.9±2.0%), and an increase in both BGP (+19.4±2.6%) and AP(+10.3±2.6%) levels were observed after 24 months of MFP administration. In this group, both vertebral BMD (+5.01±0.9%,p<0.01) and TBBM (+4.0±0.6%,p<0.05) showed a significant increase after 24 months. Present results suggest that, in osteopenic PMW, MFP administration induces a significant increase in vertebral BMD without impairment of cortical bone, with a reduction in bone resorption and an increase in bone formation rate.

Cyclic-combined Conjugated Estrogens and Dydrogesterone in the Treatment of Postmenopausal Syndrome

We report the data concerning postmenopausal women treated either with a calcium supplement (500 mg/day, group l, n = 13) or with cyclic conjugated estrogens (0.625 mg/day) and dydrogesterone (5 mg/day) for 21 days with a 7-day free interval (n = 27, group 2) for 24 months. Withdrawal bleeding was regular, starting 1–2 days after the last treatment day and defined as light or mild. No sign of endometrial hyperstimulation was found by hysteroscopy and endometrial biopsy performed after 24 months of treatment. In group 1, constant levels of both urinary excretion of hydroxyproline and plasma osteo-calcin were observed, along with a significant (p < 0.05) decrease in vertebral bone mineral density. In group 2, both urinary excretion of hydroxyproline and plasma osteocalcin levels were significantly (p < 0.05) decreased and vertebral bone density showed a slight but significant (p < 0.05) increase. In group 1, a significant (p < 0.05) increase in serum low-density lipoprotein (LDL)-cholesterol levels was observed, whereas no modification in total cholesterol, high-density lipoprotein (HDL)-cholesterol and triglycerides was found. In group 2, total cholesterol and LDL-cholesterol levels significantly (p < 0.05) decreased, whereas triglycerides levels were stable throughout the study. In this group, HDL-cholesterol levels showed a significant (p < 0.05) increase. In conclusion, the regimen for cyclic combined estrogen-progestogen therapy attenuates bleeding disturbances and results in a low dropout rate. Thus, the clinical and metabolic actions, as well as the protective effects on the endometrium, make this treatment of potential interest. Further studies are required to confirm the long-term beneficial effects of this formula on cardiovascular protection and fracture rate.

Perimenopausal Changes in Body Weight, Body Fat Distribution and Hormonal Replacement Therapy

Regional fat distribution differs between men and women, and it is well known to occur both in obese and normal subjects. The typical male fat depot is localized in the abdominal regions, while women show a typical femoral and gluteal fat distribution. Increased body weight, and particularly the central distribution of body fat, is recognized as an independent predictor of cardiovascular disease in women [1–4]. Circulating sex steroids can influence body fat distribution [4], and a trend to a progressive increase in body weight is often observed throughout the climacteric period. However, it remains to be determined if those changes are related to the menopause and estrogen deficiency, to other endocrine modifications, to the aging process, or to all these factors. The issue of body weight has a great importance regarding the acceptance and the compliance to the postmenopausal hormonal replacement therapy (HRT). In fact, HRT has been commonly thought to determine an increase in body weight. This concern represents one of the greatest obstacles for the acceptance and use of long-term HRT, which can not only alleviate subjective symptoms, but also prevent osteoporosis and reduce the risk of cardiovascular disease [5–12]. The aim of the present study was to evaluate the pattern of body weight and body fat distribution in early postmenopausal women and the effects of HRT with an oral estrogen/progestin combination.