Estrogen Hormone Replacement

The effects of cyclic hormone replacement therapy (HRT) with either transdermal estrogen or oral estrogen on BMD in the spine and proximal femur were compared to controls by Hillard et al. (126). Ninety-six Caucasian women between 6 months and 7 years postmenopausal participated in this study. Thirty women served as controls. Sixty-six women received either 0.05 mg transdermal 17-P estradiol continuously and 0.25 mg per day of norethisterone for 14 days of each cycle or oral conjugated equine estrogen 0.625 mg daily and 0.15 mg of dl-norgestrel daily for 12 days of each cycle. BMD measurements of the PA spine and proximal femur were obtained every 6 months for 3 years with DPA (Lunar DP3). In the control group, BMD in the spine declined by 4% and in the femoral neck by 5% at the end of 3 years. BMD increased at both sites in the two groups receiving some form of HRT with no significant difference between the two groups. The average increase in BMD at the spine in the transdermal estrogen-treated group at the end of the first year was 0.033 g/cm2 and at the end of the third year was 0.046 g/cm2. In the conjugated estrogen-treated group, the average increase in spine BMD was 0.032 g/cm2 at the end of the first year and 0.038 g/cm2 at the end of the third year. At the femoral neck, the average increase in the transdermal estrogen-treated group was 0.015 g/cm2 at the end of the first year and 0.020 g/cm2 at the end of the third year. In the conjugated estrogen-treated group, the average gain in femoral neck BMD was 0.003 g/cm2 at the end of the first year and 0.009 g/cm2 at the end of the third year. Six of the women receiving HRT had significant losses in BMD from the femoral neck during the 3 years of treatment despite good compliance.

The effects of HRT on BMD in women just beginning therapy were compared to the effects on BMD in women on established HRT by Lees et al. (127). Twenty-nine women who had never taken HRT and 19 women who had been taking HRT were begun on micronized estradiol 2 mg per day orally daily and dydrogesterone 10 mg per day orally for 14 days of each cycle. BMD measurements of the PA lumbar spine and proximal femur were obtained with DXA (Lunar DPX) at yearly intervals for 2 years. In the women just beginning HRT, BMD increased at the spine by 5.3% at the end of 12 months and by 6.4% at the end of 14 months. In the women who had been on HRT, BMD increased to a lesser degree in the spine by 2.1% at the end of 12 months and by 2.3% at the end of 24 months. Femoral neck BMD increased in both groups but there was no difference between the two groups. At the end of 2 years, BMD had increased at the femoral neck in the women beginning HRT by 3.27% and in the women continuing HRT by 2.28%.

The effect of ERT on BMD in women at least 10 years past menopause was evaluated by Kohrt and Birge (128). Twenty-four women ranging in age from 61 to 74 years and who were 10 to 33 years postmenopausal underwent BMD studies with DXA (Hologic QDR-1000/W) of the total body, PA spine, proximal femur, and ultradistal radius + ulna. Measurements were made at baseline and every 3 months for 1 year. Half the women received 0.625 mg of conjugated estrogen daily and 5 mg per day of medroxyprogesterone acetate for 13 consecutive days every 3 months. The other 12 women served as controls. A calcium intake of 1500 mg a day was maintained by all the subjects. In these late postmenopausal women receiving HRT, BMD increased in the total body, lumbar spine, femoral neck, trochanter, and Ward's triangle and declined insignificantly at the ultradistal radius + ulna. Compared to the placebo group, the differences were significant at all sites with the exception of the ultradistal radius + ulna. In the HRT group, BMD at the total body increased 0.013 g/cm2 or 1.4%, at the lumbar spine by 0.041 g/cm2 or 5%, at the femoral neck by 0.019 g/cm2 or 3.1%, at the trochanter by 0.017 g/cm2 or 3% and at Ward's triangle by 0.026 g/cm2 or 5.8%. The decline at the ultradistal radius + ulna was 0.001 g/cm2 or 0.3%.

Dose-response studies of four estrogen preparations indicate that there are doses of estrogen replacement that are ineffective in preserving skeletal mass. The minimum effective dose of Premarin® (Wyeth-Ayerst, Philadelphia, PA) is considered to be 0.625 mg

(129). For Estrace® (Bristol-Myers Squibb, New York, NY), the minimum dose is 0.5 mg

(130). The minimum effective dose of Ogen® (Pharmacia & Upjohn, Kalamazoo, MI) is 0.625 mg. and for Estraderm® (Novartis, East Hanover, NJ), 0.05 mg (131,132).

The effects of the withdrawal of ERT on forearm BMC were studied by Christiansen et al. (133) in 94 women who were 6 months to 3 years postmenopausal. Women who stopped HRT after 2 years lost BMC from the distal radius as measured by SPA at virtually the same rate as those who did not begin HRT. The loss of BMC was approximately 2.3% per year from the distal radius in the women stopping HRT.

The effects of withdrawal of HRT on the spine and proximal femur were reported by Tremollieres et al. in Osteoporosis International in 2001 (134). Fifty healthy postmenopausal women who had been followed with bone densitometry both during HRT and after cessation were included in this study and compared to 81 healthy postmenopausal women who had never received HRT. Bone density was measured at the PA lumbar spine with DXA or DPA followed by DXA (Lunar DPX-L and Lunar DP3). HRT consisted of either 1.5 mg/day of 17-P estradiol given percutaneously or 50 ^g/day of 17-P estradiol in a transdermal patch combined with progesterone or a 19-norprogesterone derivative. HRT was utilized for a mean of 5 years. All of the women underwent bone density measurements during the time they received HRT and at least once within the first 18 months after cessation of HRT. Of the 50 women, 30 were followed after cessation of HRT for up to 8 years. The authors found that bone loss from the spine accelerated during the first 2 years after cessation of HRT at a rate that was similar to the rate of bone loss seen in the 81 postmenopausal women who had never received HRT. The rate of loss in the HRT-treated women was -1.64% compared to -1.52% in the never-treated women. After 2 years, the yearly rate of bone loss from the spine decreased. Between years 3 and 5, the rate of bone loss slowed to -0.83% in the previously HRT-treated women compared to -0.70% in the never-treated postmenopausal women. These differences were not statistically significant. The authors concluded that the pattern of bone loss seen in the postmenopausal women stopping HRT was similar to that seen in the immediate postmenopausal years in women who do not use HRT.

The percentage of women who may lose bone despite hormone replacement therapy (HRT) was addressed by Komulainen et al. (135). A subset of 232 women from the Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) were randomized to receive sequential HRT or placebo. BMD was measured at the PA lumbar spine and femoral neck by DXA at baseline, 2.5 years, and 5 years. The women also underwent measurements of FSH, estradiol, and alkaline phosphatase. A woman was identified as a nonresponder to HRT if her 5-year change in BMD was similar to, or worse than, the mean change of the placebo group. In the HRT group, the mean change in PA lumbar spine BMD over 5 years was a significant increase of 1.5%. At the femoral neck, BMD remained stable with an insignificant decrease of 0.4%. In the placebo group, significant losses were seen at both sites, 4.6% at the spine and 4.4% at the femoral neck. Eleven percent of the women were considered nonresponders to HRT based on changes in lumbar spine BMD. Based on femoral neck BMD 26% of the women receiving HRT were considered nonresponders. Smoking and low body weight were found to be significant predictors of nonresponse to HRT. Additionally, nonresponders had higher FSH levels and smaller increases in estradiol than the responders. The mean changes in FSH and alkaline phosphatase were lower in the nonresponders than in the responders to HRT.

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