Revisiting Estrogen: Efficacy and Safety for Postmenopausal Bone Health

Table 1

Selected studies on the effect of hormone therapy on bone metabolism in postmenopausal women

Study Name	Study Type	Sample Size, Mean Age in Years (Range), and Years since Menopause	Type of Therapy	Dose	Treatment Duration	Results for BMD, BMC, or Fracture Risk
WHI Estrogen plus Progesterone Trial [9]	RCT	16608,; 63 (50–79),; $>$6 months (>12 months for 50–54 years old)	CEE + MPA or placebo	CEE: 0.625 mg/d; MPA: 2.5 mg/d (continuous)	Stopped after a mean of 5.2 years due to increases in breast cancer, stroke, CHD	HR, 0.66 [0.45–0.98$]$ for incidence of hip fractures.; HR, 0.76 [0.69–0.85$]$ for incidence of total fractures.
WHI Estrogen alone Trial [10]	RCT	10739,; 64 (50–79),; previously hysterectomized	CEE or placebo	CEE: 0.635 mg/d	Stopped after a mean of 6.8 years due to increases in stroke	HR, 0.61 [0.41–0.91] for incidence of hip fractures.; HR, 0.70 [0.63–0.79]for incidence of total fractures.
WISDOM Trial [30]	RCT	4385,; 63 (50–69),; $>$12 months or previously hysterectomized	CEE,; CEE + MPA, or placebo	CEE: 0.635 mg/d; MPA: 2.5 mg/d (continuous) or 5.0 mg/d (sequential)	Stopped after a mean of 11.9 months due to adverse findings inWHI [8]	HR, 0.69 [0.46-1.03] for incidence of osteoporotic fractures.
PEPI Trial [8]	RCT	875,; 56 (45–64),; 1 to $<$10 years (either naturally or surgically)	CEE,; CEE + MPA,; CEE + MP, or placebo	CEE: 0.625 mg/d; MPA: 2.5 mg/d (continuous) or 10 mg/d (sequential); MP: 200 mg/d (sequential)	3 years	3.5–5.0% increase in LV BMD; 1.7% increase in hip BMD with these doses.
Danish Nurse Cohort Study [12]	Prospective	14015,; 60 ($\ge$50),; Years since menopause not provided	All types (e.g., CEE, E2) and delivery methods (ex: oral, transdermal)	All Doses (ex: CEE, $>$0.625 mg/d or $\le$0.625 mg/d; E2, $>$1 mg or $\le$1 mg oral; E2, $>$50 $\mu$g or $\le$50 $\mu$g transdermal); Various doses of MPA and NA as continuous or sequential regimes	Mean years of follow-up: not reported (Range: 0–6 years)	HR, 0.69 [0.50–0.94$]$ for incidence of hip fractures with ever users.
Million Women Study [20]	Prospective	138737,; Mean age in years not provided (50–69),; Years since menopause not provided	All types (ex: CEE, E2) and delivery methods (ex: oral, transdermal)	All Doses (ex: CEE, $>$0.625 mg/d or $\le$0.625 mg/d; E2, $>$1 mg or $\le$1 mg oral; E2, $>$50 $\mu$g or $\le$50 $\mu$g transdermal); Various doses of MPA and NA as continuous or sequential regimes	Mean years of follow-up: 2.8 (Range: 1.9–3.9 years)	RR, 0.62 [0.58–0.66$]$ for incidence of fracture with current users.; RR, 1.07 [0.99–1.15$]$ for incidence of fracture with past users.
SOF Trial [31]	Prospective	9704,; 70–72 ($>$65),; 2 years before onset of menopause to $>$10 years	All types of oral preparations	All doses of oral preparations	Mean years of follow-up: 2.5 (Range: 0.02–6.5 years)	RR, 0.60 [0.36–1.02$]$ for incidence of hip fractures with current users.; RR, 0.66 [0.54–0.80] for incidence of all nonspinal fractures with current users.; RR, 0.29 [0.09–0.92] for incidence of hip fractures with current users who started HT within 5 years of menopause.; RR, 0.50 [0.36–0.70] for incidence of all nonspinal fractures with current users who started HT within 5 years of menopause.

RCT: Randomized Control Trial, CEE: Conjugated Equine Estrogen, MPA: Medroxyprogesterone Acetate, MP: Micronized Progesterone, NA: Norethisterone Acetate, E₂: 17$\beta$-estradiol, BMD: Bone Mineral Density, LV: Lumbar Vertebra, HR: Hazard Ratio, and RR: Relative Risk.