Osteoporosis is a serious public health problem, with approximately 14 million cases in the United States1 2 Osteoporosis is characterized by decreased bone mineral density (BMD) and an increased risk of bone fragility, often causing chronic pain, fracture, and disability, resulting in impaired quality of life.3 osteoporosis , also known as type I primary osteoporosis , is caused by estrogen deficiency and is the major type of osteoporosis .4 osteoporosis also called senile osteoporosis , affects both men and women.5 postmenopausal women have a greater risk of developing osteoporosis than older men. Osteopenia is an important transition stage from healthy to osteoporosis . BMD at the lumbar spine, total hip, or femoral neck measured by dual-energy x-ray absorptiometry is a key method to evaluate bone health. According to the World Health Organization (WHO) diagnostic categories, BMD that is less than 1 SD below the young adult women's mean value (peak value) is normal, BMD that lies between 1 and 2.5 SD below the peak value indicates osteopenia , and osteoporosis is defined by BMD that is 2.5 SD or more below the peak value.6
Hormone therapy (HT) is widely used for the prevention and management of osteoporosis , including estrogen-only or estrogen/progestin combo. The formulations include oral, vaginal, implant, skin patch, and cream from gel,7 8-10 11,12
Our first objective was to evaluate the associations of various hormone preparations with BMD, postmenopausal osteopenia , and postmenopausal osteoporosis . Given this controversial issue, our second objective was to explore the withdrawal effect of HT. Real-world data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were used to perform this work.
METHODS
Data source
The data used in this real-world study were extracted from NHANES, which is a survey conducted by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention since 1960. We pooled data from ten 2-year cycles of NHANES 1999-2018 to ensure a large and representative sample. The Ethics Review Board of the NCHS approved the NHANES survey protocol, and all participants received informed consent.
Study population
The participants of this study were postmenopausal women who were defined as women older than 50 years and had not menstruated for at least 1 year. We extracted 13,862 women older than 50 years from the total of 101,316 participants. Among them, 10,488 women answered the question “Age at last menstrual period?” (RHQ060), and 10,243 participants whose age at the time of the survey minus the age of last menstrual period was more than 1. In addition, 2,048 participants answered the question “When did you have last period?” (RHQ050), and 1,967 women answered “12 or more months ago”; they were also postmenopausal women . There were 10,476 postmenopausal women after removing 1,734 women who were double counted. We then excluded 23 women with missing data for hormone preparation usage and 4,418 women with missing lumbar spine BMD data. A total of 6,035 participants were used to analyze the associations of hormone preparations with BMD, postmenopausal osteopenia , and postmenopausal osteoporosis (Fig. 1 ). Among them, 1,996 participants answered the question “Taking hormone preparations now?” and they were used to analyze the withdrawal effect of HT. Besides, 3,425 young adult women aged 20 to 29 years were selected to calculate peak lumbar spine BMD.
FIG. 1: Flowchart of sample selection from the NHANES 1999-2018. NHANES, National Health and Nutrition Examination Survey .
Variables
Exposure variables included whether they had used one or more hormone preparations and the duration. According to their answers, “Use combined oral contraceptives (COC) pills/estrogen-only pills/estrogen/progestin combo pills/estrogen-only patches/estrogen/progestin combo patches?” in the Reproductive Health Questionnaire, participants were divided into eight groups: nonusers (NU) group, COC group, Epills group, EPpills group, Epatches group, EPpatches group, two kinds group, and at least three kinds group. In addition, 1,996 participants were redivided into two groups according to hormone preparation use status: current users (CU) group and past users (PU) group. The outcome variable, lumbar spine BMD, was evaluated using dual-energy x-ray absorptiometry scans with Hologic Discovery Model A densitometers (Hologic, Inc., Bedford, MA). Other outcome variables, postmenopausal osteopenia , and osteoporosis were evaluated using the WHO diagnostic categories described previously. Confounding variables included age, last menstrual age, body mass index, race, health condition, smoking (whether the participant smoked at least 100 cigarettes in life), and drinking (whether the participant drank at least once a month).4,13
Statistical analysis
The sampling weight provided in the NHANES database was used to adjust for the complex survey design (including oversampling), survey nonresponse, and poststratification adjustment, which ensured that the data were representative of the entire American noninstitutionalized population. All statistical analyses were performed using the R packages and EmpowerStats (version 2.0). The descriptive statistics of baseline characteristics are presented as the means ± SD for continuous variables and percentages for categorical variables, and P values were calculated by a weighted linear regression model and weighted χ 2 tests. Multivariable linear regression models or logistic regression models were performed to evaluate the associations of various hormone preparations with BMD, postmenopausal osteopenia , and postmenopausal osteoporosis . An unadjusted model (model 1) was created first, followed by a minimally adjusted model (model 2) using age and race. Finally, a fully adjusted model (model 3) was calculated using all confounding variables. The smooth curve fitting and generalized additive models were applied to address nonlinear or linear relationships between menopausal duration and lumbar spine BMD, duration of hormone preparation and lumbar spine BMD. When nonlinearity was observed, threshold effect analysis was conducted to calculate the inflection point using a weighted two-piecewise linear regression model. Results with P values <0.05 were considered statistically significant.
RESULTS
Mean lumbar spine BMD in young adult women
To calculate the peak lumbar spine BMD, a total of 3,425 young adult women aged 20 to 29 years were included in the study. There were 1,036 Hispanic women, 754 non-Hispanic Black women, 1,306 non-Hispanic White women, and 329 women with other racea 2 , respectively. Based on the peak values and WHO diagnostic categories, we assessed the osteoporosis status in postmenopausal women .
Characteristics of the study population
Of the 6,035 participants, 1,983 women (32.86%) never used any hormone preparation in their life; thus, they were allocated to the NU group. There were 1,949 women (32.29%) in the COC group, 614 women (10.17%) in the Epills group, 72 women (1.19%) in the EPpills group, 23 women (0.38%) in the Epatches group, and 4 women (0.07%) in the EPpatches group, respectively. Besides, 1,166 women (19.32%) used two kinds of hormone preparations and 224 women (3.71%) used more than three kinds. The ages of participants ranged from 50 to 89 years, menopausal duration ranged from 1 to 65 years, and the duration of hormone preparations ranged from 0.5 (<1 y) to 60 years. Other characteristics of the study population are listed in Table 1 . Considering that the sample size was too small to cause bias (n = 4), the EPpatches group did not undergo subsequent analysis.
TABLE 1 -
Weighted characteristics of study samples
NU (n = 1983)
Hormone preparation types
Hormone preparations use status
COC (n = 1949)
Epills (n = 614)
EPpills (n = 72)
Epatches (n = 23)
EPpatches (n = 4)
2 kinds (n = 1,166)
≥ 3 kinds (n = 224)
CU (n = 743)
PU (n = 1,253)
Age, y
67.62 ± 10.87
58.18 ± 6.56
70.05 ± 8.95
65.69 ± 9.33
66.75 ± 8.78
60.18 ± 8.68
60.26 ± 7.07
59.05 ± 5.89
61.54 ± 8.24
64.22 ± 8.74
Last menstrual age, y
46.13 ± 7.89
46.39 ± 7.09
42.19 ± 9.23
47.84 ± 5.84
41.99 ± 6.27
47.62 ± 3.93
44.26 ± 8.21
45.27 ± 8.18
43.16 ± 8.56
45.03 ± 8.16
Duration of hormone preparations , y
NA
5.53 ± 6.22
12.15 ± 11.76
5.95 ± 6.34
10.08 ± 10.93
4.00 ± 5.76
13.84 ± 10.30
15.19 ± 9.55
18.47 ± 10.71
11.09 ± 9.55
Weight, kg
73.54 ± 19.11
78.51 ± 19.84
72.40 ± 17.12
75.98 ± 20.69
81.05 ± 26.63
80.47 ± 4.24
76.64 ± 18.18
73.87 ± 15.21
73.61 ± 17.62
75.60 ± 17.16
Height, cm
158.63 ± 6.81
161.56 ± 6.81
160.14 ± 6.48
161.35 ± 6.04
162.88 ± 7.51
159.44 ± 3.94
162.33 ± 6.23
163.39 ± 5.82
162.00 ± 6.17
161.81 ± 6.36
BMI, kg/m2
29.16 ± 6.94
30.07 ± 7.31
28.10 ± 6.05
29.15 ± 7.42
30.18 ± 8.35
31.71 ± 2.16
29.06 ± 6.70
27.69 ± 5.63
27.96 ± 6.27
28.84 ± 6.26
Race, %
Hispanic
14.16
10.25
4.65
3.57
2.96
2.37
5.47
3.64
1.95
3.18
Non-Hispanic Black
11.92
14.64
5.35
2.84
2.78
6.93
6.55
5.14
4.11
5.14
Non-Hispanic White
65.74
70.57
87.75
90.32
94.26
12.55
84.56
89.17
5.27
6.11
Other
a
8.19
4.54
2.25
3.28
0.00
78.15
3.41
2.04
88.66
85.57
Lumbar spine BMD, g/cm2
Total
0.94 ± 0.17
0.98 ± 0.17
0.99 ± 0.19
1.00 ± 0.14
1.02 ± 0.15
1.08 ± 0.10
1.00 ± 0.17
0.99 ± 0.16
0.89 ± 0.17
0.99 ± 0.14
Hispanic
0.89 ± 0.16
0.93 ± 0.14
0.94 ± 0.16
0.89 ± 0.19
1.12 ± 0.12
1.16 ± 0.00
0.94 ± 0.16
1.03 ± 0.21
0.98 ± 0.15
0.94 ± 0.18
Non-Hispanic Black
1.02 ± 0.17
1.01 ± 0.19
1.06 ± 0.22
1.01 ± 0.11
1.12 ± 0.08
0.81 ± 0.00
1.05 ± 0.18
1.05 ± 0.17
1.11 ± 0.20
1.04 ± 0.18
Non-Hispanic White
0.93 ± 0.16
0.99 ± 0.17
0.99 ± 0.19
1.01 ± 0.14
1.01 ± 0.15
0.92 ± 0.00
1.00 ± 0.17
0.99 ± 0.16
1.02 ± 0.17
0.97 ± 0.17
Others
a
0.94 ± 0.15
0.98 ± 0.18
0.95 ± 0.12
1.06 ± 0.00
NA
1.13 ± 0.00
0.94 ± 0.16
0.91 ± 0.11
1.02 ± 0.17
0.98 ± 0.17
Osteoporosis status, %
Normal
53.64
66.49
64.78
72.85
74.01
6.94
71.51
70.54
73.82
67.13
Osteopenia
40.79
29.46
30.89
27.08
21.29
0.00
24.72
27.31
23.80
28.23
Osteoporosis
5.57
4.05
4.33
0.07
4.70
93.06
3.77
2.15
2.38
4.64
General health condition, %
Good
69.53
78.24
77.81
87.61
71.86
100.00
81.26
83.96
83.27
80.76
Fair
24.33
17.02
18.65
11.94
16.25
0.00
14.99
13.70
14.19
15.48
Poor
6.15
4.75
3.55
0.46
11.89
0.00
3.76
2.34
2.54
3.76
Smoking, %
Yes
34.80
46.15
42.09
41.16
80.41
21.12
47.41
53.68
54.97
52.01
No
65.20
53.85
57.91
58.84
19.59
78.88
52.59
46.32
45.03
47.99
Drinking, %
Yes
36.45
50.95
40.76
44.37
37.51
7.12
51.86
61.13
53.56
47.32
No
63.55
49.05
59.24
55.63
62.49
92.88
48.14
38.87
46.44
52.68
BMD, bone mineral density ; BMI, body mass index; COC, combined oral contraceptives; CU, current users; Epatches, estrogen-only patches; Epills, estrogen pills; EPpatches, estrogen/progestin combo patches; EPpills, estrogen/progestin combo pills; NU, nonusers; PU, past users.
a
Associations between hormone preparations and lumbar spine BMD
Multivariable linear regression models were performed to examine the association between hormone preparations and lumbar spine BMD. The regression coefficients (β ) and 95% confidence intervals (CI) were estimated in three models. After adjusting for all covariates (model 3), this positive correlation existed in the COC group (β = 0.04; 95% CI, 0.02-0.05; P < 0.0001), Epills group (β = 0.05; 95% CI, 0.03-0.08; P < 0.0001), EPpills group (β = 0.07; 95% CI, 0.02-0.12; P = 0.0040), Epatches group (β = 0.14; 95% CI, 0.04-0.23; P = 0.0072), two kinds group (β = 0.05; 95% CI, 0.03-0.07; P < 0.0001), and at least three kinds group (β = 0.04; 95% CI, 0.01-0.07; P = 0.0039). Besides, both the CU and PU groups were significantly associated with increased lumbar spine BMD, but the lumbar spine BMD in the CU group (β = 0.10; 95% CI, 0.08-0.12; P < 0.0001) was higher than that in the PU group (β = 0.04; 95% CI, 0.02-0.05; P < 0.0001). These results are presented in Table 2 .
TABLE 2 -
Association between hormone preparations and lumbar spine BMD (g/cm 2 )
Model 1: β (95% CI), P value
Model 2: β (95% CI), P value
Model 3: β (95% CI), P value
NU group
Reference
Reference
Reference
Hormone preparations group0.05 (0.04-0.06), <0.0001
0.04 (0.03-0.05), <0.0001
0.05 (0.03-0.06), <0.0001
Hormone preparation types
COC
0.04 (0.03-0.06), <0.0001
0.03 (0.02-0.04), <0.0001
0.04 (0.02-0.05), <0.0001
Epills
0.05 (0.03-0.07), <0.0001
0.05 (0.03-0.07), <0.0001
0.05 (0.03-0.08), <0.0001
EPpills
0.06 (0.03-0.10), 0.0011
0.06 (0.02-0.10), 0.0022
0.07 (0.02-0.12), 0.0040
Epatches
0.08 (0.01-0.15), 0.0186
0.08 (0.01-0.14), 0.0242
0.14 (0.04-0.23), 0.0072
2 kinds
0.06 (0.04-0.07), <0.0001
0.04 (0.03-0.06), <0.0001
0.05 (0.03-0.07), <0.0001
≥3 kinds
0.05 (0.03-0.07), <0.0001
0.04 (0.02-0.06), 0.0003
0.04 (0.01-0.07), 0.0039
Hormone preparation use status
CU
0.08 (0.07-0.10), <0.0001
0.08 (0.06-0.09), <0.0001
0.10 (0.08-0.12), <0.0001
PU
0.04 (0.03-0.05), <0.0001
0.03 (0.02-0.05), <0.0001
0.04 (0.02-0.05), <0.0001
No covariate was adjusted in model 1. Model 2 indicated that analysis was adjusted for age and race. Model 3 indicated that analysis was adjusted for age, race, last menstrual age, BMI, health condition, drinking, and smoking history.
CI, confidence interval; COC, combined oral contraceptives; CU, current users; Epatches, estrogen-only patches; Epills, estrogen pills; EPpills, estrogen/progestin combo pills; NU, non-users; PU, past users.
Associations between hormone preparations and postmenopausal osteopenia
We classified all participants into two subgroups: one with osteopenia or osteoporosis and another subgroup with normal lumbar spine BMD. As shown in Table 3 , there were significantly decreased odds ratios (OR) of postmenopausal osteopenia for the participants in most hormone preparation groups compared with the NU group after adjusting for all covariates (COC group: OR, 0.71 [95% CI, 0.59-0.86; P = 0.0004]; Epills group: OR, 0.55 [95% CI, 0.42-0.72; P < 0.0001]; EPpills group: OR, 0.28 [95% CI, 0.13-0.62; P = 0.0015]; two kinds group: OR, 0.50 [95% CI, 0.41-0.62; P < 0.0001]; at least three kinds group: OR, 0.60 [95% CI, 0.41-0.86; P = 0.0061]). Although model 1 and model 2 showed that there was a significant difference between the NU and Epatches groups in postmenopausal osteopenia , no significant difference existed in model 3 (OR, 0.30; 95% CI, 0.06-1.44; P = 0.1319). The OR values were decreased in both the CU (OR, 0.34; 95% CI, 0.26-0.45; P < 0.0001) and the PU groups (OR, 0.57; 95% CI, 0.46-0.69; P < 0.0001).
TABLE 3 -
Association between hormone preparations and postmenopausal osteopenia (n = 2,240)
Model 1: OR (95% CI), P value
Model 2: OR (95% CI), P value
Model 3: OR (95% CI), P value
NU group
Reference
Reference
Reference
Hormone preparations group0.60 (0.54-0.67), <0.0001
0.66 (0.59-0.75), <0.0001
0.60 (0.51-0.70), <0.0001
Hormone preparation types
COC
0.68 (0.60-0.77), <0.0001
0.79 (0.69-0.91), 0.0014
0.71 (0.59-0.86), 0.0004
Epills
0.66 (0.54-0.79), <0.0001
0.63 (0.52-0.77), <0.0001
0.55 (0.42-0.72), <0.0001
EPpills
0.43 (0.26-0.74), 0.0021
0.43 (0.25-0.73), 0.0019
0.28 (0.13-0.62), 0.0015
Epatches
0.43 (0.17-1.09), 0.0747
0.42 (0.17-1.08), 0.0728
0.30 (0.06-1.44), 0.1319
2 kinds
0.49 (0.42-0.57), <0.0001
0.54 (0.46-0.64), <0.0001
0.50 (0.41-0.62), <0.0001
≥3 kinds
0.52 (0.38-0.70), <0.0001
0.58 (0.43-0.79), 0.0005
0.60 (0.41-0.86), 0.0061
Hormone preparation use status
CU
0.42 (0.35-0.50), <0.0001
0.43 (0.35-0.53), <0.0001
0.34 (0.26-0.45), <0.0001
PU
0.62 (0.53-0.72), <0.0001
0.63 (0.54-0.73), <0.0001
0.57 (0.46-0.69), <0.0001
No covariate was adjusted in model 1. Model 2 indicated that analysis was adjusted for age and race. Model 3 indicated that analysis was adjusted for age, race, last menstrual age, BMI, health condition, drinking, and smoking history.
CI, confidence interval; COC, combined oral contraceptives; CU, current users; Epatches, estrogen-only patches; Epills, estrogen pills; EPpills, estrogen/progestin combo pills; NU, non-users; OR, odds ratio; PU, past users.
Associations between hormone preparations and postmenopausal osteoporosis
We further analyzed the relationship between the risk of postmenopausal osteoporosis and hormone preparations . Thus, we reclassified the participants into two subgroups: one with osteoporosis and another subgroup with normal lumbar spine BMD or osteopenia . After adjusting for all covariates, we found that there was no significant association between hormone preparations and postmenopausal osteoporosis , because the P values in the sequence of the NU group, COC group, Epills group, EPpills group, Epatches group, two kinds group, and at least three kinds group were 0.2882, 0.4030, 0.9700, 0.9854, 0.2442, and 0.7786, respectively. There was no significant association between CU (P = 0.1153) or PU (P = 0.4513) and postmenopausal osteoporosis . These results are shown in Table 4 .
TABLE 4 -
Association between various hormone preparations and postmenopausal osteoporosis (n = 306)
Model 1: OR (95% CI), P value
Model 2: OR (95% CI), P value
Model 3: OR (95% CI), P value
Control group
Reference
Reference
Reference
Hormone preparations group0.64 (0.51-0.81), 0.0002
0.84 (0.65-1.09), 0.1862
1.08 (0.75-1.56), 0.6894
Hormone preparation types
COC
0.67 (0.51-0.88), 0.0045
1.04 (0.76-1.43), 0.7884
1.27 (0.82-1.98), 0.2882
Epills
0.63 (0.41-0.96), 0.0326
0.59 (0.38-0.92), 0.0192
0.78 (0.44-1.39), 0.4030
EPpills
0.20 (0.03-1.44), 0.1102
0.21 (0.03-1.53), 0.1243
0.00 (0.00-Inf.), 0.9700
Epatches
0.64 (0.09-4.80), 0.6666
0.66 (0.09-5.01), 0.6917
0.00 (0.00-Inf), 0.9854
2 kinds
0.66 (0.47-0.92), 0.0135
0.93 (0.65-1.34), 0.7059
1.32 (0.83-2.09), 0.2442
≥3 kinds
0.46 (0.21-0.99), 0.0466
0.70 (0.32-1.54), 0.3727
0.87 (0.33-2.29), 0.7786
Hormone preparation use status
CU
0.33 (0.20-0.55), <0.0001
0.39 (0.23-0.66), 0.0005
0.58 (0.30-1.14), 0.1153
PU
0.82 (0.61-1.11), 0.2064
0.92 (0.67-1.26), 0.5837
1.18 (0.77-1.79), 0.4513
No covariate was adjusted in model 1. Model 2 indicated that analysis was adjusted for age and race. Model 3 indicated that analysis was adjusted for age, race, last menstrual age, BMI, health condition, drinking, and smoking history.
CI, confidence interval; COC, combined oral contraceptives; CU, current users; Epatches, estrogen-only patches; Epills, estrogen pills; EPpills, estrogen/progestin combo pills; Inf., infinity; NU, non-users; OR, odds ratio; PU, past users.
Association between menopausal duration and lumbar spine BMD
The associations between menopausal duration and lumbar spine BMD were confirmed by weighted generalized additive models and smooth curve fittings, and nonlinear relationship was noticed (Fig. 2 ). Stratified analysis was further carried out according to the use history of hormone preparations . The results demonstrated linear relationships between menopausal duration and lumbar spine BMD in the hormone preparation group, and a nonlinear relationship in the NU group with the infection point identified at 10 and 39 years. Specifically, in the NU group, lumbar spine BMD decreased by 0.0053 g/cm2 per year (P = 0.0166) for menopausal duration <10 years and decreased by −0.0061 g/cm2 per year (P = 0.0175) for menopausal duration >39 years, but there was no significant difference between 10 and 39 years (P = 0.6020; Table 5 ). In the hormone group, lumbar spine BMD decreases linearly with menopausal duration, but the absolute value was much higher than that of the NU group.
FIG. 2: Association between menopausal duration and lumbar spine BMD. (A ) Each black point represents a sample. (B ) The red line represents the smooth curve fit between menopausal duration and lumbar spine BMD. Blue bands represent the 95% CI from the fit. (C ) Stratified by the use history of hormone preparations , race was adjusted. BMD, bone mineral density ; CI, confidence interval.
TABLE 5 -
Threshold effect analysis of age and spinal BMD (g/cm 2 ) in nonhormone group using the two-piecewise linear regression model
Inflection points
Adjusted β (95% CI), P value
Log-likelihood ratio
<10 y
−0.0053 (−0.0096 to −0.0010), 0.0166
<0.001
10-39y
0.0003 (−0.0008 to 0.0013), 0.6020
>39y
−0.0061 (−0.0111 to −0.0011), 0.0175
Association between duration of hormone preparations and lumbar spine BMD
Similarly, we used weighted generalized additive models and smooth curve fittings to explore the associations between the duration of hormone preparations and lumbar spine BMD, and a linear relationship was observed (Fig. 3 ). Besides, after stratification based on the type of hormone preparations , a linear relationship still existed.
FIG. 3: Association between the duration of hormone preparations and lumbar spine BMD. (A ) Each black point represents a sample. (B ) The red line represents the smooth curve fit between the duration of hormone preparations and lumbar spine BMD. Blue bands represent the 95% CI from the fit. (C ) Stratified by various hormone preparations , race was adjusted. BMD, bone mineral density ; CI, confidence interval.
DISCUSSION
Osteoporosis is a systemic skeletal disease that can occur at all ages and in all sexes,14 15 postmenopausal women , however, HT may be a better choice. This therapy not only can relieve climacteric symptoms and improve sleep, aches and pains, and sexual function,16,17 18–22 23 postmenopausal women were enrolled, hormone preparations were divided into six groups, and the longest duration of hormone preparations was 60 years. From our perspective, the current study had the large sample size to explore the associations of various hormone preparations with BMD, postmenopausal osteopenia , and postmenopausal osteoporosis . In addition, the withdrawal effect of HT was also evaluated.
A COC is also made up of estrogen and progestin; however, whether it possesses positive influences on bone remains a considerable controversy. Several researchers concluded that exposure to COC may preserve or even increase BMD,24–26 27–29 30–32 osteoporosis among different groups in this study was calculated based on the peak lumbar spine BMD by race. The incidence of the NU group was 5.57%, and the incidence rates in the sequence of the COC group, Epills group, EPpills group, Epatches group, two kinds group, at least three kinds group were 4.05%, 4.33%, 0.07%, 4.70%, 3.77%, and 2.15%. As shown in Table 4 , the fully adjusted model, however, suggested that there was no statistical significance for each hormone preparation group compared with the NU group in the incidence of osteoporosis (all P > 0.05), which was different from conventional wisdom. In fact, some scholars have suggested that the concept of diagnosing osteoporosis should be discarded, because it sometimes results in neglecting the management and treatment of individuals who do not meet the diagnostic criteria.15 2 (all P < 0.05; Table 2 ), and hormonal preparations except Epatches were protective factors against osteopenia (all OR < 1 and all P < 0.05; Table 3 ). Regrettably, the NCHS did not investigate hormone types and doses used by participants, so we cannot directly compare the effects of different groups and draw conclusions about which group is the best.
Although HT has many benefits for postmenopausal women , there are also potential adverse effects such as venous thromboembolism,33 34 35 osteopenia was also higher, bone protection still existed in the PU group compared with the NU group. Unfortunately, the discontinued durations of HT were unknown, so it was not clear how long the protective effect lasted. Sirola et al36 postmenopausal women without HT from 3.8 to 8.0 years, and they noticed that BMD is rapidly lost in the first 200 months and that the rate of loss is diminished in the next 100 months. Zhai et al37 Fig. 2 A), thus filling the gap of association between longer menopausal duration and BMD. The loss of bone 39 years after menopause was 0.0061 g/cm2 per year (P = 0.0175), which was more rapid than initial menopause (adjusted β = 0.0053 g/cm2 , P = 0.0047). Thus, women who have an earlier menopause, especially with premature ovarian failure, should pay more attention to the prevention of osteoporosis .
Despite some strengths of the study, it is still essential to recognize its limitations. First, it was a cross-sectional study, with only participants' BMD available at that time; therefore, trends in BMD before and after the use of hormonal preparations could not be assessed. Further large sample prospective studies are still needed to identify the effects of hormone preparations on BMD. Second, our study was conducted in the United States, so the results may not be applied in other countries. Third, some self-reported results may be relatively inaccurate because of inevitable biases of recall and self-report bias. Fourth, although we adjusted for some confounding factors, some potentially unknown confounding factors may affect our results. Fifth, fracture is a main endpoint of osteoporosis , but we did not look at it because of the lack of data. Sixth, withdrawal time varied among the participants in the PU group, and subgroup analysis based on time since discontinuation would further reveal the duration of the withdrawal effect, but it could not be conducted in the study because of lack of data.
CONCLUSIONS
Our study indicated that various hormone preparations increase lumbar spine BMD in postmenopausal women and have a protective effect against osteopenia , and these impacts persisted after HT was discontinued. Hormone preparations , however, were not associated with osteoporosis prevalence. Hormonal preparations altered the natural history of the three-stage decline in postmenopausal lumbar spine BMD to a linear decline, but the absolute value was greater.
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