Abstract
Context
Previous studies of menopausal age and length of reproductive life on bone are limited by retrospective reproductive histories, being cross sectional, or lacking gold standard bone technologies, or information on hormone replacement therapy (HRT) or surgical treatment.
Objective
To investigate age at menopause, length of reproductive life and HRT use in relation to volumetric and areal bone mineral density (vBMD, aBMD), bone size and strength in women aged 60-64.
Design
A birth cohort study followed for 64 years with prospective measures of age at menarche and menopause and monthly HRT histories.
Setting
England, Scotland, Wales
Participants
848 women with known type of menopause and bone measures at 60-64 years
Main outcome measures
Peripheral quantitative computed tomography (pQCT) measurements of the distal radius total and trabecular vBMD; diaphyseal radius total and medullary cross sectional area, cortical vBMD and polar strength strain index (SSI); dual energy x-ray absorptiometry (DXA) measurments of aBMD at the lumbar spine and total hip.
Results
A ten year increase in age at natural (but not surgical) menopause was associated with 8.2% (95% CI: 1.3,15.1%, p=.02) greater trabecular vBMD and a 6.0% (95% CI 0.51,11.5%, p=.03) greater total vBMD; findings were similar for length of reproductive life. A ten year difference in HRT use was associated with a 6.0% (95% CI 2.6%,9.3%, p<.001) greater polar SSI and a 0.9% (95% CI 0.4%, 1.5%, p=.001) greater cortical vBMD. These estimates changed little on adjustment. Estimates for aBMD were consistent with those for pQCT.
Conclusions
The positive effects on trabecular vBMD of later natural menopause and longer reproductive life persisted into early old age. HRT use was associated with greater radius cortical vBMD and polar SSI, and spine aBMD.
Keywords: bone, menopause, reproductive life, HRT, birth cohort
Introduction
Hip fractures are an important cause of morbidity and mortality in older women, one of the main risk factors for which is low bone mineral density (BMD).(1) Over the last 25 years, earlier timing of natural menopause has been related to lower BMD or subsequent fracture in a number of studies (for example(2–6)). Some studies have investigated whether the length of reproductive life,(2;7;8) or oophorectomy and/or hysterectomy(9–12) are associated with lower BMD or fracture and the findings have been somewhat less consistent. In the UK Million Women Study post-menopausal women had double the risk of hip fracture compared to pre-menopausal of the same age; however in older women, current age had a much greater predictive value than age at menopause.(5)
It is essential to take account of hormone replacement therapy (HRT), as patterns of use vary considerably by type and timing of menopause, and HRT is associated with bone health. The Women’s Health Initiative trial demonstrated that estrogen plus progestin for healthy women with an intact uterus, and estrogen alone for those with a prior hysterectomy, increased areal (a) BMD and reduced fracture risk.(13;14) However. protection of aBMD and hip fracture starts soon after initiating HRT but does not continue after HRT ceases. (15–17) In a study of monozygotic twins comparing pairs where one twin took HRT and the other did not, HRT was associated with greater volumetric (v)BMD and bone strength at both distal and diaphyseal bone sites.(18)
Many previous studies rely on long-term recall of age at menopause, are confounded by age, are cross sectional or have short follow-up, rely solely on DXA or older quantitative bone technologies, or lack information on HRT use and other potentially important confounders or modifiers such as surgical treatment. It also remains unclear whether associations between age at menopause and bone health persist once all women are post-menopausal.
The Medical Research Council National Survey of Health and Development (NSHD), a British birth cohort study with frequent data collections from birth, fills these research gaps because it has prospectively ascertained information on length of reproductive life and type and timing of menopause (19;20) and HRT use,(21) on a large sample of postmenopausal women of the same age with detailed characterisation of bone health from DXA and pQCT scans undertaken ten years after the average age of natural menopause. Use of pQCT allows separate measurement of trabecular and cortical bone. We investigate timing of the menopause transition, length of reproductive life, and patterns of HRT use in relation to pQCT- and DXA-derived bone outcomes, taking account of current body size, smoking and socioeconomic circumstances. We hypothesised that earlier age at natural menopause and a shorter length of reproductive life would be negatively associated with trabecular vBMD, whereas HRT use would also be associated with greater cortical bone and bone strength.(18;22)
Materials and Methods
Sample
The NSHD is a prospective study of 2547 women and 2815 men followed up 24 times since their birth in a week in March 1946,(23) with a further nine postal questionnaires to women during midlife.(19) At age 60-64 years, 2856 study members (of whom 1460 were women) still alive and living at a known address in England, Scotland or Wales were invited to one of six clinical research facilities (CRFs) across the country; the remaining women were not invited because they had already died (n=312), were living abroad (n=258), had previously withdrawn from the study (n=284) or had been lost to follow-up (n=233). Of the women invited, 1162 (79.6%) were assessed: 877 women had a clinic visit, with the remaining 285 women opting for a home visit.(24) The study received Multi-Centre Research Ethics Committee approval and informed consent was provided by particpants.
Of those attending a CRF, 866 women underwent a DXA scan (QDR 4500 Discovery (Hologic Inc, Bedford, MA)) of whom 697 also had a pQCT scan (XCT 2000 (Stratec, Pforzheim, Germany)). Details of scan acquisition, data management, cross-calibration and QA/QC have been described previously.(25) Repeat precision was determined in one centre and was <1% for DXA measurements and for pQCT ranged between 1-3%. The bone outcomes were pQCT derived measures at the radius distal 4% site of total and trabecular vBMD, and at the 50% site of diaphysis and medullary cross sectional area (CSA), cortical vBMD and polar strength strain index (SSI) an estimate of torsional bone strength,(26) and DXA derived measurements of aBMD for lumbar spine (L1-L4) and total hip.
Timing of menopause
Information on menstrual irregularity, month and year of last menstrual cycle or any operation to remove the uterus or ovaries, and monthly HRT use was obtained from annual postal questionnaires between ages 47 and 54 years (inclusive) with an additional one at 57 years, and from face to face interviews with trained research nurses at 43, 53, and 60-64 years. Months since birth until periods ceased naturally or because of hysterectomy and bilateral oophorectomy (n=76), bilateral oophorectomy only (n=2), hysterectomy and unilateral oophorectomy (n=21), hysterectomy only (n=96) or for other reasons, were obtained. It was not possible to assign a date of menopause to women who started HRT before the menopause and had not come off HRT for at least a year when giving responses about period regularity and the timing of the last period.
Age at menarche and length of reproductive life
Age at menarche was obtained from reports of the mother at a medical examination and interview by a school doctor when the study member was aged ~14.5 years. For the 7% of women who had not reached menarche by the time of this examination, retrospective reports obtained from the postal questionnaire at age 48 were used instead. Length of reproductive life was derived by taking age at menarche from age at natural menopause or hysterectomy (all in months since birth).
HRT use
From the the dates of starting and stopping HRT, we derived ‘ever use’ of HRT (yes v. no), length of HRT use in years, and time since last use (within the last year, 1-5 years ago, more than 5 years ago). Women were included who provided information on HRT use for at least five of the ten possible updates.
Other covariables
Height (cm) and weight (kg) were measured according to a standard protocol at the time of the bone scans and were standardized to give a mean of 0 and a SD of 1. Smoking at age 60-64years (yes/no) and main occupation (manual vs. non-manual) according to the Registrar General’s social class classification, were also included as covariates.
Analysis
Stata v12.0 was used for all analyses. Regression models used natural logarithms of all bone variables for comparative purposes.(27) The coefficients from these models are presented as the mean percentage difference in the bone parameter at 60-64 years between groups for categorical variables or per unit change for continuous variables.
We first compared the mean and standard deviations of the bone outcomes by all of the reproductive and HRT indicators in the maximum available samples. We then fitted three sets of regression models. All were first run unadjusted and then adjusted for height and weight and then for smoking and adult occupation. First, for women with a known age at period cessation, nested regression models including type of period cessation, time since period cessation and the interaction between the two. This allowed us to obtain separate estimates for the percentage difference in the bone outcomes for a ten year difference in age at natural menopause or age at hysterectomy. We then used similar models to estimate a ten-year difference in length of reproductive life for the natural and surgical menopause groups. Second, for women with a known history of HRT, we obtained estimates for a ten-year difference in length of HRT use, and then repeated this analysis for age since last use. Third, for women with known age at period cessation and history of HRT, we repeated the first set of regression models additionally adjusted for HRT use. Sensitivity analyses were undertaken to see whether any associations between hysterectomy status and bone outcomes differed by oophorectomy status.
Results
The initial sample comprised 848 women for whom type of menopause was known and who had at least one measure from a DXA or pQCT scan at 60-64 years (Table 1). Of these, 653 women (77%) had a natural menopause and 195 (23%) had a hysterectomy and/or bilateral oophorectomy (henceforth described as hysterectomy) before the menopause. Age at period cessation was known for 709 women; dates were unknown for 134 women because of the timing of their HRT use, and for 5 women who had a hysterectomy. Women who had a hysterectomy were shorter, heavier and had greater vBMD, aBMD and SSI and strength at 60-64 years than women who had a natural menopause. The mean age of period cessation was 52.0 years for women who had a natural menopause and 44 years 6 months for women who had a hysterectomy. Mean age at menarche, mean length of reproductive life, and HRT use differed by type of menopause.
Table 1.
Characteristics of the sample of 848 women in the MRC National Survey of Health and Development with at least one bone measure and known type of menopause
| Total sample | Natural menopause | Hysterectomy and/or bilateral oophorectomy | p-value | ||||
|---|---|---|---|---|---|---|---|
| MAXIMUM SAMPLE | 1848 | 653 | 195 | ||||
| pQCT measures | No | Mean (SD) | No | Mean (SD) | No | Mean (SD) | |
| Cortical sites: 50% radius | |||||||
| Diaphysis CSA (mm2) | 681 | 112.3 (15.8) | 523 | 112.1 (15.5) | 158 | 113.3 (16.8) | .4 |
| Medullary CSA (mm2) | 681 | 35.2 (12.5) | 523 | 35.6 (12.5) | 158 | 33.8 (12.3) | .1 |
| Polar stress strain index (mm3) | 682 | 210.6 (43.1) | 524 | 208.6 (42.2) | 158 | 217.2 (45.4) | .03 |
| Trabecular sites: 4% distal radius | |||||||
| Distal CSA (mm2) | 674 | 132.7 (23.9) | 518 | 132.7 (24.5) | 156 | 132.7 (22.0) | >.9 |
| 50% radius | |||||||
| Cortical vBMD (mg/cm3) | 682 | 1148.2 (39.4) | 524 | 1146.8 (40.2) | 158 | 1152.8 (36.3) | .1 |
| Distal radius (4%) | |||||||
| Trabecular vBMD (mg/cm3) | 673 | 171.7 (42.2) | 517 | 169.7 (42.3) | 156 | 178.3 (41.0) | .02 |
| Total vBMD (mg/cm3) | 674 | 329.3 (70.4) | 518 | 325.5 (70.1) | 156 | 342.0 (69.9) | .01 |
| DXA measures | |||||||
| Spine L1-L4 aBMD (g/cm2) | 843 | .944 (.165) | 649 | .934 (.164) | 194 | .976 (.163) | .002 |
| Total hip aBMD (g/cm2) | 839 | .869 (.131) | 645 | .859 (.132) | 194 | .902 (.123) | <.001 |
| Current body size | |||||||
| Height (m) | 848 | 1.621 (.058) | 653 | 1.624 (.058) | 195 | 1.613 (.057) | .03 |
| Weight (kg) | 848 | 72.4 (14.1) | 653 | 71.5 (14.1) | 195 | 75.4 (14.0) | .001 |
| Reproductive measures | |||||||
| Age at period cessation | 709 | 50y 0mth (5y 9mths) | 519 | 52y 0mth (3y 9 mth) | 190 | 44y 6mth (6y 6mth) | <.001 |
| Age at menarche | 688 | 13y 0 mth (1 y 7 mth) | 529 | 13y 1 mth (1y 3mth) | 159 | 12y 10mth (1y 4mth) | .04 |
| Length of reproductive life | 573 | 37y 0 mths (5y 8mth) | 418 | 38y 10mths (3y 11mth) | 155 | 32y 0mth (6y 5mth) | <.001 |
| HRT use | |||||||
| Ever using HRT | <.001 | ||||||
| No | 277 | 36.40 | 247 | 42.22 | 30 | 17.05 | |
| Yes | 484 | 63.60 | 338 | 57.78 | 146 | 82.95 | |
| Unknown | 87 | 68 | 19 | ||||
| Last use of HRT | .5 | ||||||
| In the last year | 63 | 13.24 | 40 | 12.05 | 23 | 15.97 | |
| 1-5 years ago | 72 | 15.13 | 50 | 15.06 | 22 | 15.28 | |
| More than 5 years ago | 341 | 71.64 | 242 | 72.89 | 99 | 68.75 | |
| Taken HRT but last use unknown | 8 | 6 | 2 | ||||
| Total length of HRT use (years) | <.001 | ||||||
| Less than one year | 50 | 10.57 | 38 | 11.48 | 12 | 8.45 | |
| 1-2 | 79 | 16.70 | 71 | 21.45 | 8 | 5.63 | |
| 3-4 | 78 | 16.49 | 54 | 16.31 | 24 | 16.90 | |
| 5-6 | 67 | 14.16 | 39 | 11.78 | 28 | 19.72 | |
| 7-8 | 67 | 14.16 | 42 | 12.69 | 25 | 17.61 | |
| 9-10 | 53 | 11.21 | 42 | 12.69 | 11 | 7.75 | |
| 11-12 | 35 | 7.40 | 27 | 8.16 | 8 | 5.63 | |
| 13 or more | 44 | 9.30 | 18 | 5.44 | 26 | 18.31 | |
| Unknown length | 11 | 7 | 4 | ||||
| Current smoker | |||||||
| No | 760 | 90.15 | 585 | 90.14 | 175 | 90.21 | >.9 |
| Yes | 83 | 9.85 | 64 | 9.86 | 19 | 9.79 | |
| Unknown | 5 | 4 | 1 | ||||
| Adult social class | |||||||
| Non-manual | 680 | 80.28 | 534 | 81.90 | 146 | 74.87 | .03 |
| Manual | 167 | 19.72 | 118 | 18.10 | 49 | 25.13 | |
| Unknown | 1 | 1 | 0 | ||||
Sample excludes 13 women whose periods ceased because of medical treatment (e.g. chemotherapy) and 5 women who had been insufficiently followed up to determine menopause type
Unadjusted mean differences in bone size, strength and BMD by age at menopause and menarche, length of reproductive life and HRT use
Neither timing of natural menopause, age at menarche, nor length of natural reproductive life were associated with CSA (diaphyseal or medullary) or SSI (Table 2). Women who had an earlier natural menopause or a later age at menarche,had lower mean values of trabecular vBMD, total vBMD, and spine and hip vBMD, but not cortical vBMD. Those with a shorter reproductive life had lower mean values of trabecular vBMD, and spine and hip aBMD, but not cortical or total vBMD. Age at hysterectomy was not associated with BMD, size or SSI.
Table 2.
Mean and standard deviation (SD) for pQCT-derived outcomes at 60-64 years by menopausal characteristics.
| Diaphysis CSA mm2 | Medullary CSA mm2 | Total vBMD mg/cm3 | Trabecular vBMD mg/cm3 | Cortical vBMD mg/cm3 | Polar SSI mm3 | Spine L1-L4 aBMD g/cm3 | Hip aBMD g/cm3 | |
|---|---|---|---|---|---|---|---|---|
| Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | Mean (SD) | |
| Age at natural menopause (years) | ||||||||
| <45 | 111.0 (19.6) | 36.6 (13.2) | 298.2 (73.2) | 146.5 (36.2) | 1139.9 (39.7) | 204.7 (48.4) | 0.85 (0.1) | 0.83 (0.1) |
| 45-49 | 109.7 (16.0) | 37.1 (14.8) | 314.5 (72.4) | 167.0 (48.8) | 1143.3 (44.1) | 199.2 (38.4) | 0.89 (0.2) | 0.83 (0.1) |
| 50-52 | 111.9 (14.5) | 34.9 (12.1) | 320.1 (64.5) | 165.8 (40.3) | 1149.6 (38.3) | 211.8 (43.9) | 0.92 (0.2) | 0.86 (0.1) |
| 53-55 | 112.2 (16.3) | 36.2 (13.4) | 331.7 (75.9) | 171.5 (44.1) | 1144.1 (41.8) | 204.8 (43.2) | 0.94 (0.2) | 0.88 (0.1) |
| 56-62 | 112.6 (17) | 33.7 (11.1) | 321.3 (54.8) | 171.9 (35.4) | 1149.9 (36.9) | 211.9 (45.8) | 0.98 (0.2) | 0.89 (0.1) |
| p-value for trend* | .2 | .3 | .014 | .004 | .3 | .2 | <.001 | <.001 |
| Age at hysterectomy (years) | ||||||||
| <40 | 115.3 (18) | 33.5 (13.1) | 337.1 (66.8) | 178.1 (37.1) | 1150.6 (28.8) | 224.7 (47.4) | 0.96 (0.2) | 0.9 (0.1) |
| 40-44 | 113.8 (17.8) | 35.6 (12.8) | 343.9 (60.6) | 175.9 (44.3) | 1152.4 (36.9) | 216.8 (47.3) | 0.95 (0.2) | 0.9 (0.1) |
| 45-49 | 112.1 (15.6) | 32.1 (12.6) | 341.2 (82.2) | 179.8 (44.9) | 1160 (34.1) | 214 (41.5) | 0.99 (0.2) | 0.9 (0.1) |
| ≥50 | 111.9 (16.4) | 34.5 (11.1) | 347.8 (66.6) | 179.7 (37.8) | 1144.4 (43.1) | 213.5 (47.2) | 0.99 (0.2) | 0.89 (0.1) |
| p-value for trend* | .5 | .7 | .7 | >.9 | .6 | .3 | .3 | >.9 |
| Age at menarche (years) | ||||||||
| 9-10 | 111.2 (12.5) | 31.4 (9.01) | 349.3 (84) | 179.9 (40.1) | 1158.5 (32.5) | 213.2 (34.5) | 0.98 (0.1) | 0.9 (0.1) |
| 11 | 113 (17.1) | 34 (12.7) | 339.2 (69.2) | 176.7 (40.6) | 1145.7 (44.2) | 217.2 (45.1) | 0.98 (0.2) | 0.9 (0.1) |
| 12 | 114.4 (16) | 36.5 (13.2) | 340.5 (74.6) | 178.5 (46.1) | 1145.9 (39.8) | 213.1 (45) | 0.95 (0.2) | 0.87 (0.1) |
| 13 | 111.5 (16) | 35.7 (12.3) | 320.9 (69.2) | 169 (41.1) | 1148.3 (40) | 207.9 (42.5) | 0.95 (0.2) | 0.86 (0.1) |
| 14 | 111.5 (14.4) | 34.7 (11.9) | 318.9 (63.8) | 168.4 (34.9) | 1151.4 (33) | 207.5 (39) | 0.92 (0.2) | 0.85 (0.1) |
| 15-19 | 111.9 (17.5) | 34.7 (12.8) | 336.8 (68.5) | 157.7 (39.8) | 1150.9 (39.7) | 210.9 (38.5) | 0.91 (0.2) | 0.84 (0.1) |
| p-value for trend* | .4 | .7 | .03 | .01 | .9 | .2 | .004 | <.001 |
| Length of natural reproductive life | ||||||||
| ≤35 | 109.9 (18.7) | 37.3 (16.1) | 305.1 (70.3) | 155.5 (41.9) | 1140.9 (44.2) | 199.3 (41.3) | 0.86 (0.1) | 0.8 (0.1) |
| 36-37 | 109.1 (14) | 34.7 (11.2) | 324.2 (72.1) | 168.6 (46.9) | 1152.5 (40.7) | 204.6 (41.4) | 0.91 (0.2) | 0.84 (0.1) |
| 38-39 | 112 (15.4) | 35.5 (11) | 323.9 (65.6) | 173.4 (38.1) | 1151.4 (32.5) | 209.7 (46.8) | 0.91 (0.2) | 0.85 (0.1) |
| 40-41 | 112.3 (15.9) | 35.9 (14.3) | 339.3 (69.1) | 176.3 (41.1) | 1142.9 (44.7) | 207.1 (39.3) | 0.97 (0.2) | 0.9 (0.1) |
| 42-43 | 116.3 (17.6) | 35.9 (11.1) | 319.7 (67.8) | 165.1 (38.6) | 1145.4 (31.6) | 220.1 (47) | 0.95 (0.2) | 0.87 (0.1) |
| ≥44 | 109.6 (12.5) | 34.5 (8.8) | 316.6 (63.5) | 168.8 (38.4) | 1148.2 (39.3) | 198 (34.6) | 0.98 (0.2) | 0.88 (0.1) |
| p-value for trend* | .07 | .9 | .1 | .02 | .4 | .07 | <.001 | <.001 |
| Length of reproductive life (ceased surgically) | ||||||||
| ≤35 | 115.1 (16.4) | 34.3 (12.5) | 347 (70.3) | 180.4 (44.9) | 1154.6 (33.7) | 221.4 (44.0) | 0.97 (0.2) | 0.90 (0.1) |
| 36-37 | 115 (17.5) | 38.4 (9.3) | 318.4 (80.9) | 179.6 (33.6) | 1135.8 (35) | 214.6 (53.8) | 0.99 (0.2) | 0.90 (0.1) |
| 38-39 | 109.5 (14.2) | 32.2 (11.5) | 344.2 (66.3) | 177.7 (45.3) | 1151.8 (40.2) | 213.7 (39.9) | 0.95 (0.2) | 0.86 (0.1) |
| 40-41 | 102.6 (7.2) | 24.5 (5) | 405.8 (67.2) | 204.6 (13.4) | 1192.8 (20.9) | 184.0 (7.9) | 1.09 (0.01) | 1.01 (0.1) |
| 42-43 | 104.9 (17.8) | 27.3 (8.3) | 391.3 (46.6) | 192.7 (21.5) | 1169.6 (27.4) | 198.4 (43.9) | 1.1 (0.2) | 0.90 (0.1) |
| ≥44 | 122.7 (12.2) | 42.9 (16.3) | 317.1 (89.3) | 159.1 (57.8) | 1108.9 (77.5) | 235.2 (49.7) | 0.92 (0.2) | 0.88 (0.1) |
| p-value for trend | .01 | .2 | .7 | .7 | .9 | .02 | >.9 | .7 |
| Length of HRT use (years) | ||||||||
| ≥13 | 118.6 (17) | 35.4 (13.9) | 348.4 (66.4) | 174.5 (37.8) | 1165.2 (38.7) | 236.6 (49.1) | 1.01 (0.2) | 0.90 (0.1) |
| 11-12 | 111.9 (12.3) | 32.7 (8.17) | 337.6 (66.8) | 179.2 (35.7) | 1161.5 (32.1) | 215.1 (33.5) | 0.94 (0.1) | 0.88 (0.1) |
| 9-10 | 111.3 (14.2) | 32 (8.95) | 335.5 (67.2) | 175.1 (37.6) | 1156.8 (35.2) | 213.9 (43.5) | 0.95 (0.2) | 0.86 (0.1) |
| 7-8 | 113.8 (13.7) | 33.6 (11) | 334.1 (70.8) | 178.5 (40.3) | 1152.8 (34.7) | 216.6 (35) | 0.95 (0.1) | 0.87 (0.1) |
| 5-6 | 112.3 (16.4) | 35.7 (13.4) | 316.7 (64.6) | 168.1 (38.9) | 1141.1 (38) | 211.9 (46.3) | 0.97 (0.2) | 0.87 (0.1) |
| 3-4 | 113.3 (16.1) | 34.8 (12.4) | 340.1 (73.4) | 175.6 (43.8) | 1146.9 (38) | 213.5 (41) | 0.96 (0.2) | 0.88 (0.1) |
| 1-2 | 114.1 (17.4) | 36.4 (14.3) | 334.6 (81.9) | 177.9 (51.4) | 1144 (45.7) | 212.6 (48.7) | 0.94 (0.2) | 0.88 (0.1) |
| < 1 | 111.4 (13.1) | 35.1 (9.44) | 326.4 (66.2) | 170.3 (39.7) | 1145 (39) | 204.4 (39.9) | 0.95 (0.2) | 0.86 (0.1) |
| Never used HRT | 111.7 (16.4) | 36.3 (13.2) | 323.7 (66.7) | 167.5 (40.2) | 1146.7 (38.6) | 207 (43.4) | 0.92 (0.2) | 0.86 (0.1) |
| p-value for trend* | .1 | .03 | .07 | .07 | .001 | <.001 | .002 | .1 |
| Last HRT use | ||||||||
| In the last year | 115 (15.2) | 33.1 (12) | 354.1 (65.5) | 175.7 (35) | 1165.8 (33.8) | 226.1 (45.6) | 1.01 (0.1) | 0.9 (0.1) |
| 1-5 years ago | 114.1 (14.6) | 33.9 (10.9) | 343.8 (69.8) | 174.4 (41.7) | 1152.2 (34.6) | 217.2 (46.4) | 0.94 (0.2) | 0.85 (0.1) |
| > 5 years ago | 112.6 (15.5) | 35 (12.1) | 326.9 (70.9) | 174.8 (42.9) | 1146.5 (39.8) | 211.5 (41.5) | 0.95 (0.2) | 0.87 (0.1) |
| Never used HRT | 111.7 (16.4) | 36.3 (13.2) | 323.7 (66.7) | 167.5 (40.2) | 1146.7 (38.6) | 207 (43.4) | 0.92 (0.2) | 0.86 (0.1) |
| p-value (category)* | .4 | .2 | .01 | .2 | .007 | .02 | .001 | .1 |
Tests for trend or categories were based on regression models where bone outcomes were logged, and age at period cessation, and length of reproductive life and length of HT use were included as months since birth.
Length of HRT use was associated with lower medullary CSA and was strongly and positively related to polar SSI, cortical vBMD and lumbar spine aBMD; associations with total and trabecular vBMD and total hip aBMD were weaker (Table 2). Recent use of HRT was also associated with polar SSI, cortical vBMD and total vBMD, and spine aBMD. There were no associations with bone CSA at any site.
Differences in bone outcomes per 10 year difference in timing of period cessation (natural or surgical) and length of reproductive life
Women who had a later natural menopause had a 8.2% (95% CI: 1.3,15.1%, p=.02) greater trabecular vBMD and a 6.0% (95% CI 0.51,11.5%, p=.03) greater total vBMD than women with an age of menopause ten years earlier (Table 3, model 1). There were no associations with age at hysterectomy (p-value for interaction between menopause type and age at period cessation=.09 for trabecular vBMD and .02 for total vBMD). Similar sized estimates were seen for the larger sample with spine and total hip aBMD. Adjustments for current height and weight (Table 3, model 2), adult occupation and smoking had little effect on any of these estimates. Women who had a hysterectomy had better BMD than women who had a natural menopause (see Supplemental Figure 1a and 1b); the interaction with age at period cessation meant that the differences were stronger in women with a younger age at cessation. They also had greater SSI (p=.05). There were no associations between age at natural menopause or age at hysterectomy and bone size or strength. The findings for length of reproductive life were similar (Supplemental Table 1). There was no evidence that the findings for hysterectomy status differed by oophorectomy status.
Table 3.
Percentage difference in bone outcomes per 10 year difference in timing of period cessation (natural/surgical), adjusted for type of menopause, and then additionally adjusted for current height and weight
| Model 1 Adjusted for type of menopause | Model 2 Model 1 + adjusted for current height and weight | |||||
|---|---|---|---|---|---|---|
| % diff | 95% CI | p-value | % diff | 95% CI | p-value | |
| Diaphysis CSA (n=562) | ||||||
| Age at natural menopause | 2 | -1.6, 5.7 | .3 | 0.8 | -2.5, 4.1 | .6 |
| Age at hysterectomy | -1.3 | -4.6, 2.1 | .5 | -0.2 | -3.2, 2.8 | .9 |
| Medullary CSA (n=561) | ||||||
| Age at natural menopause | -4.8 | -13.9, 4.4 | .3 | -6.1 | -15.1, 2.8 | .2 |
| Age at hysterectomy | 1.7 | -6.7, 10.1 | .7 | 3 | -5.2, 11.3 | .5 |
| Total vBMD (n=555) | ||||||
| Age at natural menopause | 6 | 0.5, 11.5 | .03 | 5.9 | 0.5, 11.4 | .03 |
| Age at hysterectomy | 0.8 | -4.2, 5.8 | .8 | 0.7 | -4.3, 5.6 | .8 |
| Trabecular vBMD (n=554) | ||||||
| Age at natural menopause | 8.2 | 1.3, 15.1 | .02 | 8.2 | 1.4, 15.0 | .02 |
| Age at hysterectomy | 0.1 | -6.2, 6.4 | >.9 | -0.2 | -6.4, 6.1 | >.9 |
| Cortical vBMD (n=563) | ||||||
| Age at natural menopause | 0.5 | -0.4, 1.4 | .3 | 0.5 | -0.4, 1.4 | .3 |
| Age at hysterectomy | -0.2 | -1.1, 0.6 | .6 | -0.2 | -1, 0.6 | .6 |
| Polar SSI (n=563) | ||||||
| Age at natural menopause | 3.7 | -1.7, 9.1 | .2 | 2.1 | -2.8, 6.9 | .4 |
| Age at hysterectomy | -2.8 | -7.7, 2.1 | .23 | -1.4 | -5.8, 3.1 | .5 |
| Lumbar spine aBMD (n=703) | ||||||
| Age at natural menopause | 9.3 | 5.3, 13.3 | <.001 | 8.8 | 5.1, 12.6 | <.001 |
| Age at hysterectomy | 1.8 | -2.0, 5.6 | .4 | 2.29 | -1.3, 5.8 | .2 |
| Total hip aBMD (n=700) | ||||||
| Age at natural menopause | 6.7 | 3.2, 10.3 | <.001 | 6.4 | 3.4, 9.4 | <.001 |
| Age at hysterectomy | -0.04 | -3.3, 3.2 | >.9 | 0.4 | -2.4, 3.2 | .8 |
Differences in bone outcomes per 10 year HRT use and by time since last use
Length of HRT (Table 4) and recency of HRT use (Supplemental Table 2) were associated with greater SSI, higher cortical and total and trabecular vBMD, and greater aBMD, particularly in the lumbar spine; in some cases the estimates strengthened after adjusting for menopausal type (Table 4, model 2) and current height and weight (Table 4, model 3). For example, in the adjusted model, a ten year difference in HRT use was associated with a 6.3%, 95% CI 3.1%,9.4% (p<.001) greater polar SSI and a 0.9%, 95% CI 0.3%, 1.5% (p=.002) greater cortical vBMD. Further adjustment (not shown) for smoking and adult occupation did not change these estimates. The association between length of HRT use and spine aBMD differed by type of menopause (p-value for the interaction=.02), in that the association was less pronounced in those who had a hysterectomy compared with those with a natural menopause (Table 4 and Supplemental Table 2).
Table 4.
Percentage difference in bone outcomes per 10 years of HRT use, unadjusted, and then adjusted for type of menopause, and additionally adjusted for current height (m) and weight (kg)
| Unadjusted | Model 2 Adjusted for type of menopause | Model 3 Adjusted for type of menopause, height and weight | |||||||
|---|---|---|---|---|---|---|---|---|---|
| % diff | 95% CI | p-value | % diff | 95% CI | p-value | % diff | 95% CI | p-value | |
| Diaphysis CSA (n=603) | 1.9 | -0.4, 4.2 | .1 | 1.8 | -0.6, 4.2 | .1 | 2.4 | 0.3, 4.5 | .03 |
| Medullary CSA (n=602) | -6.5 | -12.2, -0.7 | .03 | -5.7 | -11.7, 0.2 | .06 | -5.5 | -11.4, 0.4 | .07 |
| Total vBMD (n=597) | 3.3 | -0.3, 6.8 | .07 | 2.3 | -1.3, 6 | .2 | 3.0 | -0.6, 6.7 | .1 |
| Trabecular vBMD (n=596) | 4.0 | -0.3, 8.3 | .07 | 2.9 | -1.6, 7.3 | .2 | 3.8 | -0.6, 8.2 | .09 |
| Cortical vBMD (n=604) | 0.9 | 0.4, 1.5 | .001 | 0.9 | 0.3, 1.5 | .003 | 0.9 | 0.3, 1.5 | .002 |
| Polar SSI (n=604) | 6.0 | 2.6, 9.3 | <.001 | 5.4 | 1.9, 8.9 | .003 | 6.3 | 3.1, 9.4 | <.001 |
| Spine L1-L4 aBMD (n=747) | 4.0 | 1.4, 6.5 | .002 | ||||||
| Ceased naturally | 5.3 | 2.1,8.5 | .001 | 6.6 | 3.6,9.7 | <.001 | |||
| Ceased surgically | -1.4 | -6.1,3.2 | .5 | 0.9 | -3.5,5.4 | .7 | |||
| Hip aBMD (n=742) | 1.8 | -0.4, 3.9 | .1 | 0.7 | -1.5, 3 | .5 | 2.8 | 0.8, 4.7 | .007 |
p-value=.02 for the interaction between type of menopause and length of HRT
Differences in bone outcomes per 10 year difference in timing of period cessation (natural or surgical) or length of reproductive life, additionally adjused for HRT use
After additional adjustment for length of HRT use, women with a later natural menopause still had greater trabecular vBMD and aBMD (Table 5, Supplemental Table 3). Length of HRT use, and recent HRT use remained positively associated with SSI, cortical vBMD, and aBMD, particularly of the lumbar spine. Similar results were seen for length of reproductive life (Supplemental Tables 4 and 5). Women who had a hysterectomy still had higher BMD after these adjustments than women who had a natural menopause. The interaction between menopause type and HRT use on lumbar spine was weaker (p >.1) than in the models in Table 4 (and supplemental Table 2).
Table 5.
Percentage difference in bone outcomes by type of menopause, per 10 year difference in timing of period cessation (natural or surgical), per 10-year difference in HRT use, height, weight, smoking and adult occupation.
| Diaphysis CSA (n=508)* | Medullary CSA (n=507)* | Total vBMD (mg/cm3) (n=502)* | Trabecular vBMD (mg/cm3) (n=501)* | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| % diff | 95% CI | p-value | % diff | 95% CI | p-value | |||||||
| Hysterectomy v. natural menopause (at age 50) | 0.5 | -2.7, 3.7 | .8 | -3.1 | -11.8, 5.6 | .5 | 5.8 | 0.5, 11 | .03 | 5.8 | -0.8, 12.4 | .08 |
| Age at period cessation (per 10y) | ||||||||||||
| Ceased naturally | 0.1 | -3.4, 3.5 | >.9 | -8.5 | -17.9, 0.9 | .08 | 3.7 | -2, 9.4 | .2 | 7.1 | 0.04, 14.2 | .05 |
| Ceased surgically | -0.3 | -3.6, 3 | .8 | 0.5 | -8.4, 9.4 | .9 | 2.4 | -3, 7.8 | .4 | 1.5 | -5.2, 8.2 | .7 |
| HRT use (per 10y) | 2.3 | -0.3, 4.9 | .08 | -6.3 | -13.4, 0.8 | .08 | 2.5 | -1.8, 6.8 | .3 | 4.0 | -1.4, 9.3 | .1 |
| Height (per 1 SD) | 5.1 | 3.9, 6.2 | <.001 | 7.5 | 4.5, 10.5 | <.001 | -2.5 | -4.3, -0.7 | .008 | -4.0 | -6.3, -1.8 | .001 |
| Weight (per 1 SD) | 2.9 | 1.8, 4.1 | <.001 | 0.3 | -2.9, 3.4 | .9 | 4.2 | 2.3, 6.1 | <.001 | 5.7 | 3.3, 8 | <.001 |
| Smoking v not smoking | 1.1 | -2.7, 4.9 | .6 | 2.1 | -8.2, 12.4 | .7 | 0.7 | -5.6, 7 | .8 | -1.2 | -9, 6.7 | .8 |
| Manual v non-manual social class | -0.5 | -3.4, 2.3 | .7 | 1.6 | -6.1, 9.3 | .7 | -0.6 | -5.4, 4.1 | .8 | 0.9 | -4.9, 6.7 | .8 |
| Cortical vBMD (n=509)* | Polar SSI (n=509)* | Lumbar spine aBMD (n=635)* | Total hip aBMD (n=632)* | |||||||||
| % diff | 95% CI | p-value | % diff | 95% CI | p-value | % diff | 95% CI | p-value | % diff | 95% CI | p-value | |
| Hysterectomy v. natural menopause | 0.2 | -0.7, 1 | .7 | 2.9 | -1.8, 7.6 | .2 | 6.0 | 2.3, 9.8 | .002 | 3.7 | 0.8, 6.7 | .01 |
| Age at period cessation (per 10y) | ||||||||||||
| Ceased naturally | 0.5 | -0.4, 1.4 | .3 | 1.0 | -4.1, 6.1 | .7 | 8.8 | 4.8, 12.7 | <.001 | 5.8 | 2.6, 8.9 | <.001 |
| Ceased surgically | 0.2 | -0.7, 1.1 | .6 | -0.1 | -4.9, 4.8 | >.9 | 3.3 | -0.5, 7.1 | .09 | 1.6 | -1.4, 4.6 | .3 |
| HRT use (per 10y) | 0.9 | 0.2, 1.6 | .01 | 6.3 | 2.5, 10.2 | .001 | 3.6 | 0.5, 6.6 | .02 | 2.7 | 0.3, 5.1 | .03 |
| Height (per 1 SD) | -0.01 | -0.3, 0.3 | >.9 | 6.7 | 5.1, 8.4 | <.001 | 0.7 | -0.6, 2 | .3 | -0.4 | -1.4, 0.7 | .5 |
| Weight (per 1 SD) | 0.3 | -0.03, 0.6 | .07 | 4.5 | 2.8, 6.2 | <.001 | 6.2 | 4.9, 7.5 | <.001 | 8.1 | 7.1, 9.2 | <.001 |
| Smoking v not smoking | -0.2 | -1.3, 0.8 | .6 | 1.0 | -4.6, 6.6 | .7 | -2.2 | -6.7, 2.3 | .3 | -3.2 | -6.9, 0.4 | .09 |
| Manual v non-manual social class | -0.3 | -1.1, 0.4 | .4 | -3.2 | -7.4, 1 | .1 | -0.6 | -3.9, 2.6 | .7 | -1.1 | -3.7, 1.5 | .4 |
Samples exclude between 53 and 68 women with insufficient data on HRT use
Discussion
We have shown in a large British cohort of women that a ten year later age at natural menopause was associated with an estimated 6-8% greater trabecular vBMD in women aged 60-64, even after adjusting for body size, HRT use and social and behavioral factors. A longer length of reproductive life showed similar consistent and positive associations with the same bone parameters. HRT use was associated with a 0.9% greater cortical vBMD, 6.3% smaller medullary CSA and a 6% greater SSI; the associations with total and trabecular vBMD were weaker. Age at natural menopause, length of reproductive life and HRT use in women who had a natural menopause were also associated with aBMD of the lumbar spine and total hip.
Comparison with other studies and interpretation
Natural menopause, length of reproductive life and bone
Previous studies have shown that an earlier natural menopause, and a shorter reproductive life are associated with lower BMD. (2;4;6;8) Using transilial biopsy specimens, Akhter(28) observed that across the menopause transition, there was decreasing bone tissue volume to total volume and trabecular number, and increased trabecular spacing which would explain the changes in microarchitecture detected as lower BMD using DXA or pQCT. Our findings show that the inverse associations with early menopause and shorter reproductive life persist into the seventh decade of life, and are observed for vBMD and aBMD. Whether these effects will eventually be attenuated by age as a risk factor for fracture, and so have little long-term effect on hip fracture risk, as indicated in the Million Women Study,(16) cannot yet be determined, but our study has one of the longest follow-up periods to date.
There is a need to separate age and menopause-related mechanisms that affect bone health. While the loss of BMD is initially in the trabecular compartment and in women is most strongly related to menopause, it is followed by an equivalent decline in cortical vBMD as endo- and intra-cortical resorption accelerates and periosteal expansion slows, leading to a reduction in cortical area, and consequently in bone strength.(29) Factors other than declining sex hormones may play a greater role in this aspect of bone loss and may explain why the associations between natural menopause and reproductive life and bone differed from the associations evident for HRT use.
Our finding that shorter reproductive life was associated with lower BMD suggests that lifetime cumulative oestrogen exposure may be important. In determining the duration of endogenous estrogens, Hagemans et al(30) concluded that knowing age at menarche and menopause was sufficient; having information on parity, miscarriages, lactation, oral contraceptive use and length of menstrual cycle did not explain any further variation in BMD adding strength to the observations in the current study. Various other factors which we are unable to study will contribute to menopausal bone loss such as declining levels of estradiol and FSH,(31) cytokines,(32) genetic factors,(33) and bone, muscle and fat interactions.(34)
HRT use and bone
Randomised control trials have shown increased aBMD in hip and lumbar spine and protection from fracture in HRT users. (13;14;35–39) Our finding of greater aBMD for HRT users, particularly in the lumbar spine, a site containing mostly trabecular bone, is consistent with these findings,
Findings from our study of the short-term benefits of HRT on bone are likely to be due to the mechanism by which it acts: Increased cortical vBMD and a narrower medullary cavity are likely to be due to reductions in both intracortical remodelling and endocortical resportion, both of which would increase bone strength. They support the view that HRT protects cortical bone from age-related changes in endocortical resorption and reduced bone turnover. Previous smaller studies have also shown that HRT users compared with nonusers have higher vBMD, larger cortical CSA, and greater bending and compressive bone strength in the tibial shaft, a weight-bearing site, as well as the distal radius.(40;41), which is consistent with our findings. A small longitudinal study of HRT users compared with a control group, suggested that exogenous estrogen fills the small marrow pores close to the endocortical surface, so that the pQCT-defined boundary between trabecular and cortical bone shifted in favor of cortical bone conferring greater strength to the bone.(22) Mikkola et al (18) carried out a long term follow-up of monozygotic twin pairs and showed greater cortical and trabecular vBMD at distal and diaphyseal sites in the twin taking HRT compared with the other twin who was not; these differences resulted in greater compressive and bending strength. They suggested that HRT may become more important with years from menopause as the study showed an annual increase of 2.6-2.8% in intrapair difference in bone strength. Given the results of these two studies it was surprising that we did not find an effect of HRT on trabecular or total BMD at the distal radius. This may be due to limitations in the spatial resolution of pQCT meaning we could not accurately define the cortical, sub-cortical, trabecular boundaries and so detect differences in the bone compartments.
Hysterectomy status and bone
Women in this cohort who had a hysterectomy had greater BMD than women with a natural menopause. The difference was greatest for women who had an earlier age at period cessation. It was reduced in the models that included all women where use of HRT was known, suggesting that longer use of HRT contributed to greater BMD in women with a hysterectomy. These women were also of heavier weight; and previous NSHD studies have shown they were also more likely to be overweight or obese in midlife and have an earlier menarche.(42;43) So these factors too may partly explain the association. The most common reason for a hysterectomy, particularly at earlier ages, was fibroids,(43) which may have been associated with greater estrogen exposure through earlier menarche, and contributed to greater BMD. There is little evidence from other studies that hysterectomy or oophorectomy are associated with bone outcomes or fracture risk,(9–12) although few studies have examined the reasons for the operations which may be of consequence.(11)
Strengths and limitations
The main strengths of this study are the prospective, detailed and longitudinal collection of data on menopausal characteristics in relation to gold standard bone outcomes on a relatively large sample of British women followed into early old-age. pQCT and DXA measurements were obtained; pQCT enables the investigation of bone size, strength and vBMD of trabecular and cortical compartments with less confounding by body size which is a limitation of aBMD obtained by DXA. That all the women were born in the same week, and that the scans took place over a narrow age range ten years after the average age at menopause, limited potential confounding by age and enabled an assessment of the persistence of menopause-related effects on bone. It also allowed the study of how HRT use may protect from fracture through slowing down age-related changes in vBMD and endocortical resportion that decrease bone strength.
A limitation is that we did not collect HRT dose and data on types of HRT preparations was insufficiently complete to use. We have previously reported that the vast majority on HRT who had had a hysterectomy were taking estrogen alone, whereas other women were taking a combined preparation.(44) Data on length of use and age at last use were advantages over studies which have only collected measures of current and past HRT use. Another limitation is that the sample was all born in the early post war period; our findings may not be generalizable to later born cohorts. While these cohorts have experienced little change in the timing of natural menopause, HRT use has declined since the adverse reports from clinical trials, and there has been a small decline in pubertal timing.(45) HRT use in this cohort showed a distinct drop during 2002 (age 56) at the time of adverse trial reports.(46) In this context, HRT prescriptions for participants whose periods ceased from this time (who were more likely to have greater BMD) were less likely, whereas HRT may still have been prescribed to women seen to be at high risk of fracture (including those with early period cessation). Thus associations between HRT use and BMD could have been weakened.
In conclusion, this study shows that later natural menopause and longer reproductive life are associated with greater trabecular vBMD and aBMD in early old age, and that HRT use is associated with greater cortical vBMD, bone strength, and spine aBMD. Whilst HRT is not likely to be restored as an agent for common use primarily for prevention of osteoporosis, this study showed protective effects on bone for women with natural menopause taking the therapy.
Acknowledgements
The authors would like to thank the reviewers who raised additional points for discussion. The authors are grateful to NSHD study members who took part in the clinic data collection for their continuing support. We thank members of the NSHD scientific and data collection teams at the following centres: MRC Unit for Lifelong Health and Ageing; Welcome Trust (WT) Clinical Research Facility (CRF) Manchester; WTCRF and Medical Physics at the Western General Hospital in Edinburgh; WTCRF and Department of Nuclear Medicine at University Hospital Birmingham; WTCRF and the Department of Nuclear Medicine at University College London Hospital; CRF and the Department of Medical Physics at the University Hospital of Wales; CRF and Twin Research Unit at St Thomas’ Hospital London.
Funding:This work was supported by the UK Medical Research Council which provides core funding for the MRC National Survey of Health and Development and supports DK, SM, RC, RH by MC_UU_12019/1, MC_UU_12019/4, and KW by U105960371.
Footnotes
Disclosure statement: DK, SM, RC, KM, JEA, RH and KAW have nothing to declare. C.C. has received consultancy, lecture fees and honoraria from Alliance for Better Bone Health, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, Takeda and UCB.
References
- 1.Abrahamsen B, van ST, Ariely R, Olson M, Cooper C. Excess mortality following hip fracture: a systematic epidemiological review. Osteoporos Int. 2009;20(10):1633–1650. doi: 10.1007/s00198-009-0920-3. [DOI] [PubMed] [Google Scholar]
- 2.Kritz-Silverstein D, Barrett-Connor E. Early menopause, number of reproductive years, and bone mineral density in postmenopausal women. Am J Public Health. 1993;83(7):983–988. doi: 10.2105/ajph.83.7.983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Johnell O, Gullberg B, Kanis JA, et al. Risk factors for hip fracture in European women: the MEDOS Study. Mediterranean Osteoporosis Study. J Bone Miner Res. 1995;10(11):1802–1815. doi: 10.1002/jbmr.5650101125. [DOI] [PubMed] [Google Scholar]
- 4.Osei-Hyiaman D, Satoshi T, Ueji M, Hideto T, Kano K. Timing of menopause, reproductive years, and bone mineral density: a cross-sectional study of postmenopausal Japanese women. Am J Epidemiol. 1998;148(11):1055–1061. doi: 10.1093/oxfordjournals.aje.a009582. [DOI] [PubMed] [Google Scholar]
- 5.Banks E, Reeves GK, Beral V, Balkwill A, Liu B, Roddam A. Hip fracture incidence in relation to age, menopausal status, and age at menopause: prospective analysis. PLoS Med. 2009;6(11):e1000181. doi: 10.1371/journal.pmed.1000181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Sullivan SD, Lehman A, Thomas F, et al. Effects of self-reported age at nonsurgical menopause on time to first fracture and bone mineral density in the Women's Health Initiative Observational Study. Menopause. 2015;22(10):1035–1044. doi: 10.1097/GME.0000000000000451. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Gerdhem P, Obrant KJ. Bone mineral density in old age: the influence of age at menarche and menopause. Journal of Bone and Mineral Metabolism. 2004;22(4):372–375. doi: 10.1007/s00774-004-0497-z. [DOI] [PubMed] [Google Scholar]
- 8.Sioka C, Fotopoulos A, Georgiou A, Xourgia X, Papadopoulos A, Kalef-Ezra JA. Age at menarche, age at menopause and duration of fertility as risk factors for osteoporosis. Climacteric. 2010;13(1):63–71. doi: 10.3109/13697130903075337. [DOI] [PubMed] [Google Scholar]
- 9.Kritz-Silverstein D, von Muhlen DG, Barrett-Connor E. Hysterectomy and oophorectomy are unrelated to bone loss in older women. Maturitas. 2004;47(1):61–69. doi: 10.1016/s0378-5122(03)00242-1. [DOI] [PubMed] [Google Scholar]
- 10.Antoniucci DM, Sellmeyer DE, Cauley JA, et al. Postmenopausal bilateral oophorectomy is not associated with increased fracture risk in older women. J Bone Miner Res. 2005;20(5):741–747. doi: 10.1359/JBMR.041220. [DOI] [PubMed] [Google Scholar]
- 11.Melton LJ, III, Achenbach SJ, Gebhart JB, Babalola EO, Atkinson EJ, Bharucha AE. Influence of hysterectomy on long-term fracture risk. Fertil Steril. 2007;88(1):156–162. doi: 10.1016/j.fertnstert.2006.11.080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Vesco KK, Marshall LM, Nelson HD, et al. Surgical menopause and nonvertebral fracture risk among older US women. Menopause. 2012;19(5):510–516. doi: 10.1097/gme.0b013e318239caeb. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. Jama. 2003;290(13):1729–1738. doi: 10.1001/jama.290.13.1729. [DOI] [PubMed] [Google Scholar]
- 14.Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. Jama. 2004;291(14):1701–1712. doi: 10.1001/jama.291.14.1701. [DOI] [PubMed] [Google Scholar]
- 15.Barrett-Connor E, Wehren LE, Siris ES, et al. Recency and duration of postmenopausal hormone therapy: effects on bone mineral density and fracture risk in the National Osteoporosis Risk Assessment (NORA) study. Menopause. 2003;10(5):412–419. doi: 10.1097/01.GME.0000086467.82759.DA. [DOI] [PubMed] [Google Scholar]
- 16.Banks E, Beral V, Reeves G, Balkwill A, Barnes I. Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women. Jama. 2004;291(18):2212–2220. doi: 10.1001/jama.291.18.2212. [DOI] [PubMed] [Google Scholar]
- 17.Karim R, Dell RM, Greene DF, Mack WJ, Gallagher JC, Hodis HN. Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organization. Menopause. 2011;18(11):1172–1177. doi: 10.1097/gme.0b013e31821b01c7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Mikkola TM, Heinonen A, Kovanen V, et al. Influence of long-term postmenopausal hormone-replacement therapy on estimated structural bone strength: a study in discordant monozygotic twins. J Bone Miner Res. 2011;26(3):546–552. doi: 10.1002/jbmr.255. [DOI] [PubMed] [Google Scholar]
- 19.Mishra G, Hardy R, Kuh D. Are the effects of risk factors for timing of menopause modified by age? Results from a British birth cohort study. Menopause. 2007;14(4):717–724. doi: 10.1097/GME.0b013e31802f3156. [DOI] [PubMed] [Google Scholar]
- 20.Hardy R, Mishra GD, Kuh D. Body mass index trajectories and age at menopause in a British birth cohort. Maturitas. 2008;59(4):304–314. doi: 10.1016/j.maturitas.2008.02.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Mishra GD, Kuh D. Health symptoms during midlife in relation to menopausal transition: British prospective cohort study. BMJ. 2012;344:e402. doi: 10.1136/bmj.e402. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Muller ME, Webber CE, Adachi JD. Hormone replacement therapy improves distal radius bone structure by endocortical mineral deposition. Can J Physiol Pharmacol. 2003;81(10):952–958. doi: 10.1139/y03-096. [DOI] [PubMed] [Google Scholar]
- 23.Kuh D, Pierce M, Adams J, et al. Cohort profile: updating the cohort profile for the MRC National Survey of Health and Development: a new clinic-based data collection for ageing research. Int J Epidemiol. 2011;40(1):e1–e9. doi: 10.1093/ije/dyq231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Stafford M, Black S, Shah I, et al. Using a birth cohort to study ageing: representativeness and response rates in the National Survey of Health and Development. Eur J Ageing. 2013;10(2):145–157. doi: 10.1007/s10433-013-0258-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Kuh D, Wills AK, Shah I, et al. Growth from birth to adulthood and bone phenotype in early old age: A British birth cohort study. Journal of Bone and Mineral Research. 2014;29(1):123–133. doi: 10.1002/jbmr.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Ferretti JL, Capozza RF, Zanchetta JR. Mechanical validation of a tomographic (pQCT) index for noninvasive estimation of rat femur bending strength. Bone. 1996;18(2):97–102. doi: 10.1016/8756-3282(95)00438-6. [DOI] [PubMed] [Google Scholar]
- 27.Cole TJ. Sympercents: symmetric percentage differences on the 100 loge scale simplify the presentation of log transformed data. Stat Med. 2000;19:3109–3125. doi: 10.1002/1097-0258(20001130)19:22<3109::aid-sim558>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
- 28.Akhter MP, Lappe JM, Davies KM, Recker RR. Transmenopausal changes in the trabecular bone structure. Bone. 2007;41(1):111–116. doi: 10.1016/j.bone.2007.03.019. [DOI] [PubMed] [Google Scholar]
- 29.Riggs BL, Melton LJ, III, Robb RA, et al. Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites. J Bone Miner Res. 2004;19(12):1945–1954. doi: 10.1359/JBMR.040916. [DOI] [PubMed] [Google Scholar]
- 30.Hagemans ML, van der Schouw YT, de Kleijn MJ, et al. Indicators for the total duration of premenopausal endogenous estrogen exposure in relation to BMD. Hum Reprod. 2004;19(9):2163–2169. doi: 10.1093/humrep/deh381. [DOI] [PubMed] [Google Scholar]
- 31.Sowers MR, Zheng H, Greendale GA, et al. Changes in bone resorption across the menopause transition: effects of reproductive hormones, body size, and ethnicity. J Clin Endocrinol Metab. 2013;98(7):2854–2863. doi: 10.1210/jc.2012-4113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Brincat SD, Borg M, Camilleri G, Calleja-Agius J. The role of cytokines in postmenopausal osteoporosis. Minerva Ginecol. 2014;66(4):391–407. [PubMed] [Google Scholar]
- 33.Kosa JP, Balla B, Speer G, et al. Effect of menopause on gene expression pattern in bone tissue of nonosteoporotic women. Menopause. 2009;16(2):367–377. doi: 10.1097/gme.0b013e318188b260. [DOI] [PubMed] [Google Scholar]
- 34.Maltais ML, Desroches J, Dionne IJ. Changes in muscle mass and strength after menopause. Journal of Musculoskeletal & Neuronal Interactions. 2009;9(4):186–197. [PubMed] [Google Scholar]
- 35.Komulainen M, Kroger H, Tuppurainen MT, et al. Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women: a population-based 5-year randomized trial. J Clin Endocrinol Metab. 1999;84(2):546–552. doi: 10.1210/jcem.84.2.5496. [DOI] [PubMed] [Google Scholar]
- 36.Cauley JA, Black DM, Barrett-Connor E, et al. Effects of hormone replacement therapy on clinical fractures and height loss: The Heart and Estrogen/Progestin Replacement Study (HERS) Am J Med. 2001;110(6):442–450. doi: 10.1016/s0002-9343(01)00647-7. [DOI] [PubMed] [Google Scholar]
- 37.Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J Am Med Assoc. 1998;280:605–613. doi: 10.1001/jama.280.7.605. [DOI] [PubMed] [Google Scholar]
- 38.Wells G, Tugwell P, Shea B, et al. Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women. Endocr Rev. 2002;23(4):529–539. doi: 10.1210/er.2001-5002. [DOI] [PubMed] [Google Scholar]
- 39.Jackson RD, Wactawski-Wende J, LaCroix AZ, et al. Effects of conjugated equine estrogen on risk of fractures and BMD in postmenopausal women with hysterectomy: results from the women's health initiative randomized trial. J Bone Miner Res. 2006;21(6):817–828. doi: 10.1359/jbmr.060312. [DOI] [PubMed] [Google Scholar]
- 40.Uusi-Rasi K, Beck TJ, Sievanen H, Heinonen A, Vuori I. Associations of hormone replacement therapy with bone structure and physical performance among postmenopausal women. Bone. 2003;32:704–710. doi: 10.1016/s8756-3282(03)00098-x. [DOI] [PubMed] [Google Scholar]
- 41.Oliver H, Jameson KA, Sayer AA, Cooper C, Dennison EM. Growth in early life predicts bone strength in late adulthood: the Hertfordshire Cohort Study. Bone. 2007;41(3):400–405. doi: 10.1016/j.bone.2007.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Cooper R, Hardy R, Kuh D. Is adiposity across life associated with subsequent hysterectomy risk? Findings from the 1946 British birth cohort study. BJOG. 2008;115(2):184–192. doi: 10.1111/j.1471-0528.2007.01569.x. [DOI] [PubMed] [Google Scholar]
- 43.Cooper R, Hardy R, Kuh D. Timing of menarche, childbearing and hysterectomy risk. Maturitas. 2008;61(4):317–322. doi: 10.1016/j.maturitas.2008.09.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Kuh D, Hardy R, Wadsworth M. Social and behavioural influences on the uptake of hormone replacement therapy among younger women. Br J Obstet Gynaecol. 2000;107:731–739. doi: 10.1111/j.1471-0528.2000.tb13333.x. [DOI] [PubMed] [Google Scholar]
- 45.Cole TJ, Kuh D, Johnson W, et al. Using SITAR to relate pubertal growth to bone health in later life: the MRC National Survey of Health and Development. Int J Epidemiol. 2016 doi: 10.1093/ije/dyw134. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Mishra G, Kok H, Ecob R, Cooper R, Hardy R, Kuh D. Cessation of hormone replacement therapy after reports of adverse findings from randomized controlled trials: evidence from a British Birth Cohort. Am J Public Health. 2006;96(7):1219–1225. doi: 10.2105/AJPH.2005.071332. [DOI] [PMC free article] [PubMed] [Google Scholar]