0021-972X/90/7001 -0083$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1990 by The Endocrine Society
Vol. 70, No. 1 Printed in U.S.A.
The Relative Contributions of Age and Years since Menopause to Postmenopausal Bone Loss B. E. CHRISTOPHER NORDIN, ALLAN G. NEED, BARRY E. CHATTERTON, MICHAEL HOROWITZ, AND HOWARD A. MORRIS Division of Clinical Chemistry, Institute of Medical and Veterinary Science (B.E.C., A.G.N., H.A.M.), and the Department of Pathology (B.E.C.), University of Adelaide; and the Departments of Nuclear Medicine (B.E.C.) and Medicine (M.H.), Royal Adelaide Hospital, Adelaide, South Australia
and an age-related component which is linear and starts in the mid-50s. According to this model, a 70-yr-old woman has lost 11% of her bone due to menopause and 18% as a function of age. Thereafter, the age-related function is dominant. Early menopause is associated with a self-limiting loss of bone which does not progress further until aging exerts its effect. The main conclusion is that the significance of early menopause as a risk factor for osteoporosis has been overstated. (J Clin Endocrinol Metab 70: 83, 1990)
ABSTRACT. We have estimated the relative contributions of age and menopause to forearm mineral density in 485 normal postmenopausal women up to age 75 yr. In 87 pairs matched for years since menopause, in which 1 member was below 61 yr and the other was 61 yr or older, the mean bone density was significantly lower in the older than in the younger subjects despite their identical years since menopause (P < 0.001). Further analysis suggested a model for bone loss after the menopause which comprises a menopausal component of exponential type
A
can be linearized by logarithmic transformation of menopausal age. However, none of these studies has distinguished between the age-related and menopause-related components of bone loss. In a previous publication (7) we attempted to fit an exponential-type function with a minimum value to cross-sectional postmenopausal bone density data, but found that this minimum value became progressively lower with the inclusion in the data of women further and further from the menopause, and therefore older and older. We suggested that this was due to an aging component in bone loss, but were unable to satisfactorily express the two components in consistent quantitative terms or to decide the age at which the aging component became operative. We have now done this by regressing bone density simultaneously on age and the logarithm of years since menopause.
LTHOUGH it is generally agreed that women start L to lose bone at or about the time of the menopause, and that this process is rapid at first but subsequently slows (1, 2), it is not clear how much of the subsequent bone loss should be attributed to the menopause and how much should be attributed to aging. It has been suggested (3) that there is an aging component in bone loss which is common to both sexes, and that the menopausal component in women accounts for an accelerated phase of loss in the early years, but no systematic attempt has been made to separate the two components or to express each in quantitative terms. It was probably Johnston, Jr., et al. (4) who first suggested, on the basis of cross-sectional data, that the loss of bone in postmenopausal women could be described by an exponential function with a minimum value, but their analysis could not separate a menopausal from an ageing component in this process. Nilas et al. (5) have demonstrated a similar pattern of bone loss at three different sites. More recently, Gallagher et al. (6) have confirmed that the rate of fall in total body calcium and in bone density at three different sites after the menopause diminishes with time, and that the regression of bone mass and density on years since menopause (YSM)
Materials and Methods The analysis is based on forearm bone density measurements in 2 groups of normal postmenopausal women. The first comprises all 485 volunteers from our total series of 557 in whom the age at menopause could be established. The 557 were in turn selected from over 1000 applicants who responded to a call for postmenopausal women to take part in a bone density survey that started in 1983. Questionnaires were sent to all applicants, and those who were taking any drug or suffering from any disease likely to affect bone were excluded. The remainder (~600) underwent biochemical and hormonal tests,
Received December 28,1988. Address all correspondence and requests for reprints to: Prof. B. E. C. Nordin, Division of Clinical Chemistry, Institute of Medical and Veterinary Science, Frome Road, Adelaide 5000, South Australia.
83
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NORDIN ET AL.
84
after which those who were found to be premenopausal or showed evidence of hyperparathyroidism, Paget's disease, renal failure, or other relevant systemic illness were excluded. We were left with a final set of 557 apparently healthy postmenopausal women who have been described in more detail previously (7). The 485 subjects whose menopausal age could be established form the main group in this paper. Their mean age was 59.0 ± 0.3 yr (range, 33-75), their mean YSM was 9.8 ± 0.3 yr (range, 1-28), and their mean age at menopause was 49.2 ± 0.21 yr (range, 30-58). Seventy-five had been oophorectomized (mean age, 58.0 yr; mean yr since menopause, 13.4). None was receiving hormone therapy when seen, but 39 had taken hormones for a short time around the time of menopause; only 3 had taken estrogen for more than 12 months, and they had discontinued it many years before presentation. The second group comprises 103 postmenopausal women referred to our Bone
and Menopause Clinic who had no history of peripheral fracture nor any crush fractures of the spine and who have been described by us previously in another context (8). Their mean age was 59.1 ± 0.9 yr (range, 36-83), and their mean YSM was 12.0 ± 0.9 (range, 1-34). Forearm bone densitometry was performed by single photon absorptiometry with the Molsgaard Bone Mineral Analyzer. The arm was immersed in a water bath, and six scans of the distal forearm were performed at 4-mm intervals proximal to the point where the interosseous space reached 8 mm. The bone mineral units generated by the instrument were converted into grams of bone mineral per cm by a conversion factor of 0.032 and divided by derived cross-sectional area to yield forearm mineral density (FMD) (milligrams per cc) as previously described (7, 9). The FMD values were regressed on age in years and on the natural logarithm of YSM. The logarithmic transformation already used by Gallagher et al. (6) was employed because preliminary analysis showed that, unlike the arithmetic function (7), it yielded an extrapolated value in the first year after menopause that was compatible with the mean value in premenopausal women (9) (see Results). By contrast, logarithmic transformation of age did not yield meaningful results. Because the 485 volunteers were all postmenopausal [as confirmed by estrogen assay (7)], the lowest value for YSM is 1, although there are a few subjects within a year of their last menstrual period. The data were analyzed by the Minitab program, using simple and multiple regressions and the two-tailed t test.
Results In an initial analysis to establish whether age affected FMD independently of menopause, we compared the bone densities of younger and older women matched for YSM. In the 485 normal women, it was possible to match for YSM 87 women over the age of 60 yr with 87 women up to age 60 yr (Table 1). The mean FMD was significantly lower in the women over 60 yr than in those up to 60 yr despite their identical menopausal age. The 6-yr chronological age difference between the 2 groups was
JCE & M • 1990 Vol70«Nol
TABLE 1. Mean FMD in 87 pairs of women up to and over 60 yr old matched for YSM Variable
Up to 60 yr
Over 60 yr
t
Age YSM FMD (mg/cc)
57.2 ± 0.36 11.6 ± 0.48 393 ± 6.6
63.1 ± 0.26 11.6 ± 0.48 350 ± 6.9
4.5
Vol. 70, No. 1 Printed in U.S.A.
The Relative Contributions of Age and Years since Menopause to Postmenopausal Bone Loss B. E. CHRISTOPHER NORDIN, ALLAN G. NEED, BARRY E. CHATTERTON, MICHAEL HOROWITZ, AND HOWARD A. MORRIS Division of Clinical Chemistry, Institute of Medical and Veterinary Science (B.E.C., A.G.N., H.A.M.), and the Department of Pathology (B.E.C.), University of Adelaide; and the Departments of Nuclear Medicine (B.E.C.) and Medicine (M.H.), Royal Adelaide Hospital, Adelaide, South Australia
and an age-related component which is linear and starts in the mid-50s. According to this model, a 70-yr-old woman has lost 11% of her bone due to menopause and 18% as a function of age. Thereafter, the age-related function is dominant. Early menopause is associated with a self-limiting loss of bone which does not progress further until aging exerts its effect. The main conclusion is that the significance of early menopause as a risk factor for osteoporosis has been overstated. (J Clin Endocrinol Metab 70: 83, 1990)
ABSTRACT. We have estimated the relative contributions of age and menopause to forearm mineral density in 485 normal postmenopausal women up to age 75 yr. In 87 pairs matched for years since menopause, in which 1 member was below 61 yr and the other was 61 yr or older, the mean bone density was significantly lower in the older than in the younger subjects despite their identical years since menopause (P < 0.001). Further analysis suggested a model for bone loss after the menopause which comprises a menopausal component of exponential type
A
can be linearized by logarithmic transformation of menopausal age. However, none of these studies has distinguished between the age-related and menopause-related components of bone loss. In a previous publication (7) we attempted to fit an exponential-type function with a minimum value to cross-sectional postmenopausal bone density data, but found that this minimum value became progressively lower with the inclusion in the data of women further and further from the menopause, and therefore older and older. We suggested that this was due to an aging component in bone loss, but were unable to satisfactorily express the two components in consistent quantitative terms or to decide the age at which the aging component became operative. We have now done this by regressing bone density simultaneously on age and the logarithm of years since menopause.
LTHOUGH it is generally agreed that women start L to lose bone at or about the time of the menopause, and that this process is rapid at first but subsequently slows (1, 2), it is not clear how much of the subsequent bone loss should be attributed to the menopause and how much should be attributed to aging. It has been suggested (3) that there is an aging component in bone loss which is common to both sexes, and that the menopausal component in women accounts for an accelerated phase of loss in the early years, but no systematic attempt has been made to separate the two components or to express each in quantitative terms. It was probably Johnston, Jr., et al. (4) who first suggested, on the basis of cross-sectional data, that the loss of bone in postmenopausal women could be described by an exponential function with a minimum value, but their analysis could not separate a menopausal from an ageing component in this process. Nilas et al. (5) have demonstrated a similar pattern of bone loss at three different sites. More recently, Gallagher et al. (6) have confirmed that the rate of fall in total body calcium and in bone density at three different sites after the menopause diminishes with time, and that the regression of bone mass and density on years since menopause (YSM)
Materials and Methods The analysis is based on forearm bone density measurements in 2 groups of normal postmenopausal women. The first comprises all 485 volunteers from our total series of 557 in whom the age at menopause could be established. The 557 were in turn selected from over 1000 applicants who responded to a call for postmenopausal women to take part in a bone density survey that started in 1983. Questionnaires were sent to all applicants, and those who were taking any drug or suffering from any disease likely to affect bone were excluded. The remainder (~600) underwent biochemical and hormonal tests,
Received December 28,1988. Address all correspondence and requests for reprints to: Prof. B. E. C. Nordin, Division of Clinical Chemistry, Institute of Medical and Veterinary Science, Frome Road, Adelaide 5000, South Australia.
83
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 15 November 2015. at 05:58 For personal use only. No other uses without permission. . All rights reserved.
NORDIN ET AL.
84
after which those who were found to be premenopausal or showed evidence of hyperparathyroidism, Paget's disease, renal failure, or other relevant systemic illness were excluded. We were left with a final set of 557 apparently healthy postmenopausal women who have been described in more detail previously (7). The 485 subjects whose menopausal age could be established form the main group in this paper. Their mean age was 59.0 ± 0.3 yr (range, 33-75), their mean YSM was 9.8 ± 0.3 yr (range, 1-28), and their mean age at menopause was 49.2 ± 0.21 yr (range, 30-58). Seventy-five had been oophorectomized (mean age, 58.0 yr; mean yr since menopause, 13.4). None was receiving hormone therapy when seen, but 39 had taken hormones for a short time around the time of menopause; only 3 had taken estrogen for more than 12 months, and they had discontinued it many years before presentation. The second group comprises 103 postmenopausal women referred to our Bone
and Menopause Clinic who had no history of peripheral fracture nor any crush fractures of the spine and who have been described by us previously in another context (8). Their mean age was 59.1 ± 0.9 yr (range, 36-83), and their mean YSM was 12.0 ± 0.9 (range, 1-34). Forearm bone densitometry was performed by single photon absorptiometry with the Molsgaard Bone Mineral Analyzer. The arm was immersed in a water bath, and six scans of the distal forearm were performed at 4-mm intervals proximal to the point where the interosseous space reached 8 mm. The bone mineral units generated by the instrument were converted into grams of bone mineral per cm by a conversion factor of 0.032 and divided by derived cross-sectional area to yield forearm mineral density (FMD) (milligrams per cc) as previously described (7, 9). The FMD values were regressed on age in years and on the natural logarithm of YSM. The logarithmic transformation already used by Gallagher et al. (6) was employed because preliminary analysis showed that, unlike the arithmetic function (7), it yielded an extrapolated value in the first year after menopause that was compatible with the mean value in premenopausal women (9) (see Results). By contrast, logarithmic transformation of age did not yield meaningful results. Because the 485 volunteers were all postmenopausal [as confirmed by estrogen assay (7)], the lowest value for YSM is 1, although there are a few subjects within a year of their last menstrual period. The data were analyzed by the Minitab program, using simple and multiple regressions and the two-tailed t test.
Results In an initial analysis to establish whether age affected FMD independently of menopause, we compared the bone densities of younger and older women matched for YSM. In the 485 normal women, it was possible to match for YSM 87 women over the age of 60 yr with 87 women up to age 60 yr (Table 1). The mean FMD was significantly lower in the women over 60 yr than in those up to 60 yr despite their identical menopausal age. The 6-yr chronological age difference between the 2 groups was
JCE & M • 1990 Vol70«Nol
TABLE 1. Mean FMD in 87 pairs of women up to and over 60 yr old matched for YSM Variable
Up to 60 yr
Over 60 yr
t
Age YSM FMD (mg/cc)
57.2 ± 0.36 11.6 ± 0.48 393 ± 6.6
63.1 ± 0.26 11.6 ± 0.48 350 ± 6.9
4.5
