- Email: [email protected]
What should be done at the time of menopause?
What Should Be Done at the Time of Menopause? CLAUS CHRISTIANSEN, M.D., Ballerup, Denmark
Peak bone mass and aggregate bone loss each c o n t r i b u t e t o l o w b o n e m a s s f o u n d l a t e r in life, a n d o b v i o u s l y t h e c o n t r i b u t i o n o f b o n e l o s s w i l l i n c r e a s e a s p e o p l e age. M e n o p a u s e is the time where bone loss begins to accelerate f r o m t h e e x i s t i n g p e a k b o n e m a s s . It t h u s s e e m s o b v i o u s t h a t , in o r d e r t o s t r a t i f y t h e f e m a l e p o p u l a t i o n i n t o g r o u p s a t v a r i o u s risk, bone mass and rate of loss are the parameters to determine. Which site to measure for the most effective risk assessment has not b e e n d e t e r m i n e d . All s i t e s s e e m t o g i v e a rela t i v e l y s i m i l a r a s s e s s m e n t o f r i s k f o r all subs e q u e n t f r a c t u r e s . I f t h e m e a s u r e m e n t is > 1 standard deviation (SD) above the mean for young normals, no further measurement would be needed and no intervention undert a k e n . I f t h e m e a s u r e m e n t is < 1 SD b e l o w the mean for young normals, intervention w o u l d be r e c o m m e n d e d ( p r o v i d e d n o c o n t r a indications were present). For those within _+1 SD, t h e r a t e o f l o s s s h o u l d b e d e t e r m i n e d . S o m e i n d i v i d u a l s l o s e b o n e at a m o r e rapid r a t e t h a n o t h e r s , a n d t h i s rapid r a t e m a y pers i s t in s o m e o f t h e s e i n d i v i d u a l s o v e r a period of years. Studies have shown that women that were classified to be fast losers at menop a u s e h a v e l o s t a p r o x i m a t e l y 50% m o r e b o n e m a s s a t t h e w r i s t , s p i n e , a n d h i p w i t h i n 12 years after menopause than those diagnosed as normal bone losers. The rate of bone loss in p o s t m e n o p a u s a l w o m e n m a y b e i n d i r e c t l y a s s e s s e d by u s e o f a n u m b e r o f b i o c h e m i c a l markers. Fast losers have elevated concentrations of these markers compared with slow bone losers. The risk of developing osteopor o s i s l a t e r in life is t h e r e b y d e t e r m i n e d by combining the values for the present measured bone mass and the magnitude of the estimated future bone loss.
From the Center for Chnlcal and Basic Research, Ballerup, Denmark. Requestsfor repr,nts should be addressedto Claus Chnst,ansen, M.D., Center for Clinical and Basic Research, Ballerup Byve] 222, 2750 Ballerup, Denmark.
,2A-56S
bone mass and bone loss each contribute to p eak low bone mass found later in life, and it is obvious that the contribution of bone loss will increase as people age. Nevertheless, peak bone mass makes an important contribution, and small changes in peak bone mass could make large differences in fracture risk in the population. Given that fracture risk changes between 50% and 150% for each standard deviation (SD) difference in bone mass [1-3] ( F i g u r e 1), even relatively small increases in peak bone, e.g., 0.5 SD, would be expected to reduce substantially the age-adjusted fracture rates. This implies that population interventions aimed at children could result in improved skeletal health throughout life. It is questionable whether the needed political will and capability is present for such programs. Furthermore, such population interventions should follow clinical trials that documerit the effects. It is questionable whether the needed resources for such trials will be made available.
WHAT SHOULDBE DONE AT MENOPAUSETO IDENTIFY THE WOMEN AT RISK? Menopause is the time where bone loss starts to accelerate from the existing peak bone mass. It thus seems obvious that, in order to stratify the female population into groups at various risk, bone mass and rate of loss are the parameters to determine.
BONE MASS What should the clinician use now as criteria for intervention? A practical approach may be suggested. A measurement of bone mass should be made only when intervention to prevent bone loss can be prescribed and will be accepted. Most commonly, such a measurement would take place at menopause, to inform consideration of intervention with hormone replacement therapy (HRT). But other forms of therapy are under development for which similar criteria could be applied. If the measurement were >1 SD above the mean for young normals, no further measurement would be needed and no intervention undertaken. If the measurement were <1 SD below the mean for young norreals, intervention would be recommended (provided no contraindications were present).
February27, 1995 The AmericanJournalof Medicine Volume98 (suppl 2A)
SYMPOSIUMON OSTEOPOROSIS/ CHRISTIANSEN
For those within _+1 SD, the bone mass measurement could be repeated in 1-5 years. A measurement at 1 year would probably pick up the extremely fast bone losers, but a clinically relevant bone loss of 3%/year could often be within the error of the method used to measure bone density [4]. Waiting for 5 years could thus result in a 15-30% loss of bone mass before treatment was instituted. Alternatively, a determination of one of two biochemical markers of bone turnover could reveal the rate of loss (see below). Which site to measure for the most effective risk assessment has not been determined. All sites seem to give a relatively similar assessment for risk for all subsequent fractures [5,6]. A problem of misclassification always exists, since some individuals with low bone mass at one measured site have relatively normal measurements at other sites [7]. Multiple measurements could be made, but this would substantially increase the cost of the risk assessment with unproven benefits in fracture risk prediction. Perhaps the approach outlined above will suffice, since those whose measurements at one site are not as low as those at another site would probably fall in the intermediate zone (within -+1 SD from the mean of young normals), and subsequent measurement of markers (or bone mass) would be done.
BONE LOSS The longitudinal measures of radial bone mass made on various samples of postmenopausal women have been examined. The influence of bone loss increased with age so that by age 70 years both the peak bone mass and loss contributed equally to bone mass in the radius [8]. Bone loss, by simply decreasing the bone mass, is probably an important determinant of fracture risk, but other factors associated with bone loss, such as development of mi-
croarchitectural abnormalities and microdamage, could be contributing as well. Some individuals lose bone at a more rapid rate than others, and this rapid rate may persist in some of these individuals over a period of years [9-11]. Such rapid loss could result in trabecular damage and additional risk of fracture above that contributed by the loss of bone alone. It is also possible that even a relatively short period (2-3 years) of rapid bone loss might contribute to perforation of trabecular and thus to increased fracture incidence. Long-term prospective studies of bone loss from the spine and hip have yet to be published, due primarily to the more recent availability of techniques to measure these sites. However, a prospective study [11] has shown that women that were classifled to be fast losers at menopause have a 50% higher rate of bone loss at the wrist, spine, and hip measured 12 years after menopause than those diagnosed as normal bone losers. Cross-sectional data indicate the same difference between fast and slow losers at the spine and the hip (unpublished data).
ASSESSMENTOF BONE LOSS BY BIOCHEMICAL MARKERSOF BONE TURNOVER The rate of bone loss in postmenopausal women may be indirectly assessed by use of a number of biochemical markers. It is established that the biochemical estimates of bone formation and bone resorption increase sharply at the menopause [12] (Table I) and that the higher the bone turnover, the higher the rate of bone loss [9,10]. Fast losers have elevated concentrations of these markers compared with slow bone losers [9,10]. Plasma total or bone-specific alkaline phosphatase and osteocalcin are markers for bone formation. Hydroxyproline and calcium, determined in a fasting urine sample and corrected for creatinine,
DR = Distal Radius
DH = Distal H u m e r u s FN = F e m u r (neck) FT = F e m u r (trocanter) Figure 1. The relative risk of having a fracture at dLfferent sites of the skeleton by each standard deviation decrease In forearm bone densrty compared to normal mean. Bone mass was only measured tn the forearm. RR = relative risk. (Adapted from [3],)
DR DH FN FT
February 27, 1995
F!
F[
= F e m u r (inter troc.)
S
= Lumbar spine
S
The American Journal of Medicine Volume 98 (suppl 2A)
2A-57S
SYMPOSIUM ON OSTEOPOROSIS / CHRISTIANSEN
TABLE I Changes in Biochemical Markers from Pre- to Postmenopausal Women Marker 6steocalctn Bonealkahne ph0sphatase "Oste0mark" "CrossLaps"
Premenopausal AbsoluteValues
EarlyPostmenopausal % Increase
LatePostmenopausal % Increase
93 -+3.1 (ng/mL)
147%
151%
8.5 -+2.6 (ng/mL) 21.9 ± 9.2 (ng/mL) 186 +- 108(ng/mL)
158% i94% 192%
153% 184% 178%
From Garneroet al, ASBMR1994, abstract# C254.
50
BMC (L?. years)
40 •
•
~_ o •
•
eo•
30
. ,~,o71/~"/~•
20 / ~ -
r.09
°
rl = 121
y = 09x.32
•
10 10
2'0
Calculated
bone
3'0
4'0
5'0
mass (BMCto-~BMC
x t)
Figure 2. The correlation between the estimated 12 years bone mass (from basehne bone mass and estimated bone loss) and the measured 12 years bone mass. (Repnnted from [11] wtth permfssion.
tent and/or the highest postmenopausal bone loss are at the higher future risk of developing osteoporosis [11]. In a prospective study over 12 years, the correlation between baseline bone mass minus the estimated rate of loss and the bone mass after 12 years is very strong [11] (Figure 2). New markers are currently being developed, ineluding the amino- and carboxyterminal propeptides of type I proeollagen (PICP, PINP), the collagen erosslinks (pyridinoline [Pyr] and deoxypyridinoline [D-Pyr]) and the amino- and earboxyterminal telopeptides of type I collagen, without or with erosslinks (Osteomark [13], CrossLaps [14]). The telopeptides can now be determined by easy-to-handle enzyme-linked immunosorbet assay (ELISA) kits, and these markers seem to be very sensitive to changes in bone turnover [12,14,15] (Figure 3). The use of such markers may simplify the procedure where rate of loss is assessed by the biochemical approach.
125 CrossLaps~M/Cr (%)
REFERENCES
25-t 0J [
I
I
3
6
I
12
i
24 Time (months)
Figure 3. The response in CrossLaps to treatment of postmenopausal women with hormone replacement therapy
are markers for bone resorption. By a combination of the above-mentioned biochemical markers for resorption and formation, it is possible to estimate the rate of the bone loss [9,10]. The risk of developing osteoporosis later in life is thereby determined by combining the values for the present measured bone mass and the magnitude of the estimated future bone loss. Those women with the lowest present bone mineral con2A-58S
February 27, 1995
The American Journal of Medicme
1. Nut SL, Slemenda CW, Johnston CC. Baseline measurement of bone mass predtcts fracture in whtte women. Ann Intern Med 1989; 111:355-61 2, WasnJch RD, et al. Predtctlon of postmenopausal fracture risk with use of bone mtneral measurements. Am J Obstet Gynecol 1985; 153: 745-51. 3. Gardsell P, Johnell O, Ndsson BE. The predtct~vevalue of bone loss for fragthty fractures in women: a longitudinal study over 15 years. Calcff T,ssue Int 1991; 49: 90-4. 4. Heaney RP. En recherche de la difference (p <0 05). Bone Mineral 1986; 1: 99-114. 5. Melton JL, Atkinson EJ, O'Fallon WM, Wahner HW, Rtggs BL. Long-term fracture prediction by bone mineral assessed at different skeletal sttes. J Bone Mm Res 1993; 8: 1227-33. 6. Cummings SR, Black DM, Nevltt MC, et al, Append~cular bone dens,ty and age predict hip fractures m women. JAMA 1990; 263: 665-8. 7. La K, Rencken M, Drinkwater B, Chesnut C. Stte of bone density measurement may affect therapy dectston. Calcff Tissue Int 1993, 53: 225-8. 8. Hul SL, Slemenda CW, Johnston CC. The contribution of bone loss to postmenopausal osteoporosts. OsteoporosJs Int 1990;1: 30-4. 9. Chrtstiansen C, Rtts BJ, Redbro P. Predlctton of rapid bone loss ,n postmenopausal women. Lancet 1987; n 1105-8 10. Chnstiansen C, RLIs BJ, Redbro P. Screenmg procedure for women at risk of developing postmenopausal osteoporosis. Osteoporosis Int 1990; 1: 35-40. 11. Hansen MA, Overgaard K, Rits BJ, Chnstlansen C. Role of peak bone mass and bone loss in postmenopausal osteoporos~s. 12 year study. Br Med J 1991, 303. 961-4. 12. Garnero P, Sornay-'RenduE, Delmas PD. Assessment of age-related changes of
Volume 98 (suppl 2A)
SYMPOSIUMON OSTEOPOROSIS/ CHRISTIANSEN bone turnover ~n normal women w~th new b~ochemJcalmarkers. J Bone Mrn Res 1994; 9 (suppl 1): $389. 13. Hanson DA, Weiss MAE, Ballen AM, Maslan SL, Singer FR, Eyre DR. A specfflc ~mmunoassayfor monltonng human bone resorption: quantification of type I collagen cross-hnked N-telopeptldes Jn urine. J Bone Min Res 1992; 7: 1251-8. 14. Qvlst P, Bonde M, Rosenqvlst C, ChrlstJansen C. Use of a new b~ochemrcal
marker (CrossLapsTM) for the estimation of rate of postmenopausal bone loss. J Bone Mrn Res 1994; 1 (Suppl 1): $334. 15. Bonde M, Qvlst P, FledehusC, R~esBJ, ChnsbansenC. Applications of an enzyme Jmmunoassayfor a new marker of bone resorption (CrossLaps")--follow up on hormone replacement therapy and osteoporosls risk assessment. J Chn Endocrlnol Metab 1994; ~n press.
February 27, 1995 The American Journal of Medicrne Volume 98 (suppl 2A)
2A-59S
Peak bone mass and aggregate bone loss each c o n t r i b u t e t o l o w b o n e m a s s f o u n d l a t e r in life, a n d o b v i o u s l y t h e c o n t r i b u t i o n o f b o n e l o s s w i l l i n c r e a s e a s p e o p l e age. M e n o p a u s e is the time where bone loss begins to accelerate f r o m t h e e x i s t i n g p e a k b o n e m a s s . It t h u s s e e m s o b v i o u s t h a t , in o r d e r t o s t r a t i f y t h e f e m a l e p o p u l a t i o n i n t o g r o u p s a t v a r i o u s risk, bone mass and rate of loss are the parameters to determine. Which site to measure for the most effective risk assessment has not b e e n d e t e r m i n e d . All s i t e s s e e m t o g i v e a rela t i v e l y s i m i l a r a s s e s s m e n t o f r i s k f o r all subs e q u e n t f r a c t u r e s . I f t h e m e a s u r e m e n t is > 1 standard deviation (SD) above the mean for young normals, no further measurement would be needed and no intervention undert a k e n . I f t h e m e a s u r e m e n t is < 1 SD b e l o w the mean for young normals, intervention w o u l d be r e c o m m e n d e d ( p r o v i d e d n o c o n t r a indications were present). For those within _+1 SD, t h e r a t e o f l o s s s h o u l d b e d e t e r m i n e d . S o m e i n d i v i d u a l s l o s e b o n e at a m o r e rapid r a t e t h a n o t h e r s , a n d t h i s rapid r a t e m a y pers i s t in s o m e o f t h e s e i n d i v i d u a l s o v e r a period of years. Studies have shown that women that were classified to be fast losers at menop a u s e h a v e l o s t a p r o x i m a t e l y 50% m o r e b o n e m a s s a t t h e w r i s t , s p i n e , a n d h i p w i t h i n 12 years after menopause than those diagnosed as normal bone losers. The rate of bone loss in p o s t m e n o p a u s a l w o m e n m a y b e i n d i r e c t l y a s s e s s e d by u s e o f a n u m b e r o f b i o c h e m i c a l markers. Fast losers have elevated concentrations of these markers compared with slow bone losers. The risk of developing osteopor o s i s l a t e r in life is t h e r e b y d e t e r m i n e d by combining the values for the present measured bone mass and the magnitude of the estimated future bone loss.
From the Center for Chnlcal and Basic Research, Ballerup, Denmark. Requestsfor repr,nts should be addressedto Claus Chnst,ansen, M.D., Center for Clinical and Basic Research, Ballerup Byve] 222, 2750 Ballerup, Denmark.
,2A-56S
bone mass and bone loss each contribute to p eak low bone mass found later in life, and it is obvious that the contribution of bone loss will increase as people age. Nevertheless, peak bone mass makes an important contribution, and small changes in peak bone mass could make large differences in fracture risk in the population. Given that fracture risk changes between 50% and 150% for each standard deviation (SD) difference in bone mass [1-3] ( F i g u r e 1), even relatively small increases in peak bone, e.g., 0.5 SD, would be expected to reduce substantially the age-adjusted fracture rates. This implies that population interventions aimed at children could result in improved skeletal health throughout life. It is questionable whether the needed political will and capability is present for such programs. Furthermore, such population interventions should follow clinical trials that documerit the effects. It is questionable whether the needed resources for such trials will be made available.
WHAT SHOULDBE DONE AT MENOPAUSETO IDENTIFY THE WOMEN AT RISK? Menopause is the time where bone loss starts to accelerate from the existing peak bone mass. It thus seems obvious that, in order to stratify the female population into groups at various risk, bone mass and rate of loss are the parameters to determine.
BONE MASS What should the clinician use now as criteria for intervention? A practical approach may be suggested. A measurement of bone mass should be made only when intervention to prevent bone loss can be prescribed and will be accepted. Most commonly, such a measurement would take place at menopause, to inform consideration of intervention with hormone replacement therapy (HRT). But other forms of therapy are under development for which similar criteria could be applied. If the measurement were >1 SD above the mean for young normals, no further measurement would be needed and no intervention undertaken. If the measurement were <1 SD below the mean for young norreals, intervention would be recommended (provided no contraindications were present).
February27, 1995 The AmericanJournalof Medicine Volume98 (suppl 2A)
SYMPOSIUMON OSTEOPOROSIS/ CHRISTIANSEN
For those within _+1 SD, the bone mass measurement could be repeated in 1-5 years. A measurement at 1 year would probably pick up the extremely fast bone losers, but a clinically relevant bone loss of 3%/year could often be within the error of the method used to measure bone density [4]. Waiting for 5 years could thus result in a 15-30% loss of bone mass before treatment was instituted. Alternatively, a determination of one of two biochemical markers of bone turnover could reveal the rate of loss (see below). Which site to measure for the most effective risk assessment has not been determined. All sites seem to give a relatively similar assessment for risk for all subsequent fractures [5,6]. A problem of misclassification always exists, since some individuals with low bone mass at one measured site have relatively normal measurements at other sites [7]. Multiple measurements could be made, but this would substantially increase the cost of the risk assessment with unproven benefits in fracture risk prediction. Perhaps the approach outlined above will suffice, since those whose measurements at one site are not as low as those at another site would probably fall in the intermediate zone (within -+1 SD from the mean of young normals), and subsequent measurement of markers (or bone mass) would be done.
BONE LOSS The longitudinal measures of radial bone mass made on various samples of postmenopausal women have been examined. The influence of bone loss increased with age so that by age 70 years both the peak bone mass and loss contributed equally to bone mass in the radius [8]. Bone loss, by simply decreasing the bone mass, is probably an important determinant of fracture risk, but other factors associated with bone loss, such as development of mi-
croarchitectural abnormalities and microdamage, could be contributing as well. Some individuals lose bone at a more rapid rate than others, and this rapid rate may persist in some of these individuals over a period of years [9-11]. Such rapid loss could result in trabecular damage and additional risk of fracture above that contributed by the loss of bone alone. It is also possible that even a relatively short period (2-3 years) of rapid bone loss might contribute to perforation of trabecular and thus to increased fracture incidence. Long-term prospective studies of bone loss from the spine and hip have yet to be published, due primarily to the more recent availability of techniques to measure these sites. However, a prospective study [11] has shown that women that were classifled to be fast losers at menopause have a 50% higher rate of bone loss at the wrist, spine, and hip measured 12 years after menopause than those diagnosed as normal bone losers. Cross-sectional data indicate the same difference between fast and slow losers at the spine and the hip (unpublished data).
ASSESSMENTOF BONE LOSS BY BIOCHEMICAL MARKERSOF BONE TURNOVER The rate of bone loss in postmenopausal women may be indirectly assessed by use of a number of biochemical markers. It is established that the biochemical estimates of bone formation and bone resorption increase sharply at the menopause [12] (Table I) and that the higher the bone turnover, the higher the rate of bone loss [9,10]. Fast losers have elevated concentrations of these markers compared with slow bone losers [9,10]. Plasma total or bone-specific alkaline phosphatase and osteocalcin are markers for bone formation. Hydroxyproline and calcium, determined in a fasting urine sample and corrected for creatinine,
DR = Distal Radius
DH = Distal H u m e r u s FN = F e m u r (neck) FT = F e m u r (trocanter) Figure 1. The relative risk of having a fracture at dLfferent sites of the skeleton by each standard deviation decrease In forearm bone densrty compared to normal mean. Bone mass was only measured tn the forearm. RR = relative risk. (Adapted from [3],)
DR DH FN FT
February 27, 1995
F!
F[
= F e m u r (inter troc.)
S
= Lumbar spine
S
The American Journal of Medicine Volume 98 (suppl 2A)
2A-57S
SYMPOSIUM ON OSTEOPOROSIS / CHRISTIANSEN
TABLE I Changes in Biochemical Markers from Pre- to Postmenopausal Women Marker 6steocalctn Bonealkahne ph0sphatase "Oste0mark" "CrossLaps"
Premenopausal AbsoluteValues
EarlyPostmenopausal % Increase
LatePostmenopausal % Increase
93 -+3.1 (ng/mL)
147%
151%
8.5 -+2.6 (ng/mL) 21.9 ± 9.2 (ng/mL) 186 +- 108(ng/mL)
158% i94% 192%
153% 184% 178%
From Garneroet al, ASBMR1994, abstract# C254.
50
BMC (L?. years)
40 •
•
~_ o •
•
eo•
30
. ,~,o71/~"/~•
20 / ~ -
r.09
°
rl = 121
y = 09x.32
•
10 10
2'0
Calculated
bone
3'0
4'0
5'0
mass (BMCto-~BMC
x t)
Figure 2. The correlation between the estimated 12 years bone mass (from basehne bone mass and estimated bone loss) and the measured 12 years bone mass. (Repnnted from [11] wtth permfssion.
tent and/or the highest postmenopausal bone loss are at the higher future risk of developing osteoporosis [11]. In a prospective study over 12 years, the correlation between baseline bone mass minus the estimated rate of loss and the bone mass after 12 years is very strong [11] (Figure 2). New markers are currently being developed, ineluding the amino- and carboxyterminal propeptides of type I proeollagen (PICP, PINP), the collagen erosslinks (pyridinoline [Pyr] and deoxypyridinoline [D-Pyr]) and the amino- and earboxyterminal telopeptides of type I collagen, without or with erosslinks (Osteomark [13], CrossLaps [14]). The telopeptides can now be determined by easy-to-handle enzyme-linked immunosorbet assay (ELISA) kits, and these markers seem to be very sensitive to changes in bone turnover [12,14,15] (Figure 3). The use of such markers may simplify the procedure where rate of loss is assessed by the biochemical approach.
125 CrossLaps~M/Cr (%)
REFERENCES
25-t 0J [
I
I
3
6
I
12
i
24 Time (months)
Figure 3. The response in CrossLaps to treatment of postmenopausal women with hormone replacement therapy
are markers for bone resorption. By a combination of the above-mentioned biochemical markers for resorption and formation, it is possible to estimate the rate of the bone loss [9,10]. The risk of developing osteoporosis later in life is thereby determined by combining the values for the present measured bone mass and the magnitude of the estimated future bone loss. Those women with the lowest present bone mineral con2A-58S
February 27, 1995
The American Journal of Medicme
1. Nut SL, Slemenda CW, Johnston CC. Baseline measurement of bone mass predtcts fracture in whtte women. Ann Intern Med 1989; 111:355-61 2, WasnJch RD, et al. Predtctlon of postmenopausal fracture risk with use of bone mtneral measurements. Am J Obstet Gynecol 1985; 153: 745-51. 3. Gardsell P, Johnell O, Ndsson BE. The predtct~vevalue of bone loss for fragthty fractures in women: a longitudinal study over 15 years. Calcff T,ssue Int 1991; 49: 90-4. 4. Heaney RP. En recherche de la difference (p <0 05). Bone Mineral 1986; 1: 99-114. 5. Melton JL, Atkinson EJ, O'Fallon WM, Wahner HW, Rtggs BL. Long-term fracture prediction by bone mineral assessed at different skeletal sttes. J Bone Mm Res 1993; 8: 1227-33. 6. Cummings SR, Black DM, Nevltt MC, et al, Append~cular bone dens,ty and age predict hip fractures m women. JAMA 1990; 263: 665-8. 7. La K, Rencken M, Drinkwater B, Chesnut C. Stte of bone density measurement may affect therapy dectston. Calcff Tissue Int 1993, 53: 225-8. 8. Hul SL, Slemenda CW, Johnston CC. The contribution of bone loss to postmenopausal osteoporosts. OsteoporosJs Int 1990;1: 30-4. 9. Chrtstiansen C, Rtts BJ, Redbro P. Predlctton of rapid bone loss ,n postmenopausal women. Lancet 1987; n 1105-8 10. Chnstiansen C, RLIs BJ, Redbro P. Screenmg procedure for women at risk of developing postmenopausal osteoporosis. Osteoporosis Int 1990; 1: 35-40. 11. Hansen MA, Overgaard K, Rits BJ, Chnstlansen C. Role of peak bone mass and bone loss in postmenopausal osteoporos~s. 12 year study. Br Med J 1991, 303. 961-4. 12. Garnero P, Sornay-'RenduE, Delmas PD. Assessment of age-related changes of
Volume 98 (suppl 2A)
SYMPOSIUMON OSTEOPOROSIS/ CHRISTIANSEN bone turnover ~n normal women w~th new b~ochemJcalmarkers. J Bone Mrn Res 1994; 9 (suppl 1): $389. 13. Hanson DA, Weiss MAE, Ballen AM, Maslan SL, Singer FR, Eyre DR. A specfflc ~mmunoassayfor monltonng human bone resorption: quantification of type I collagen cross-hnked N-telopeptldes Jn urine. J Bone Min Res 1992; 7: 1251-8. 14. Qvlst P, Bonde M, Rosenqvlst C, ChrlstJansen C. Use of a new b~ochemrcal
marker (CrossLapsTM) for the estimation of rate of postmenopausal bone loss. J Bone Mrn Res 1994; 1 (Suppl 1): $334. 15. Bonde M, Qvlst P, FledehusC, R~esBJ, ChnsbansenC. Applications of an enzyme Jmmunoassayfor a new marker of bone resorption (CrossLaps")--follow up on hormone replacement therapy and osteoporosls risk assessment. J Chn Endocrlnol Metab 1994; ~n press.
February 27, 1995 The American Journal of Medicrne Volume 98 (suppl 2A)
2A-59S