JOURNAL OF BONE AND MINERAL RESEARCH Volume 6, Number 5, 1991 Mary Ann Liebert, Inc., Publishers

The Impact of Menopausal Age on Future Fragility Fracture Risk PER GARDSELL, OLOF JOHNELL, and BO E. NILSSON

ABSTRACT Altogether 733 postmenopausal women were interviewed with regard to their age at menopause. Subsequent fragility fractures over an 11 year period were recorded. Fragility fractures had occurred in 212 women. These women had an earlier menopause, but the deviation from the nonfracture group was significant only in those who were < 70 years at the beginning of the fracture catchment period. Women 50-69 years of age, in the lowest quartile of menopausal age, sustained 50% more fragility fractures than those in the highest quartile. In older women menopausal age does not predict fragility fractures. Women < 7 0 with an early menopause had a significantly lower initial bone mass.

INTRODUCTION LBRIGHT et aI.(l' suspected a connection between menopause and bone loss in women and designated this condition postmenopausal osteoporosis. This relationship was confirmed by Nordin et al.(21Today it is accepted that postmenopausal bone loss is an important factor in the development of osteoporosis in women. Several authors have demonstrated that the time elapsed after menopause influences bone loss more than, or at least as much as, chronologic age.(3-r1An early menopause may be a risk factor to be considered when selecting women for preventive measures. Since the impact of menopause on bone loss becomes less with advancing age and other risk factors become more salient, it is reasonable to question its importance for fracture risk in women over 70, when most fragility fractures occur.

A

MATERIALS AND METHODS Included in this study were 733 women over 50 years of age who at some time between 1970 and 1976 were questioned with regard to their menarcheal and menopausal age; this was done in conjunction with a bone mineral study."] Only those with natural menopause (cessation of bleeding) were included. The fertile period (the time period

between menarche and menopause) was also calculated (Table 1). The bone mineral content (BMC) was measured with single-photon absorptiometry (SPA) according to the method of NauclCr et al.(81This method employs an 14'Am radiation source. Transverse scans of the radius and ulna (both arms) at a distance of 1 and 6 cm from the tip of the styloid process of the ulna were taken. The BMC was expressed as the average bone mass in the pathway of the beam (mg/cm', BMC 1 and BMC 6 cm, respectively). All fractures sustained between 1975 and 1985 were recorded. In Malmo all emergency roentgen examinations are undertaken in the Department of Diagnostic Radiology at the Malmo General Hospital, where the reports are kept on file for each patient, so that the data on all fractures that occurred during the period in question could be collected. There is only one department of orthopedics in the city. Our national population records make it possible to locate at any given time all citizens in the city. Fractures of the vertebrae, the proximal end of the femur, the proximal end of the humerus, the distal end of the forearm, the rami of the pelvis, and the tibia condyles were classified as fragility fractures. The cohort was then separated into those who sustained a fragility fracture during the observation period and those who had never had a fracture. All women (group A) were in-

Department of Orthopaedics, Malmo General Hospital, Lund University, s-214 01 Malmo, Sweden.

429

430

GARDSELL ET AL.

cluded in the analysis. Some women died or moved from the city during the collection period, and the analysis was repeated excluding these women (group B). Consistent with our previous study") the cohort was separated into the age groups 50-59, 60-69, and 2 7 0 in advance. The risk ratio for women still living in the city at the end of 1985 and 50-69 years of age was calculated by dividing the fracture rate (number of fragility fractures per lo00 women-years) in the lowest quartile of menopausal age by the rate in the highest quartile. The quartile cutoffs for menopausal age were 50 (p = 0.01) in age group 50-69 (p =

TABLE2. MENOPAUSAL AGEAND FERTILEPERIOD FOR THOSESUSTAINING FRAGILITY FRACTURES IN 1975-1985 COMPARED WITH THOSEWHONEVERHADA FRACTURE^

Fertile period Menopause Entrance age (Years) 50-59 60-69

> 70 50-69

Fragility fracture

Nonfractured

FragiIity fracture

Nonfractured

Group

n

Mean

I SD

n

Mean

I SD

Mean

I SD

Mean

I SD

A B A B A B

55 50 73 61 84 39

48.0 48.0 47.6b 47.4 48.4 48.5

4.2 4.3 4.1 4.2 5.4 5.3

66 42 82 46 48 8

48.7 49.2 49.2 50.0 47.2 47.0

4.5 4.9 5.0 4.5 4.7 3.9

34.0 34.2 33.0 33.0c 34.0 34.0

4.4 4.5 4.3 4.5 5.3 5.0

34.5 35.1 34.3 35.4 33.0 32.1

4.8 5.1 5.2 4.5 4.9 3.3

A

128

148

49.0

4.8

33.5

4.4

34.4

5.0

111

47.8b 47.F

4.1

B

4.2

88

49.6

4.8

333

4.5

35.3

4.8

aA = total cohort; B = women still living in Malmo by the end of 1985. bp < 0.05. cp < 0.01.

431

MENOPAUSE AND FRACTURE RISK TABLE3. SAMPLE SIZE,MEANS,AND STANDARD DEVIATION FOR QUARTILES OF AGEAT ME NO PAUSE^

Age at menopause, quartiles (years) Age N Mean SD BMC 1 cm N Mean SD BMC 6 cm N Mean SD Age at menopause N Mean SD Individuals with fragility fracture, N

THE

VARIOUS

42

48

so

54

79 59.6 5.6

95 60.1 5.2

81 60.3 5

87 60.4 5

57

94 260 73

79 264 88

86 270 68

79 435c 86

94 449 86

81 459 85

87 48 1 80

78 249b

79 42.2 3.1 34

95 47.8 1.1 34

81 50.3 0.5 21

87 53.7 1.8 21

aWomen 50-69 years still living in the city at the end of 1985. bp

cp

< 0.05. < 0.001.

Fregllity tracturea per 101 women years 70

0--4

50-69 years

60

50

40

0.003), but not >70. When BMC 1 cm and BMC 6 cm were entered separately the significance of menopausal age for fracture risk still remained in the age group 50-69 but was weaker (p = 0.01 a n d p = 0.04, respectively). When age at menopause, age, and BMC 6 cm were entered in a logistic regression, menopausal age was not significantly related to fracture risk but remained significant (p = 0.01) in the model with BMC 1 cm and age. The odds ratio for fragility fracture risk for a 3, 5, and 10 year difference in menopausal age is shown in Table 6. The Cox proportional hazard model was used to model time from BMC measurement to first fracture as a function of age at menopause, age, BMC 1 cm, and BMC 6 cm. Only age, BMC 1 cm, and BMC 6 cm remained independently significant variables in the Cox proportional hazard model.

DISCUSSION 30

Understanding of osteoporosis is hampered by the multifactorial risks and the long turnover time of bone tissue. RiggsC9Jfocused on five major risk factors for osteoporosis: age, initial bone mass, age at menopause, bioavailabil-

20

10

41

,

I

42

40

50

54

Ouartlles Menopsumal age

FIG. 1. Fragility fractures per lo00 women-years (observed between 1975 and 1985) for the various quartiles of menopausal age. The bars indicate the confidence intervals (95%).

432

CARDSELL ET AL.

TABLE4. DISTRIBUTION OF FRAGILITY FRACTURES FOR THE VARIOUS QUARTILES OF MENOPAUSAL AGE(WOMEN 50-69

YEARS)

Hip Age at menopause, quartiles @ears) 42 ( 0 = 48 ( n = 50 ( n = 54 ( n = Total

79) 95) 81) 87)

Distal end of radius

Proximal end of humerus

Cervical

Trochanteric

Vertebrae

Pelvis

11 13 I1 11 46

6 8 4 6 24

6 5 4 2 17

4 4 1 4 13

19 22 12 11 54

1 2 1 3 7

TABLE5. ODDSRATIO(OR) FOR A FRAGILITY FRACTURE^ OR

Unadjusted Adjusted for age Adjusted for age. BMC 1 cm, and BMC 6 cm

ql versus 42

ql versus 43

1.2 (0.49) 1.3 (0.47) 1.1 (0.76)

2.3 (0.02) 2.4 (0.01) 2.3 (0.02)

ql versus q4 2.3 (0.01) 2.4 (0.001) 2.0 (0.06)

aWhen comparing the lowest quartile (ql) of age at menopause with the other quartiles (q2, q3, and q4). P values in parentheses.

ity of calcium, and sporadic factors. Yano et a1.t1O) found that such variables as age, sex, height, and weight contributed to at most one-third of the variability of bone mass in postmenopausal women. Richelson et al.("] compared bone mass in women who had undergone oophorectomy in young adulthood, perimenopausal women, and normal postmenopausal women and came to the conclusion that the predominant cause of bone loss during the first two postmenopausal decades was estrogen deficiency. In a recent study Georgiou et al.I5) stressed the importance of total estrogenic effect during the reproductive years on later bone mineral content by showing that the BMC had a better linear correlation with the total number of menstrual cycles than with the years elapsed since menopause or with chronologic age. Drinkwater'll) also demonstrated the importance of menstrual history and its connection with current bone mass.

Tibia1 condyle 2 1

0 1 4

The duration of the fertile period and the age at menopause appear to be directly correlated. In the present study this seems to influence BMC and the fracture risk as well. The risk conferred by early menopause is therefore probably due to a longer exposure at a low bone mass level. The menopausal age is not in the present study correlated with fracture over age 70. This age limit can hardly be strict, since biologic and chronologic age do not always correspond. One problem with a longitudinal study over 11 years is that in the oldest age group there are fewer survivors. However, including all patients > 70, and those who died during the study, the menopausal age was still the same for the fracture and nonfracture groups. In old women bone mass is almost always low and, of course, an important risk factor. Fracture therefore becomes almost certain to occur in the event of a fall or other precipitating event. This may explain why functional(13)and social('4) factors become more important in old age as predictors of fracture risk than factors correlated with peri- or postmenopausal events. One could also argue that disease, medication, disability, and social factors, not possible to predict many years ahead, may influence bone mass and fracture risk more in older women and therefore obscure any remaining influence of age at menopause. When selecting women for preventive measures in middle age, menopausal age, just as BMC, seems to be of limited value for predicting most fragility fractures (those that occur in the oldest women),(') whereas in the decades following the menopause, the menopausal age, because of its influence on BMC, is a good predictor of future fracture, as we have shown earlier for BMC. However, Cummings et al.t15' found that low bone density was associated with an increased risk of hip fracture in women >65 years, but this accounted for only part of the age-related increase in risk of hip fracture.

433

MENOPAUSE AND FRACTURE RISK

TABLE6. ODDSRATIO(OR) FOR FRAGILITY FRACTURE RISKFOR CHANGES IN AGEAT ME NO PAUSE^

OR

Earlier menopause (years) 3

5 10

Menopausal age unadjusted

Adjusted for age

1.4 (1.1- 1.7) 1.7 (1.2-2.4) 2.8 (1.4-5.6)

1.4 ( 1 . 1 - 1.7) 1.7 (1.2-2.4) 2.9 (1 -4-5.7)

Adjusted

Adjusted

for BMC 1 cm

for BMC 6 cm

1.3

1.3

( 1 .1 - 1.6)

( 1 .O- 1.5)

1.6 (1.1-2.2) 2.5 (1.2-5.0)

1.4 (1 .o-2.1) 2.1 (1.0-4.3)

Adjusted f o r weight 1.4 (1.1- 1.7) 1.7 (1.2-2.4) 2.8 (1.4-5.6)

-

Confidence interval (95%) within brackets.

ACKNOWLEDGMENTS This work was supported by the Swedish Medical Research Council project no. B90-17X-07975-04A and the Herman Jarnhardt, Greta and Johan Kock, and Alfred Osterlund Foundations.

7. Gardsell P, Johnell 0, Nilsson BE 1989 Predicting fractures

8.

9.

10.

11.

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osteoporosis in normal women: Its relation to age and the menopause. Q J Med 35:25. Nilsson BE 1970 Menopause and femur density. In: Proceedings of Bone Measurement Conference (CONF 700515). United States Atomic Energy Commission, Division of Technical Information, pp. 334-337. Guesens P, Dequeker J , Verstraeten A, Nijs J 1986 Age, sex and menopause related changes of vertebral and peripheral bone: Population study using dual and single photon absorptiometry and radiogrammetry. J Nucl Med 27:1540-1549. Georgiou E, Korkotsidis A, Metallinos I, Ntalles K, Proukakis C 1987 Retrospective estimation of endogenous estrogens for explaining bone mineral loss in postmenopausal women. In: Christiansen C, Johansen JS, Riis BJ (eds) Osteoporosis 1987. Osteopress, Copenhagen, pp. 575-577. Nordin BE, Polley KJ, Chatterton BE, Walker CJ 1987 Factors influencing and reflecting the rate of peripheral bone loss in normal postmenopausal women. In: Christiansen C, Johansen JS, Riis BJ (eds) Osteoporosis 1987. Osteopress, Copenhagen, pp. 132-133.

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in women by using forearm bone densitometry. Calcif Tissue lnt 44:235-242. Naucler LOW, Nilsson BE, Westlin NE 1974 An apparatus for gamma absorptiometry of bone- technical data. Opuscula Medicotechnica 12:1231. Riggs BL 1987 Pathogenesis of osteoporosis. Am J Obstet Gynecol 156:1342- 1346. Yano K, Wasnich RD, Vogel JM, Heilbrun LK 1984 Bone mineral measurements among middle aged and elderly Japanese residents in Hawaii. Am J Epidemiol 119:751-764. Richelson LS, Wahner HW, Melton LJ 111, Riggs BL 1984 Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 311:1273-1275. Drinkwater BL 1987 Maximizing bone mass in the premenopausal years: Positive and negative factors. In: Christiansen C, Johansen JS, Riis BJ (eds) Osteoporosis 1987. Osteopress, Copenhagen, pp. 484-488. Gardsell P, Johnell 0, Nilsson BE, Nilsson JA 1989 The predictive value of fracture, disease, and falling tendency for fragility fractures in women. Calcif Tissue Int 45:327-330. Sernbo I 1988 Hip fracture. Doctoral dissertation, Lund University, Sweden. Cummings SR, Black DM, Nevitt MC, Browner WS, Cauley JA, Genant HK, Macioli SR, Scott JC, Seeley DG. Steiger P, Vogt TM, Study of Osteoporotic Fractures Research Group 1990 Appendicular bone density and age predict hip fracture in women. JAMA 263:665-668.

Address reprint requests to: Dr. Per GZirdseN Department of Orthopaedics Malmo General Hospital S-214 01 Malmo, Sweden Received for publication January 22, 1990; in revised form November 28, 1990; accepted November 28, 1990.

The impact of menopausal age on future fragility fracture risk.

Altogether 733 postmenopausal women were interviewed with regard to their age at menopause. Subsequent fragility fractures over an 11 year period were...
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