- Email: [email protected]
Oral contraception and other factors in relation to hospital referral for fracture
ORIGINAL RESEARCH ARTICLE
Oral Contraception and Other Factors in Relation to Hospital Referral for Fracture Findings in a Large Cohort Study Martin Vessey,* Jonathan Mant,* and Rosemary Painter* There is good evidence that estrogens and progestogens have an important effect on bone metabolism. This article explores the relationship between oral contraceptive (OC) use and fractures occurring at various sites among the 17,032 participants in the Oxford-Family Planning Association contraceptive study, which now includes information accumulated during 310,000 woman-years of observation between 1968 and 1994. In total, 1308 women suffered at least one fracture during the follow-up period, which was largely confined to premenopausal years. When all fractures were combined, there was a modest, but highly significant trend (p ,0.001) of increasing risk with total duration of oral contraceptive use. In addition, there was statistically significant heterogeneity (p ,0.01) when overall fracture rates were examined in relation to recency of oral contraceptive use during the premenopausal lifespan. The highest relative risk (1.3, 95% CI 1.1–1.5) was for current or recent oral contraceptive users; however, viewed as a whole, no clear pattern of risk was apparent. Examination of the data for individual fracture sites (including the lower end of the radius/ulna) did not provide any evidence of a protective effect of oral contraceptive use. These results are closely similar to those reported from the Royal College of General Practitioners Oral Contraception Study in 1993. CONTRACEPTION 1998;57:231–235 © 1998 Elsevier Science Inc. All rights reserved. KEY WORDS:
oral contraceptive, fractures, cohort study, body mass index
Introduction
E
strogens and progestogens are known to have important effects on bone metabolism.1,2 Accordingly, it is not surprising that a considerable number of studies have been conducted seeking to *Division of Public Health and Primary Health Care, Institute of Health Sciences, Oxford, England Name and address for correspondence: Professor Martin Vessey, Division of Public Health and Primary Health Care, Institute of Health Sciences, Old Road, Headington, Oxford, OX3 7LF, England; Tel: 144-1865-227-030; Fax: 1441865-226-655 Submitted for publication November 21, 1997 Revised March 6, 1998 Accepted for publication March 13, 1998
© 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
find a relationship between oral contraceptive use and bone mass at different ages and at various skeletal sites. A comprehensive review published in 1993 on the epidemiology of bone mass in premenopausal women came to the conclusion that oral contraceptive studies published up to that time had given conflicting results.3 The review also stressed the numerous problems that had to be resolved in trying to produce a clear answer. A more recent review reported on eight studies showing a positive effect of oral contraceptives (OC) on bone mineral density and four studies showing no such effect.4 The author considered that the weight of the evidence suggested that premenopausal use of OC is beneficial for preserving bone mass. This issue, however, remains highly controversial.5 In 1993, the Royal College of General Practitioners (RCGP) Oral Contraception Study provided the first prospective data concerned with oral contraceptive use and fracture risk— clearly a more important outcome measure than bone mass.6 Surprisingly, the risk of fracture for all sites combined among those who had ever used OC was slightly but significantly greater than that among those who had never used OC (relative risk 1.20, 95% CI 1.08 –1.34). No relationship between pill use and forearm fracture risk was detectable. The authors recognized that the study did not provide much information on older women, but nonetheless stressed that the findings were not suggestive of a beneficial effect of OC. In view of the report from the RCGP study, it was considered worthwhile to examine the corresponding data in the Oxford-Family Planning Association (Oxford-FPA) contraceptive study. The findings are summarized below.
Methods A detailed description of the methods used in the Oxford-FPA study has been given elsewhere.7 In brief, 17,032 women were recruited at 17 large family planning clinics in England and Scotland between 1968 and 1974. At the time of recruitment, each ISSN 0010-7824/98/$19.00 S0010-7824(98)00026-2
232
Vessey et al.
Contraception 1998;57:231–235
Table 1. Summary of associations between first hospital referral rates for fractures and age, parity, social class, smoking, height, weight and body mass index (BMI); the rates on which the table is based were standardized for age Site of fracture Skull and facial bones Spine Ribs, pelvis, other trunk Clavicle Humerus Radius/ulna (lower end) Radius/ulna (not lower end) Carpal bones Metacarpals Phalanges (hand) Neck of femur Tibia and fibula Ankle Tarsals/metatarsals Phalanges (foot) All fractures*
No. of women
Age
Parity
Social class
Smoking
Height
Weight
77 72 108 25 80 205 100 45 37 102 23 70 193 168 127 1308
22 2 111 2 111 111 111 111 2 1 111 111 111 1 2 111
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2
2 2 2 2 2 2 2 2 2 2 2 1 2 2 2 2
2 2 2 2 2 2 2 2 2 2 2 2 2 2 1 2
2 2 2 2 1 2 2 2 2 2 2 2 2 11 2 2
2 2 2 2 2 2 2 2 2 2 2 2 111 11 2 2
Body mass Index 2 2 2 2 2 2 2 2 2 2 2 111 2 2 2
Not shown: scapula (2), unclassified upper limb (1), femoral shaft (9), patella (13), other lower limb (13), unclassified lower limb (7). *Some women had more than one fracture. Hence, the sum of the individual fractures is greater than the total of all of the fractures. 1positive association; 2negative association; 2 no association; one arrow, p ,0.05; two arrows, p ,0.01; three arrows, p ,0.001 (based on x2 trend) Groupings used in trend analysis: Age (years) 25–34, 35–39, 40 – 44, 45– 49, 50 –54, 55–59, 601. Parity (term births) 0, 1, 2, 3, 41. Social class (Registrar General’s Classification) I–II, III, IV–V (1 forces, unemployed). Smoking (cigarettes/day); never, ex-smoker, 1–14, 151. Height (cm) ,154, 154 –164, $165. Weight (kg) ,51, 51–57, 58 – 63, 64 –70, .70. Body Mass Index (kg/m2) ,20, 20 –21.9, 22–23.9, 24 –25.9, 26 –27.9, $28.
woman had to be: 1) aged 25–39 years, 2) married, 3) white and British, 4) willing to cooperate, and 5) either a current user of OC of $5 months standing or a current user of a diaphragm or an intrauterine device of $5 months standing without previous exposure to the pill. Among other items, each woman was asked questions at entry to the study about her age, childbearing history, contraceptive history, height and weight, social class, smoking behavior, and past medical history. During follow up, each woman was questioned by a doctor or a nurse at return visits to the clinic and certain items of information were noted on a special form. These included details of pregnancies and their outcome, changes in contraceptive practices and reasons for the changes, and particulars of any referrals to hospital either as an outpatient or an inpatient. Diagnoses on discharge from hospital were confirmed by obtaining copies of discharge letters, summaries, and pathology reports. Women who stopped attending the clinic were sent a postal version of the follow-up form and, if this was not returned, were interviewed by telephone or at a home visit. The work was coordinated by a part-time research assistant in each clinic and yearly follow up was maintained until age 45 with an annual loss of contact of only about 0.4%. On reaching the age of 45 years, each woman was allocated to one of three groups: 1) OC never used, 2) OC used for a total of $8 years, and 3) other durations of oral contraceptive use. Only the women in the first
two groups were followed annually until 1994 in the detailed way described earlier. Accordingly, women in group c have been omitted from the present analysis from the age of 45 onward. This analysis is based on the computation of woman-years of observation terminated by the occurrence of the first referral to hospital for the fracture under consideration, by release from follow-up (emigration, death, short-term pill users reaching age 45 years), by loss to follow-up, or by the end of the study (July 1994). Both inpatient and outpatient referrals to hospital for fracture were included in the analysis. Indirectly standardized fracture rates were calculated by the method described by Vessey et al,7 and tests of significance and the calculation of confidence intervals were based on methods described by Breslow and Day.8 Analyses were conducted separately for women aged ,45 years and for women aged $45 years. The results in the two sets of analyses were similar; accordingly, only the overall figures are given here.
Results The study includes 310,000 woman-years of observation, 123,000 in those never using OC and 187,000 in those ever having done so. Of the total number of woman-years of observation, 44,000 (14%) relate to those aged $50 years of age. Table 1 shows the fracture sites under consideration and the number of women with the different
Contraception 1998;57:231–235
OC and Fractures
233
Table 2. Associations between first hospital referral rates for the three most commonly occurring types of fracture (and for all fractures) and other factors given in Table 1; data are relative risks and 95% confidence intervals (adjusted for age) Fracture site Variable Age (years) Parity (no. of births) Social class Smoking (cigs/day) Height (cm) Weight (kg) Body mass index (kg/m2)
Baseline group
Comparison group
Radius/ulna (lower end)
Ankle
Tarsals/metatarsals
All fractures
25–34 0 I–II Never ,154 ,51
55–59* 41 IV–V 151 $165 .70
10.1 (5.5–19.1) 0.4 (0.2–0.9) 0.9 (0.5–1.4) 0.8 (0.5–1.3) 1.0 (0.6–1.8) 0.9 (0.5–1.6)
3.7 (2.0–6.5) 0.8 (0.4–1.4) 0.9 (0.5–1.6) 0.8 (0.5–1.4) 0.7 (0.4–1.2) 2.2 (1.3–3.8)
1.4 (0.5–3.1) 0.9 (0.5–1.6) 0.9 (0.6–1.5) 1.1 (0.7–1.7) 2.3 (1.1–5.8) 2.2 (1.1–4.7)
2.9 (2.3–3.7) 0.9 (0.7–1.1) 0.9 (0.8–1.1) 1.0 (0.8–1.2) 1.0 (0.8–1.3) 1.2 (0.9–1.5)
,20
$28
0.9 (0.4–1.8)
3.5 (2.0–6.1)
1.0 (0.4–2.1)
1.2 (0.9–1.6)
*This group was chosen for comparison because the 601 group was small. Cigs, cigarettes.
fractures. In total, 1308 women suffered at least one fracture during the follow-up period. It should be noted that the distinction between fractures of the lower end of the radius and fractures of the carpal bones was not clear in all cases because injuries were sometimes described in generic terms as “fractures of the wrist.” Uncertain cases were counted in with fractures of the lower end of the radius/ulna. Table 1 also shows in summary form which relationships between the various first hospital referral rates and a range of other factors of potential importance reached statistical significance. The direction of the significant relationships is also indicated. There was a highly significant positive association (p ,0.001) between age and fracture risk overall and also between age and fractures of the ribs/pelvis, humerus, radius/ulna (lower end), radius/ulna (not lower end), carpal bones, femoral neck, tibia/fibula, and ankle. Similar but less highly significant associations were seen between age and fractures of the phalanges (hand) and tarsals/metatarsals. Fractures of the skull and facial bones showed a significant negative association with age. Apart from age, the only other highly significant associations (p ,0.001) found were positive correlations between ankle fractures and weight and body mass index. There were similar but less highly significant associations between fractures of the tarsals/ metatarsals and height and weight and between fractures of the humerus and height. Fractures of the skull and facial bones showed a negative association with weight that was of borderline significance. Associations of marginal significance were found sporadically between the risk of fracture at certain sites and the other variables investigated; it seems reasonable to attribute them to the play of chance in the absence of any other explanation. Table 2 provides simple information concerning the magnitude of the associations between first hos-
pital referral rates for the three most commonly occurring types of fracture (radius/ulna (lower end), ankle, tarsals/metatarsals), and for all fractures combined, and the other factors included in Table 1. Fractures of the radius/ulna (lower end) in particular, but also fractures of the ankle, were strongly related to age. Other elevated relative risks were generally of the order of two- to threefold, but the relative risk of 3.5 (2.0 – 6.1) for ankle fracture contrasting women with a high body mass index ($28 kg/m2) with those with a low body mass index (,20 kg/m2) should be noted. To examine the possible association between fractures and oral contraceptive use, two measures of pill exposure were used: total duration of use and interval since last use. Table 3 shows that when all fractures were combined, there was a modest but highly significant trend (p ,0.001) of increasing risk with total duration of oral contraceptive use. Table 3 also shows that there was a significant trend (p 5 0.017) for fractures of the radius/ulna (lower end) but not for fractures of the ankle or tarsals/metatarsals. Of the data not shown in Table 3, the only other statistically significant trends (both positive) were for fractures of the ribs/pelvis/other trunk (p 5 0.039) and of the phalanges of the foot (p 5 0.039). Data for recency of oral contraceptive use are given in Table 4. There was statistically significant heterogeneity (p 5 0.009) when overall fracture rates were examined. The highest relative risk (1.3; 1.1–1.5) was for current or recent users of OC, but viewed overall, no clear pattern of risk was apparent. The relative risks for fracture of the radius/ulna (lower end) were also significantly heterogeneous, but no pattern was discernible. Relative risks for ankle fractures and fractures of the tarsals/metatarsals were unremarkable, as were the relative risks for the fracture sites not shown in Table 4.
234
Vessey et al.
Contraception 1998;57:231–235
Table 3. Associations between first hospital referral rates for the three most commonly occurring types of fracture (and for all fractures) by total duration of pill use; data are relative risks and 95% confidence intervals (adjusted for age) Total duration of oral contraceptive use (months) Nonuser #12 13–24 25–48 49–72 73–96 971 x2 heterogeneity x2 trend
Fracture site Radius/ulna (lower end) 1.0 1.1 (0.3–2.8) 1.8 (0.8–3.8) 1.3 (0.7–2.2) 1.1 (0.6–2.0) 1.1 (0.6–2.1) 1.5 (1.1–2.1) 8.3 (p 5 0.216) 5.7 (p 5 0.017)
Ankle
Tarsals/metatarsals
1.0 0.7 (0.1–2.1) 1.6 (0.7–3.2) 0.9 (0.4–1.6) 0.7 (0.3–1.3) 1.3 (0.7–2.3) 1.0 (0.7–1.5) 5.2 (p 5 0.516) 0.0 (p 5 0.826)
Discussion The analyses summarized here were undertaken in response to the findings in the RCGP study published in 1993.6 In total, 1365 women suffered at least one fracture during 482,000 woman-years of observation in the RCGP study6; the corresponding figures in the Oxford-FPA study were 1308 women with fractures during 310,000 woman-years of observation. Using data given in the RCGP study report,6 it is possible to show that if the age-specific fracture rates found in the Oxford-FPA study had applied in the RCGP study, 2050 women would have suffered a fracture rather than the 1365 reported. The overall distributions of fractures by site in the two studies were similar, with fractures of the radius/ulna, tarsal/metatarsal bones, and ankle at the head of both lists. It is, of course, impossible to be sure about the explanation for the difference in fracture rates between the two studies, but differences in the characteristics of the populations other than their age distributions or underreporting of fractures in the RCGP study are both possibilities. Both the RCGP study and the Oxford-FPA study
1.0 0.4 (0.0–1.5) 0.9 (0.3–2.2) 1.2 (0.7–2.0) 1.2 (0.7–2.0) 1.2 (0.6–2.0) 0.8 (0.5–1.2) 5.3 (p 5 0.505) 0.2 (p 5 0.626)
All fractures 1.0 0.8 (0.5–1.2) 0.9 (0.6–1.3) 1.2 (1.0–1.5) 1.2 (0.9–1.4) 1.2 (1.0–1.5) 1.2 (1.1–1.4) 15.8 (p 5 0.015) 11.2 (p ,0.001)
include relatively few observations on women $50 years of age and practically none .65 years. Accordingly, it might be too early to expect to show any beneficial effect of oral contraceptive use on fracture risk. Another limitation is that of the three sites where fracture risk is most strongly related to low bone mineral content—the wrist, spine, and femoral neck—substantial numbers of events in the two studies have accumulated only for the wrist. Nonetheless, both studies include a high proportion of women with many years of OC use, a fact that provides justification for the present evaluation. In any event, the main findings in the two studies are closely similar. Neither has provided any evidence of a protective effect of OC; on the contrary, both suggest about a 20% increase in the overall risk of fracture comparing women who have used OC at any point with those who have never used OC. In the Oxford-FPA study there was a slight (but statistically significant) increase in overall risk with total duration of oral contraceptive use; this was not the case in the RCGP study. No significant effect of oral contraceptive use on forearm fractures was apparent in the
Table 4. Associations between first hospital referral rates for the three most commonly occurring types of fracture (and for all fractures) by interval since last pill use; data are relative risks and 95% confidence intervals (adjusted for age) Interval since oral contraceptives last used (months) Nonuser Current user (#12) 13–24 25–48 49–72 73–96 97–120 1211 x2 heterogeneity
Fracture site Radius/ulna (lower end) 1.0 1.2 (0.7–1.8) 1.2 (0.4–2.8) 1.0 (0.4–1.9) 1.7 (0.9–3.0) 2.5 (1.5–4.0) 1.6 (0.8–2.8) 1.1 (0.7–1.8) 18.8 (p 5 0.009)
Ankle 1.0 1.2 (0.8–1.8) 1.0 (0.4–2.3) 1.0 (0.5–1.9) 0.7 (0.3–1.5) 0.9 (0.4–1.8) 1.1 (0.5–2.1) 0.9 (0.5–1.4) 3.1 (p 5 0.871)
Tarsals/metatarsals 1.0 1.1 (0.7–1.6) 1.1 (0.4–2.3) 1.2 (0.6–2.2) 0.8 (0.3–1.6) 0.8 (0.4–1.8) 0.8 (0.3–1.8) 0.7 (0.3–1.2) 4.0 (p 5 0.780)
All fractures 1.0 1.3 (1.1–1.5) 1.2 (0.9–1.6) 1.0 (0.8–1.3) 1.1 (0.8–1.4) 1.2 (0.9–1.5) 1.3 (1.0–1.6) 1.0 (0.8–1.2) 18.7 (p 5 0.009)
Contraception 1998;57:231–235
RCGP study, but the results in the Oxford-FPA study for fractures of the lower end of the radius/ulna were similar to those for fractures overall. As pointed out in the RCGP study report,6 the finding of a 20% increase in the risk of all fractures among users of OC is difficult to interpret. An adverse effect of the pill on bone is unlikely and it may be that behavioral characteristics of pill users underlie the differences. For example, in both studies, oral contraceptive users were more likely to be cigarette smokers than were nonusers. Although cigarette smoking per se does not appear to have confounded the association between use of OC and fractures (see Tables 1 and 2), it may be an indicator of differences in other important aspects of lifestyle between users and nonusers of OC. For example, it almost certainly implies a greater intake of alcohol among oral contraceptive users and possibly a generally more relaxed attitude toward indulging in risky behavior—which might, on occasion, increase the chances of a fracture occurring. One thing, at least, is clear. Neither of the two large British cohort studies of oral contraceptive use provide any evidence thus far that pill use offers any important protection against the occurrence of fractures in premenopausal women.
Acknowledgments We thank Mrs. D Collinge, Mrs. J Winfield, and the research assistants, doctors, and nurses who worked
OC and Fractures
235
in the participating clinics for their important contribution. We are also grateful to the Medical Research Council and the Knott Family Trust for financial support.
References 1. The Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineral density. Results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1996;276:1389 –96. 2. Gallagher JC, Kable WT. Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. Am J Med 1991;90:171– 8. 3. Sowers MR, Galuska DA. Epidemiology of bone mass in premenopausal women. Epidemiol Rev 1993;15:374 –98. 4. DeCherney A. Bone-sparing properties of oral contraceptives. Am J Obstet Gynecol 1996;174:15–20. 5. Hartard M, Bottermann P, Bartenstein P, Jeschke D, Schwaiger M. Effects on bone mineral density of lowdosed oral contraceptives compared to and combined with physical activity. Contraception 1997;55:87–90. 6. Cooper C, Hannaford P, Croft P, Kay CR. Oral contraceptive pill use and fractures in women: a prospective study. Bone 1993;14:41–5. 7. Vessey MP, Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up study of women using different methods of contraception—an interim report. J Biosoc Sci 1976;8:373– 427. 8. Breslow NE, Day NE. Statistical Methods in Cancer Research, Vol II. The Design and Analysis of Cohort Studies. Lyon: International Agency for Research on Cancer, 1987.
Oral Contraception and Other Factors in Relation to Hospital Referral for Fracture Findings in a Large Cohort Study Martin Vessey,* Jonathan Mant,* and Rosemary Painter* There is good evidence that estrogens and progestogens have an important effect on bone metabolism. This article explores the relationship between oral contraceptive (OC) use and fractures occurring at various sites among the 17,032 participants in the Oxford-Family Planning Association contraceptive study, which now includes information accumulated during 310,000 woman-years of observation between 1968 and 1994. In total, 1308 women suffered at least one fracture during the follow-up period, which was largely confined to premenopausal years. When all fractures were combined, there was a modest, but highly significant trend (p ,0.001) of increasing risk with total duration of oral contraceptive use. In addition, there was statistically significant heterogeneity (p ,0.01) when overall fracture rates were examined in relation to recency of oral contraceptive use during the premenopausal lifespan. The highest relative risk (1.3, 95% CI 1.1–1.5) was for current or recent oral contraceptive users; however, viewed as a whole, no clear pattern of risk was apparent. Examination of the data for individual fracture sites (including the lower end of the radius/ulna) did not provide any evidence of a protective effect of oral contraceptive use. These results are closely similar to those reported from the Royal College of General Practitioners Oral Contraception Study in 1993. CONTRACEPTION 1998;57:231–235 © 1998 Elsevier Science Inc. All rights reserved. KEY WORDS:
oral contraceptive, fractures, cohort study, body mass index
Introduction
E
strogens and progestogens are known to have important effects on bone metabolism.1,2 Accordingly, it is not surprising that a considerable number of studies have been conducted seeking to *Division of Public Health and Primary Health Care, Institute of Health Sciences, Oxford, England Name and address for correspondence: Professor Martin Vessey, Division of Public Health and Primary Health Care, Institute of Health Sciences, Old Road, Headington, Oxford, OX3 7LF, England; Tel: 144-1865-227-030; Fax: 1441865-226-655 Submitted for publication November 21, 1997 Revised March 6, 1998 Accepted for publication March 13, 1998
© 1998 Elsevier Science Inc. All rights reserved. 655 Avenue of the Americas, New York, NY 10010
find a relationship between oral contraceptive use and bone mass at different ages and at various skeletal sites. A comprehensive review published in 1993 on the epidemiology of bone mass in premenopausal women came to the conclusion that oral contraceptive studies published up to that time had given conflicting results.3 The review also stressed the numerous problems that had to be resolved in trying to produce a clear answer. A more recent review reported on eight studies showing a positive effect of oral contraceptives (OC) on bone mineral density and four studies showing no such effect.4 The author considered that the weight of the evidence suggested that premenopausal use of OC is beneficial for preserving bone mass. This issue, however, remains highly controversial.5 In 1993, the Royal College of General Practitioners (RCGP) Oral Contraception Study provided the first prospective data concerned with oral contraceptive use and fracture risk— clearly a more important outcome measure than bone mass.6 Surprisingly, the risk of fracture for all sites combined among those who had ever used OC was slightly but significantly greater than that among those who had never used OC (relative risk 1.20, 95% CI 1.08 –1.34). No relationship between pill use and forearm fracture risk was detectable. The authors recognized that the study did not provide much information on older women, but nonetheless stressed that the findings were not suggestive of a beneficial effect of OC. In view of the report from the RCGP study, it was considered worthwhile to examine the corresponding data in the Oxford-Family Planning Association (Oxford-FPA) contraceptive study. The findings are summarized below.
Methods A detailed description of the methods used in the Oxford-FPA study has been given elsewhere.7 In brief, 17,032 women were recruited at 17 large family planning clinics in England and Scotland between 1968 and 1974. At the time of recruitment, each ISSN 0010-7824/98/$19.00 S0010-7824(98)00026-2
232
Vessey et al.
Contraception 1998;57:231–235
Table 1. Summary of associations between first hospital referral rates for fractures and age, parity, social class, smoking, height, weight and body mass index (BMI); the rates on which the table is based were standardized for age Site of fracture Skull and facial bones Spine Ribs, pelvis, other trunk Clavicle Humerus Radius/ulna (lower end) Radius/ulna (not lower end) Carpal bones Metacarpals Phalanges (hand) Neck of femur Tibia and fibula Ankle Tarsals/metatarsals Phalanges (foot) All fractures*
No. of women
Age
Parity
Social class
Smoking
Height
Weight
77 72 108 25 80 205 100 45 37 102 23 70 193 168 127 1308
22 2 111 2 111 111 111 111 2 1 111 111 111 1 2 111
2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2
2 2 2 2 2 2 2 2 2 2 2 1 2 2 2 2
2 2 2 2 2 2 2 2 2 2 2 2 2 2 1 2
2 2 2 2 1 2 2 2 2 2 2 2 2 11 2 2
2 2 2 2 2 2 2 2 2 2 2 2 111 11 2 2
Body mass Index 2 2 2 2 2 2 2 2 2 2 2 111 2 2 2
Not shown: scapula (2), unclassified upper limb (1), femoral shaft (9), patella (13), other lower limb (13), unclassified lower limb (7). *Some women had more than one fracture. Hence, the sum of the individual fractures is greater than the total of all of the fractures. 1positive association; 2negative association; 2 no association; one arrow, p ,0.05; two arrows, p ,0.01; three arrows, p ,0.001 (based on x2 trend) Groupings used in trend analysis: Age (years) 25–34, 35–39, 40 – 44, 45– 49, 50 –54, 55–59, 601. Parity (term births) 0, 1, 2, 3, 41. Social class (Registrar General’s Classification) I–II, III, IV–V (1 forces, unemployed). Smoking (cigarettes/day); never, ex-smoker, 1–14, 151. Height (cm) ,154, 154 –164, $165. Weight (kg) ,51, 51–57, 58 – 63, 64 –70, .70. Body Mass Index (kg/m2) ,20, 20 –21.9, 22–23.9, 24 –25.9, 26 –27.9, $28.
woman had to be: 1) aged 25–39 years, 2) married, 3) white and British, 4) willing to cooperate, and 5) either a current user of OC of $5 months standing or a current user of a diaphragm or an intrauterine device of $5 months standing without previous exposure to the pill. Among other items, each woman was asked questions at entry to the study about her age, childbearing history, contraceptive history, height and weight, social class, smoking behavior, and past medical history. During follow up, each woman was questioned by a doctor or a nurse at return visits to the clinic and certain items of information were noted on a special form. These included details of pregnancies and their outcome, changes in contraceptive practices and reasons for the changes, and particulars of any referrals to hospital either as an outpatient or an inpatient. Diagnoses on discharge from hospital were confirmed by obtaining copies of discharge letters, summaries, and pathology reports. Women who stopped attending the clinic were sent a postal version of the follow-up form and, if this was not returned, were interviewed by telephone or at a home visit. The work was coordinated by a part-time research assistant in each clinic and yearly follow up was maintained until age 45 with an annual loss of contact of only about 0.4%. On reaching the age of 45 years, each woman was allocated to one of three groups: 1) OC never used, 2) OC used for a total of $8 years, and 3) other durations of oral contraceptive use. Only the women in the first
two groups were followed annually until 1994 in the detailed way described earlier. Accordingly, women in group c have been omitted from the present analysis from the age of 45 onward. This analysis is based on the computation of woman-years of observation terminated by the occurrence of the first referral to hospital for the fracture under consideration, by release from follow-up (emigration, death, short-term pill users reaching age 45 years), by loss to follow-up, or by the end of the study (July 1994). Both inpatient and outpatient referrals to hospital for fracture were included in the analysis. Indirectly standardized fracture rates were calculated by the method described by Vessey et al,7 and tests of significance and the calculation of confidence intervals were based on methods described by Breslow and Day.8 Analyses were conducted separately for women aged ,45 years and for women aged $45 years. The results in the two sets of analyses were similar; accordingly, only the overall figures are given here.
Results The study includes 310,000 woman-years of observation, 123,000 in those never using OC and 187,000 in those ever having done so. Of the total number of woman-years of observation, 44,000 (14%) relate to those aged $50 years of age. Table 1 shows the fracture sites under consideration and the number of women with the different
Contraception 1998;57:231–235
OC and Fractures
233
Table 2. Associations between first hospital referral rates for the three most commonly occurring types of fracture (and for all fractures) and other factors given in Table 1; data are relative risks and 95% confidence intervals (adjusted for age) Fracture site Variable Age (years) Parity (no. of births) Social class Smoking (cigs/day) Height (cm) Weight (kg) Body mass index (kg/m2)
Baseline group
Comparison group
Radius/ulna (lower end)
Ankle
Tarsals/metatarsals
All fractures
25–34 0 I–II Never ,154 ,51
55–59* 41 IV–V 151 $165 .70
10.1 (5.5–19.1) 0.4 (0.2–0.9) 0.9 (0.5–1.4) 0.8 (0.5–1.3) 1.0 (0.6–1.8) 0.9 (0.5–1.6)
3.7 (2.0–6.5) 0.8 (0.4–1.4) 0.9 (0.5–1.6) 0.8 (0.5–1.4) 0.7 (0.4–1.2) 2.2 (1.3–3.8)
1.4 (0.5–3.1) 0.9 (0.5–1.6) 0.9 (0.6–1.5) 1.1 (0.7–1.7) 2.3 (1.1–5.8) 2.2 (1.1–4.7)
2.9 (2.3–3.7) 0.9 (0.7–1.1) 0.9 (0.8–1.1) 1.0 (0.8–1.2) 1.0 (0.8–1.3) 1.2 (0.9–1.5)
,20
$28
0.9 (0.4–1.8)
3.5 (2.0–6.1)
1.0 (0.4–2.1)
1.2 (0.9–1.6)
*This group was chosen for comparison because the 601 group was small. Cigs, cigarettes.
fractures. In total, 1308 women suffered at least one fracture during the follow-up period. It should be noted that the distinction between fractures of the lower end of the radius and fractures of the carpal bones was not clear in all cases because injuries were sometimes described in generic terms as “fractures of the wrist.” Uncertain cases were counted in with fractures of the lower end of the radius/ulna. Table 1 also shows in summary form which relationships between the various first hospital referral rates and a range of other factors of potential importance reached statistical significance. The direction of the significant relationships is also indicated. There was a highly significant positive association (p ,0.001) between age and fracture risk overall and also between age and fractures of the ribs/pelvis, humerus, radius/ulna (lower end), radius/ulna (not lower end), carpal bones, femoral neck, tibia/fibula, and ankle. Similar but less highly significant associations were seen between age and fractures of the phalanges (hand) and tarsals/metatarsals. Fractures of the skull and facial bones showed a significant negative association with age. Apart from age, the only other highly significant associations (p ,0.001) found were positive correlations between ankle fractures and weight and body mass index. There were similar but less highly significant associations between fractures of the tarsals/ metatarsals and height and weight and between fractures of the humerus and height. Fractures of the skull and facial bones showed a negative association with weight that was of borderline significance. Associations of marginal significance were found sporadically between the risk of fracture at certain sites and the other variables investigated; it seems reasonable to attribute them to the play of chance in the absence of any other explanation. Table 2 provides simple information concerning the magnitude of the associations between first hos-
pital referral rates for the three most commonly occurring types of fracture (radius/ulna (lower end), ankle, tarsals/metatarsals), and for all fractures combined, and the other factors included in Table 1. Fractures of the radius/ulna (lower end) in particular, but also fractures of the ankle, were strongly related to age. Other elevated relative risks were generally of the order of two- to threefold, but the relative risk of 3.5 (2.0 – 6.1) for ankle fracture contrasting women with a high body mass index ($28 kg/m2) with those with a low body mass index (,20 kg/m2) should be noted. To examine the possible association between fractures and oral contraceptive use, two measures of pill exposure were used: total duration of use and interval since last use. Table 3 shows that when all fractures were combined, there was a modest but highly significant trend (p ,0.001) of increasing risk with total duration of oral contraceptive use. Table 3 also shows that there was a significant trend (p 5 0.017) for fractures of the radius/ulna (lower end) but not for fractures of the ankle or tarsals/metatarsals. Of the data not shown in Table 3, the only other statistically significant trends (both positive) were for fractures of the ribs/pelvis/other trunk (p 5 0.039) and of the phalanges of the foot (p 5 0.039). Data for recency of oral contraceptive use are given in Table 4. There was statistically significant heterogeneity (p 5 0.009) when overall fracture rates were examined. The highest relative risk (1.3; 1.1–1.5) was for current or recent users of OC, but viewed overall, no clear pattern of risk was apparent. The relative risks for fracture of the radius/ulna (lower end) were also significantly heterogeneous, but no pattern was discernible. Relative risks for ankle fractures and fractures of the tarsals/metatarsals were unremarkable, as were the relative risks for the fracture sites not shown in Table 4.
234
Vessey et al.
Contraception 1998;57:231–235
Table 3. Associations between first hospital referral rates for the three most commonly occurring types of fracture (and for all fractures) by total duration of pill use; data are relative risks and 95% confidence intervals (adjusted for age) Total duration of oral contraceptive use (months) Nonuser #12 13–24 25–48 49–72 73–96 971 x2 heterogeneity x2 trend
Fracture site Radius/ulna (lower end) 1.0 1.1 (0.3–2.8) 1.8 (0.8–3.8) 1.3 (0.7–2.2) 1.1 (0.6–2.0) 1.1 (0.6–2.1) 1.5 (1.1–2.1) 8.3 (p 5 0.216) 5.7 (p 5 0.017)
Ankle
Tarsals/metatarsals
1.0 0.7 (0.1–2.1) 1.6 (0.7–3.2) 0.9 (0.4–1.6) 0.7 (0.3–1.3) 1.3 (0.7–2.3) 1.0 (0.7–1.5) 5.2 (p 5 0.516) 0.0 (p 5 0.826)
Discussion The analyses summarized here were undertaken in response to the findings in the RCGP study published in 1993.6 In total, 1365 women suffered at least one fracture during 482,000 woman-years of observation in the RCGP study6; the corresponding figures in the Oxford-FPA study were 1308 women with fractures during 310,000 woman-years of observation. Using data given in the RCGP study report,6 it is possible to show that if the age-specific fracture rates found in the Oxford-FPA study had applied in the RCGP study, 2050 women would have suffered a fracture rather than the 1365 reported. The overall distributions of fractures by site in the two studies were similar, with fractures of the radius/ulna, tarsal/metatarsal bones, and ankle at the head of both lists. It is, of course, impossible to be sure about the explanation for the difference in fracture rates between the two studies, but differences in the characteristics of the populations other than their age distributions or underreporting of fractures in the RCGP study are both possibilities. Both the RCGP study and the Oxford-FPA study
1.0 0.4 (0.0–1.5) 0.9 (0.3–2.2) 1.2 (0.7–2.0) 1.2 (0.7–2.0) 1.2 (0.6–2.0) 0.8 (0.5–1.2) 5.3 (p 5 0.505) 0.2 (p 5 0.626)
All fractures 1.0 0.8 (0.5–1.2) 0.9 (0.6–1.3) 1.2 (1.0–1.5) 1.2 (0.9–1.4) 1.2 (1.0–1.5) 1.2 (1.1–1.4) 15.8 (p 5 0.015) 11.2 (p ,0.001)
include relatively few observations on women $50 years of age and practically none .65 years. Accordingly, it might be too early to expect to show any beneficial effect of oral contraceptive use on fracture risk. Another limitation is that of the three sites where fracture risk is most strongly related to low bone mineral content—the wrist, spine, and femoral neck—substantial numbers of events in the two studies have accumulated only for the wrist. Nonetheless, both studies include a high proportion of women with many years of OC use, a fact that provides justification for the present evaluation. In any event, the main findings in the two studies are closely similar. Neither has provided any evidence of a protective effect of OC; on the contrary, both suggest about a 20% increase in the overall risk of fracture comparing women who have used OC at any point with those who have never used OC. In the Oxford-FPA study there was a slight (but statistically significant) increase in overall risk with total duration of oral contraceptive use; this was not the case in the RCGP study. No significant effect of oral contraceptive use on forearm fractures was apparent in the
Table 4. Associations between first hospital referral rates for the three most commonly occurring types of fracture (and for all fractures) by interval since last pill use; data are relative risks and 95% confidence intervals (adjusted for age) Interval since oral contraceptives last used (months) Nonuser Current user (#12) 13–24 25–48 49–72 73–96 97–120 1211 x2 heterogeneity
Fracture site Radius/ulna (lower end) 1.0 1.2 (0.7–1.8) 1.2 (0.4–2.8) 1.0 (0.4–1.9) 1.7 (0.9–3.0) 2.5 (1.5–4.0) 1.6 (0.8–2.8) 1.1 (0.7–1.8) 18.8 (p 5 0.009)
Ankle 1.0 1.2 (0.8–1.8) 1.0 (0.4–2.3) 1.0 (0.5–1.9) 0.7 (0.3–1.5) 0.9 (0.4–1.8) 1.1 (0.5–2.1) 0.9 (0.5–1.4) 3.1 (p 5 0.871)
Tarsals/metatarsals 1.0 1.1 (0.7–1.6) 1.1 (0.4–2.3) 1.2 (0.6–2.2) 0.8 (0.3–1.6) 0.8 (0.4–1.8) 0.8 (0.3–1.8) 0.7 (0.3–1.2) 4.0 (p 5 0.780)
All fractures 1.0 1.3 (1.1–1.5) 1.2 (0.9–1.6) 1.0 (0.8–1.3) 1.1 (0.8–1.4) 1.2 (0.9–1.5) 1.3 (1.0–1.6) 1.0 (0.8–1.2) 18.7 (p 5 0.009)
Contraception 1998;57:231–235
RCGP study, but the results in the Oxford-FPA study for fractures of the lower end of the radius/ulna were similar to those for fractures overall. As pointed out in the RCGP study report,6 the finding of a 20% increase in the risk of all fractures among users of OC is difficult to interpret. An adverse effect of the pill on bone is unlikely and it may be that behavioral characteristics of pill users underlie the differences. For example, in both studies, oral contraceptive users were more likely to be cigarette smokers than were nonusers. Although cigarette smoking per se does not appear to have confounded the association between use of OC and fractures (see Tables 1 and 2), it may be an indicator of differences in other important aspects of lifestyle between users and nonusers of OC. For example, it almost certainly implies a greater intake of alcohol among oral contraceptive users and possibly a generally more relaxed attitude toward indulging in risky behavior—which might, on occasion, increase the chances of a fracture occurring. One thing, at least, is clear. Neither of the two large British cohort studies of oral contraceptive use provide any evidence thus far that pill use offers any important protection against the occurrence of fractures in premenopausal women.
Acknowledgments We thank Mrs. D Collinge, Mrs. J Winfield, and the research assistants, doctors, and nurses who worked
OC and Fractures
235
in the participating clinics for their important contribution. We are also grateful to the Medical Research Council and the Knott Family Trust for financial support.
References 1. The Writing Group for the PEPI Trial. Effects of hormone therapy on bone mineral density. Results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. JAMA 1996;276:1389 –96. 2. Gallagher JC, Kable WT. Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. Am J Med 1991;90:171– 8. 3. Sowers MR, Galuska DA. Epidemiology of bone mass in premenopausal women. Epidemiol Rev 1993;15:374 –98. 4. DeCherney A. Bone-sparing properties of oral contraceptives. Am J Obstet Gynecol 1996;174:15–20. 5. Hartard M, Bottermann P, Bartenstein P, Jeschke D, Schwaiger M. Effects on bone mineral density of lowdosed oral contraceptives compared to and combined with physical activity. Contraception 1997;55:87–90. 6. Cooper C, Hannaford P, Croft P, Kay CR. Oral contraceptive pill use and fractures in women: a prospective study. Bone 1993;14:41–5. 7. Vessey MP, Doll R, Peto R, Johnson B, Wiggins P. A long-term follow-up study of women using different methods of contraception—an interim report. J Biosoc Sci 1976;8:373– 427. 8. Breslow NE, Day NE. Statistical Methods in Cancer Research, Vol II. The Design and Analysis of Cohort Studies. Lyon: International Agency for Research on Cancer, 1987.