1 Departments of Obstetrics & Gynaecology, 2 Clinical Physics & Bone Densitometry and 3 Medical Statistics & Evaluation, ICSM at St Mary's and 4 Hammersmith Hospital, Praed Street, London W2 1PG, UK
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Abstract |
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Key words: bone density/heparin/pregnancy/prospective study
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Introduction |
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Heparin-induced osteoporosis was first reported in 1965 (Griffith et al., 1965). Several studies have since reported that long-term heparin treatment during pregnancy is associated with reduced bone density (de Swiet et al., 1983
; Dahlman et al., 1990
, 1994
; Barbour et al., 1994
; Douketis et al., 1996
) and vertebral bone fractures (Squires and Pinch, 1979
; Wise and Hall, 1980
; Griffith and Liu, 1984
; Dahlman, 1993
; Haram et al., 1993
). However, these findings may occur in pregnancies in which no pharmacological treatment is given (Drinkwater and Chestnut, 1991
; Khastgir and Studd, 1994
; Smith et al., 1995
; Khastgir et al., 1996
; Shefras and Farquharson, 1996
). It is therefore unclear what proportion of the reported reduction in bone density associated with long-term treatment with heparin during pregnancy is attributable to pregnancy itself and what proportion may be caused by heparin. This is compounded by the fact that earlier studies reporting heparin-induced osteoporosis during pregnancy used relatively imprecise radiological methods which suffer from poor sensitivity and reproducibility (Dahlman et al., 1990
). The recent introduction of dual photon X-ray absorptiometry (DEXA) has been an important step forward in assessing bone density.
We used DEXA to measure prospectively bone mineral density (BMD) at the lumbar spine (L2L4), the neck of femur and the forearm during pregnancy and the puerperium in women with a history of recurrent miscarriage and antiphospholipid antibodies treated with low-dose heparin and low-dose aspirin.
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Materials and methods |
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Bone densitometry
After obtaining informed patient consent, dual energy X-ray densitometry (DEXA, Lunar Corporation, Madison, Wisconsin, USA) was used to measure the BMD at the lumbar spine (L2L4), neck of femur and the forearm at 12 weeks gestation (baseline), immediately postpartum (2 weeks after delivery) and 12 weeks postpartum. The precision of DEXA for BMD is 1% at the lumbar spine and 2% at the femoral neck and the effective radiation dose at the lumbar spine and neck of femur is 1 µSv (WHO Study Group, 1994
).This is less than the radiation exposure of a passenger on a trans-Atlantic flight (70 µSv).
Based on the T-score, i.e. the BMD of an individual relative to that of a reference population of young adults, women were classified as having a BMD that was either normal, osteopenic (between 1 and 2.5 SD below that of the normal range) or osteoporotic (>2.5 SD below that of the normal range) (WHO Study Group, 1994).
Statistical analysis
Differences within the groups were tested for normality with the ShapiroFrancia test (Altman, 1991) for normal data and found suitable for Student's t-test for paired data. Differences between the groups were estimated by Student's t-test for unpaired data, Fisher's exact test, and the MannWhitney U-test. Multiple regression analysis was used to predict the changes in bone density from demographic and clinical details. P < 0.05 was considered to be statistically significant.
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Results |
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There was a significant decrease in the BMD at both the lumbar spine [mean decrease 0.046 g/cm2 (3.7%); P < 0.001] and at the neck of femur [0.01 g/cm2 (0.9%), P = 0.007] between 12 weeks gestation (baseline) and immediately post partum. There was no significant change in the BMD measurements at the forearm (Table II and Figure 1
). Women who breast-fed had a significant bone density loss at the lumbar spine and femoral neck compared with women who did not breast-feed (Table III
). There was no significant difference in BMD changes during pregnancy between those women receiving unfractionated heparin compared with those receiving low-molecular-weight heparin (Tables IV and V
).
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Discussion |
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In this large prospective study, we used DEXA, a sensitive and precise method of assessing BMD, to determine the changes in BMD at three sites (lumbar spine, neck of femur and forearm) in pregnant women receiving aspirin and heparin. During pregnancy, there was a significant decrease in bone density of 3.7% at lumbar spine (which consists predominantly of trabecular bone) and of 0.9% at the femoral neck (predominantly cortical bone) with no significant change at the forearm. These results are similar to those of prospective studies of BMD changes in untreated pregnancies (Drinkwater and Chestnut, 1991; Barbour et al., 1994
; Khastgir et al., 1996
; Shefras and Farguharson, 1996). Whether high oestrogen concentrations during pregnancy mitigate against the osteopenic effect of heparin, if such exists, remains unclear.
The precision of DEXA for BMD is 2% at the femoral neck; thus the drop of 0.9% in femoral neck BMD during pregnancy in our study may not be important. The presence of a near-term fetus at 34 weeks of pregnancy precludes BMD lumbar spine (L2L4) measurements, therefore we were not able to determine potential BMD changes between stopping the heparin at 34 weeks and the immediate postpartum period.
Importantly, we found that 8% of women were osteopenic at the lumbar spine at 12 weeks gestation despite the significant increase in bone density that occurred in the first trimester. This indicates that a considerable proportion of women have low bone density prior to pregnancy.
Prospective data relative to the effect of pregnancy on bone density (Drinkwater and Chestnut, 1991; Khastgir et al., 1996
; Shefras and Farguharson, 1996) indicate a fall of 3% in the lumbar spine bone density between pre-conceptual and immediate postpartum measurements. Pregnancy and lactation impose stress on maternal calcium homeostasis. Mineralization of the fetal skeleton is normally met by a series of hormone-mediated adjustments in maternal calcium metabolism during pregnancy including increased levels of 1,25-dihydroxyvitamin D, calcitonin and parathyroid hormone-related protein. Pregnancy-associated osteoporosis may stem from a failure of these physiological changes (Smith et al., 1985
). Alternatively, pregnancy may be a stress that unmasks a defective maternal skeleton in women with pre-existing osteopenia (Khastgir and Studd, 1994
).
Heparin has been reported to have a number of effects on bone metabolism. Avioli (1975) has suggested that heparin (i) as a chelating agent, binds calcium ions, resulting in secondary hyperparathyroidism with enhanced bone resorption, (ii) has a direct effect on bone cells with decreased osteoblastic or increased osteoclastic activity, and (iii) exerts its effect on the skeleton by disturbance of the bone matrix mucopolysaccharides leading to defective ossification. In-vitro animal data show that heparin induces an increase in osteoclastic bone resorption through binding and enhancement of an osteoclastic resorption-stimulating activity present in serum (Fuller et al., 1991). More recently, it has been reported that in the absence of parathyroid hormone or serum, heparin can stimulate bone resorption in fetal rat calvaria (Shaughnessy et al., 1995
). Heparin has also been shown to inhibit new bone formation via inhibition of collagen and DNA synthesis in fetal rat calvaria in vitro (Hurley et al., 1990
).
Previous longitudinal bone density studies suggest that lactation is associated with reversible bone loss (Sowers et al., 1993; Kalkwarf et al., 1995). However, it is not clear whether this loss of bone density is simply due to the relative oestrogen deficiency of lactation or a more complex mechanism. The findings from our study are consistent with previous reports showing that women who breast-feed have a significant decrease in BMD at both the lumbar spine and the neck of femur compared with women who do not breast-feed.
Low molecular weight heparin offers the important advantage of requiring less frequent administration compared with unfractionated heparin preparations. Our data indicate that the use of low-molecular-weight heparin (enoxaparin 20 mg daily) during pregnancy is associated with a decrease in bone density of the same low magnitude (34%) as unfractionated heparin (calciparine 5000 U twice daily), with no significant difference between the two heparin preparations in BMD changes at all three sites studied.
In conclusion, pregnant women requiring thromboprophylaxis can be reassured that the loss in lumbar spine BMD associated with low-dose long-term heparin therapy is similar to that which occurs physiologically during pregnancy.
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Acknowledgments |
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Notes |
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References |
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Submitted on April 13, 1999; accepted on July 22, 1999.