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Original articles

Do combined oral contraceptive pills affect serum alkaline phosphatase level and bone mineral density?

Awad, Mohamed H.a; Mansour, Sahar M.b; Abbas, Reham M.c

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Evidence Based Women's Health Journal: August 2014 - Volume 4 - Issue 3 - p 164-167
doi: 10.1097/01.EBX.0000440899.07571.51
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Abstract

Introduction

Osteoporosis is a disease of bone, leading to an increased risk for fracture. In osteoporosis, the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of noncollagenous proteins in bone is altered. Osteoporosis is defined by the WHO in women as a BMD 2.5 SD below peak bone mass (of a 20-year-old sex-matched healthy person average) as measured by dual energy X-ray absorptiometry (DEXA); the term ‘established osteoporosis’ includes the presence of a fragility fracture 1.

Osteoporosis is most common in postmenopausal women. Yet, it may develop in premenopausal women in the presence of particular hormonal disorders or as a result of smoking and medications, specifically glucocorticoids, when the disease is called steroid-induced or glucocorticoid-induced osteoporosis 2.

The etiology of low bone density in the premenopausal women needs to be clarified with meticulous exclusion of secondary causes of bone loss. Menstrual status is an important determinant of peak bone mass as well as the development of bone loss in women before the onset of menopause. Subclinical decreases in circulating gonadal steroids may be associated with a lower peak bone mass as well as progressive bone loss in otherwise reproductively normal women. Elevation of follicle-stimulating hormone of greater than 20 mIU/l is associated with evidence of increased bone turnover marker activity and correlates with progressive bone loss in premenopausal women 3.

Osteoporosis itself has no specific symptoms; its main consequence is the increased risk for fractures. Osteoporotic fractures are those that occur in situations where healthy people would not normally break a bone; they are therefore regarded as fragility fractures. Typical fragility fractures occur in the vertebral column, hip, and wrist. The symptoms of a vertebral collapse ‘compression fracture’ are acute back pain, often with radiculopathic pain. Multiple vertebral fractures lead to a stooped posture, loss of height, and chronic pain with resultant reduction in mobility 4.

Despite the highly prevalent and long-term use of oral contraceptive pills (OCPs) worldwide, the available evidence of their effects on bone health in young adult women continues to be inconclusive 5. Many studies showed a positive correlation between OCPs and bone mass. Up to 12% greater bone mass density was seen in OCP users versus women who used other methods of birth control 6. However, other studies 5,7 showed a negative correlation between OCPs and bone mass.

Estrogen acts through two receptors: estrogen receptor ERα and ERβ. ERα appeared to be the primary mediator of estrogen’s actions on the skeleton. Osteoblasts do express ERβ, but the actions of ERβ agonists on bone are less clear. Many studies suggest that the effects of estrogen signaling through ERα and ERβ are in opposition, whereas others suggest that activation of these two receptors has similar effects on bone 8.

The immature osteoblasts secrete proteins such as the bone isoform of alkaline phosphatase, which is involved in the mineralization of bone, and the type I collagen propeptides from the C-terminal and N-terminal. The latter are cleaved from type I procollagen after its secretion from the osteoblasts. The mature osteoblasts secrete osteocalcin, the marker that is most specific to the osteoblasts 9.

The WHO Scientific Group on the Prevention and Management of Osteoporosis 10 noted that DXA, formerly DEXA, is considered the gold standard for the diagnosis of osteoporosis. Osteoporosis is diagnosed when the BMD is less than or equal to 2.5 SD below that of a young adult reference population. This is translated as a T-score.

Bone density can also be measured by quantitative computed tomography. This technique can analyze trabecular and cortical bone separately and is a sensitive measure of early bone loss in the vertebrae 11.

Another key predictor is the rate of bone remodeling. Increased rates of osteoclastic bone resorption, measured by the level of collagen breakdown products, as well as increased bone formation, measured by bone-specific alkaline phosphatase, osteocalcin, or procollagen peptide levels, are associated with an increase in risk for bone loss and fragility fractures 12.

Bone-specific alkaline phosphatase is the most important marker for osteoblast differentiation; furthermore, the serum level of its activity may reflect the process of osteoporosis 13.

Although hip fracture prediction with BMD alone is at least as good as blood pressure readings to predict stroke, the predictive value of BMD can be enhanced by use of other factors such as biochemical indices of bone resorption and clinical risk factors. Clinical risk factors that contribute to fracture risk independently of BMD include age, previous fragility fracture, premature menopause, a family history of hip fracture, and the use of oral corticosteroids 14.

Patients and methods

Between May 2011 and December 2012, an analytical cross-sectional retrospective study was conducted at Department of Obstetrics and Gynecology in Al Maadi Military Hospital in collaboration with Department of Radiology, to define the relationship between OCPs, BMD, and serum alkaline phosphatase.

Informed written consent was obtained from all participants. The study was approved by the departmental ethical committee.

Sixty healthy women were divided into two groups: group I included 30 women who used combined OCPs [0.15 mg levonorgestrel or desogestrel respectively+0.03 mg ethinyl estradiol (EE)] for 12 months and group II included 30 women who had never used any hormonal contraceptives.

The main purpose of this analysis was to compare the serum alkaline phosphatase level and BMD measurements among two groups of women: group I using hormonal OCPs versus group II (controls or nonuser).

Women included in the study were aged between 25 and 35 years, nonlactating, never used any medications that affect calcium metabolism (such as glucocorticoids, anticonvulsants, long-term heparin, excessive thyroid hormone, and cholestyramines), and did not have any chronic diseases that affect calcium metabolism (such as thyroid diseases, parathyroid diseases, malabsorption syndrome, chronic liver diseases, and chronic renal failure).

Exclusion criteria included age less than 25 years or more than 35 years, breastfeeding, smoking, alcohol intake, history of oophorectomy, and use of medications or presence of chronic disease that affect calcium metabolism.

BMD was measured by DEXA at the spine, right femur, and left femur using DEXA Scan General Electric Health Care Lunar Prodigy DF+301030 Machine (USA).

Osteoporosis is diagnosed when the BMD is less than or equal to 2.5 SD below that of a young adult reference population. This is translated as a T-score.

  • −1 to −1.5=mild osteopenia,
  • −1.5 to −2=moderate osteopenia,
  • −2 to −2.5=severe osteopenia,
  • −2.5 to −3.5=osteoporosis,
  • Less than −3.5=osteoporosis with high risk for fracture.

Serum alkaline phosphatase was measured using autoanalyzer method (normal=30–120 U/l).

The collected data were organized, tabulated, and analyzed. The statistical tests (the Mann–Whitney U-test, the χ2-test, and the T-test) were used when appropriate. Computer program SPSS version 15 for Microsoft Windows (Statistical Package for the Social Sciences; SPSS Inc., Chicago, Illinois, USA) was used.

Results

Characteristics of the study population are presented in Table 1. There were no statistically significant differences between the two groups regarding age, BMI, parity, and occupation.

T1-10
Table 1:
Descriptive statistics of the study groups

There were statistically significant differences between the two groups with respect to BMD, degree of osteoporosis, serum alkaline phosphatase levels, and T-score at the spine and left femur, but difference between both groups with respect to right femur T-score was not statistically significant (Table 2).

T2-10
Table 2:
Comparison between both groups with respect to BMD, T-score, degree of osteoporosis, and serum alkaline phosphatase levels

Discussion

Many factors influence bone mass and the risk for osteoporotic fracture. Bone mass begins to increase at the time of menarche, continues to increase until the late 20s to early 30s, and then begins to decrease. Peak bone mass determines the risk for osteoporotic fracture. The factors that influence peak bone mass are not fully understood 15.

OCPs may affect bone health. The effect of OCPs on bone health is difficult to be determined and whether combined OCPs affect fracture risk cannot be judged from current data. However, osteoporosis is a major public health concern.

Several observational studies have examined the effect of combined OCPs on bone health. Some reports did not suggest any consistent or important effect on fracture risk in premenopausal women 16, whereas others associated OCPs with changes in BMD.

In the current study, the demographic data, age, parity, occupation, and BMI, showed no statistically significant differences between both groups. This agreed with the study by Guthrie et al. 17 who noted that there was no impact of gynecologic history (parity, age of menarche, and BMI) on BMD. However, Petitti et al. 15 reported statistically significant (P<0.05) associations of age, parity, and BMI with BMD. BMD was also significantly associated with occupation.

In the current study, DXA results showed that the degree of osteoporosis was higher in group I (pills users) than in group II (nonusers), and the difference was statistically significant. This agreed with the study by Wasnich and Miller 18 who showed that combined OCP use in premenopausal women was associated with lower BMD measurements in the lumbar vertebrae and trochanter, and numerically lower levels were consistent across all measurement sites. In addition, Endrikat et al. 19 reported similar effect of levonorgestrel (150 μg) and EE (30 μg) on BMD of the lumbar spine at 36 months as well as results of serum alkaline phosphatase. DXA results showed slight decreases in BMD, which agreed also with the study by Hartard et al. 20 who studied the effect of desogestrel (150 μg) and EE (20 μg) on 52 premenopausal women in Germany. Relevant outcomes were BMD at the lumbar spine and femoral neck, as well as bone-specific alkaline phosphatase. By 13 months, there was a slight decrease in BMD at the spine and femoral neck.

In contrast, Kuohung et al. 6 showed a positive association between OCPs use and BMD. Up to 12% greater BMD was seen in OCPs users as against women who used other methods of birth control. In addition, Berenson et al. 7 reported the effect of desogestrel (150 μg) and EE (30 μg) on BMD of the lumbar spine at 12 months. DXA results showed an increase in BMD at the lumbar spine at 12 months.

In contrast to the aforementioned studies, Nappi et al. 21 noted that premenopausal women BMD at the spine, hip, and whole body did not differ between combined OCP (≤35 μg EE) users and nonusers over 1-year or 3-year follow-up, and Wanichsetakul et al. 22 showed that there were no significant differences in BMD values at all bone sites between combined OCP users and controls.

In the current study, serum alkaline phosphatase was higher in group I (users) than in group II (nonusers), and the difference was statistically significant. This agreed with the results of Endrikat et al. 19 who reported increased serum alkaline phosphatase levels. However, Hartard et al. 20 reported a decrease in serum bone-specific alkaline phosphatase.

Strengths of the current study include multivariable adjustment for numerous potentially related covariates and selection of OCPs users and the control group participants from the same defined population.

This study’s main limitation is that these cross-sectional associations between OCPs dose and duration and lower bone density may not be causal.

Previous studies generally had sufficient duration to detect changes in bone, but none included fractures as an outcome. Longer trials would be necessary for meaningful assessment of fracture. However, as fragility fractures are rare in young people, fracture is not usually an outcome in studies of premenopausal bone health. In addition, longer trials may provide information on whether there is any reversal of earlier decreases in BMD and may answer the question whether or not bone loss during contraceptive use is temporary (like the one which occurs during pregnancy or breastfeeding).

Conclusion

Prolonged use of current OCPs may adversely impact young adult women’s bone density. Young adult users generally have decreased BMD compared with young adult nonusers.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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Keywords:

bone mineral density; oral contraceptive pills; serum alkaline phosphatase

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