Research paperCalcium plus vitamin D supplementation and lung cancer incidence among postmenopausal women in the Women’s Health Initiative
Introduction
Lung cancer is one of the most common cancers and remains the leading cause of cancer death among women in the United States [1]. Although tobacco smoking is the key risk factor, approximately 20–50% of lung cancer cases in women in the US are not attributed to smoking [2], [3]. It is still important to identify other modifiable factors in order to develop novel prevention strategies for lung cancer.
There have been several observational studies of calcium intake and lung cancer risk; results have not been consistent [4], [5], [6], [7], [8], [9], [10]. Results have included findings of lower risk [6], [7], [10], no association [8], [9], and increased risk [5]. One potential explanation for the inconsistency is that magnesium status and its interaction with calcium was not considered.
Calcium shares the same homeostatic regulatory system with magnesium [11], [12], and directly or indirectly competes with magnesium for (re)absorption in the intestine and kidneys [11], [13]. Calcium and magnesium also antagonize each other in many physiological activities including pathways related to the pathogenesis of cancer [11], [14]. Moreover, magnesium ion transient channel receptors (e.g., transient receptor potential melastatin 6 (TRPM6) and 7 (TRPM7)) have been shown to be permeable to calcium ion [15], and can be expressed in both lung and gastrointestinal tract (GI) tissues [16], [17]. Results of a clinical trial of calcium supplementation (1200 mg/day) and colorectal adenomas recurrence showed that calcium supplementation reduced recurrence risk only among those with a low baseline calcium to magnesium (Ca:Mg) intake ratio (≤2.63) (RR = 0.68, 95% CI, 0.52–0.90) (test for interaction, p = 0.075) [18]. There is evidence of similar modifying effect of Ca:Mg intake ratio in studies of other GI neoplasias, including colorectal adenocarcinoma, Barrett’s esophagus and esophageal adenocarcinoma [19], [20].
The Women’s Health Initiative (WHI), randomized controlled calcium plus vitamin D supplementation trial (CaD) was initiated to assess whether 1000 mg of calcium carbonate daily plus 400 IU vitamin D3 reduced the risk of hip fracture and colorectal cancer among 36,282 otherwise healthy postmenopausal women [21], [22]. The CaD trial enrollment began in 1994 and intervention period ended in 2005; no significant differences were found between treatment and placebo arms during the active intervention period for a number of outcomes [23], [24], [25], [26], including the incidence of breast cancer [26], colorectal cancer [25] or lung cancer [24]. However, there was no investigation of potential interaction between the calcium and magnesium status in the WHI CaD trial. To address this issue, we conducted post hoc analyses to examining whether the ratio of baseline Ca:Mg intake modify the effects of supplementation of calcium and vitamin D on lung carcinogenesis in the WHI CaD trial by including post-intervention lung cancer cases through an additional 4.9 years (mean) follow-up for a mean cumulative follow-up of 11.1 years.
Section snippets
WHI overview
Details of the WHI CaD trial have been published elsewhere [21], [22], [27]. Briefly, postmenopausal women enrolled in WHI hormone therapy (HT) or dietary modification (DM) trials were invited to join the CaD trial at their first or second annual follow-up visit. Eligible women for the WHI trials were 50–79 years old at baseline enrollment with anticipated survival of at least 3 years, no prior breast cancer, and no other cancer within 10 years [27]. For the CaD trial, personal supplemental
Results
Baseline characteristics and disease risk factors, including age, race/ethnicity, and tobacco exposure, were balanced between randomized groups (Table 1). Self-reported baseline average daily dietary intakes of calcium, magnesium and vitamin D were similar in the randomization groups. At baseline, total intakes of calcium, magnesium and vitamin D, reflecting both dietary intake and supplement use, as well as Ca:Mg intake ratio were also similar in the two randomized groups. The CaD participant
Discussion
In the previous report of WHI clinical trial evaluating the effect of calcium and vitamin D on lung cancer risk in postmenopausal women, there was no association with lung cancer incidence during the active trial phase (0.90% as compared to 0.10%, HR = 0.86; 95% CI: 0.67–1.12) [24]. After 11 years’ cumulative follow-up, we found that daily supplementation with 1000 mg of elemental calcium combined with 400 IU of vitamin D3 was still not associated with lung cancer risk among postmenopausal women
Disclosure
None declared.
Funding support
The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. This work was supported in part by the National Cancer Institute (R03CA184327). Dr. Qi Dai’s effort was supported by R01 CA149633 and U01 CA182364.
Conflict of interest
All authors have no conflicts of interests.
Acknowledgments
We acknowledge the dedicated efforts of investigators and staffs at the WHI clinical centers, the WHI Clinical Coordinating Center, and the Nation Hear, Lung and Blood program office (listing available at http://www.whi.org). We also recognize the WHI participants for their extraordinary contributions to the WHI program.
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