Lung cancer is 1 of the most common cancers and it is the leading cause of cancer death among American women. Therefore, it is essential to emphasize the significance of modifiable risk factors. In addition, identifying other modifiable risk factors may be helpful for developing novel prevention strategies. (http://links.lww.com/MD/F117)
Osteoporosis is a major health issue among elder, and it can increase the morbidity and mortality in the older.[2,3] Osteoporosis can appear in both gender and it is more common for postmenopausal women and old-age males. At present, bisphosphonate has become a major drug for the treatment of osteoporosis patients. However, there are some adverse reactions to oral bisphosphonate, such as esophagitis and gastric irritation.[5–8] Moreover, there are many adverse reactions that have not been found. Our study population is people who suffer from osteoporosis and use bisphosphonate for treatment.
Recently, the study Tao et al indicated that the risk of lung cancer could be decreased in postmenopausal women who use the bisphosphonates (BPs) and never smoke(odds ratio [OR] 0.57, 95% confidence interval [CI] 0.39–0.84). However, other studies[10–12] showed that there was no significant association between BPs and lung cancer. Therefore, we could know that BPs may affect the incidence of lung cancer from these studies.
Though some studies have shown that BPs are associated with the decreased risk of breast and colorectal cancer,[13–15] there are many adverse reactions that have not been found. BPs have been reported to increase the risk of esophageal cancer, but the carcinogenic mechanism of BPs remains unclear. Most previous studies always focused on the role of BPs in the treatment and prevention of cancer metastasis but little research focused on whether the use of bisphosphonate would affect the risk of cancer. At present, much research has focused on the effects of BPs on the esophagus[17–19] but little research has been done on the lung, especially lung cancer.
Therefore, we want to figure out the relationship between the incidence of lung cancer and BPs in order to guide patients in the selection of osteoporosis treatments.
2.1 Search strategy
We conducted a systematic review and meta-analysis which followed the MOOSE guidelines. We searched the databases of PubMed and Embase from their inception to March 2020 and there was no language restriction in our search. The main search terms were “Lung Cancer” or “Lung Neoplasms” or “Pulmonary Neoplasms” or “Cancer of the Lung” or “bisphosphonate” and “etidronate” or “alendronate” or “ibandronate.” We also reviewed the reference list of included literature for study that may have been overlooked from the search.
2.2 Study selection
- (1) duplicate studies.
- (2) no relevant studies
- (3) no available data in the studies
- (4) reviews, protocol, case reports, commentaries, letters.
- (1) cohort studies or case-control studies of BPs use.
- (2) studies on the use of BPs and the risk of lung cancer.
- (3) risk estimate was supplied by OR, relative ratio (RR) or hazard ratio (HR).
- (4) 95%CI was reported from the studies.
Two reviewers independently evaluated all relevant studies, and through the discussion of the disagreements were resolved.
2.3 Data extraction
The Newcastle-Ottawa Scale (NOS) was used to assess the quality of the included literature by 2 authors. The author and published year, country, gender, study type, age, follow-up, sample size, adjusted RR/ OR /HR, 95%CI, type of BPs, adjusted variables were extracted from the included literature. We did not contact the authors of the including studies.
2.4 Statistical analysis
The data was analyzed using STATA version 12.0 (Stata Corp, College Station, TX). RR, HR, OR were used to calculate the pooled effect size, and we used the OR as the pooled effect size in our analysis. The main outcome of our analysis was focused on the effect of BPs exposure on the risk of lung cancer, and the secondary outcome was the effect of alendronate exposure on the risk of lung cancer.
We used the Cochran Q statistic to evaluate the heterogeneity, for quantified the degree of heterogeneity we used the I2 statistic. Heterogeneity existed when P<.10 or I2 >50%. We used a random-effects model to calculate the pooled estimates when substantial heterogeneity appeared(P<.10 or I2>50%). The stability of the results was evaluated by the sensitivity analysis. The Egger test was used to assess publication bias.
2837 studies initially identified from the databases of PubMed and Embase. 222 duplications and 2608 studies were excluded by screening the title and abstract. Finally, 4 studies[9–12] were included in our analysis (Fig. 1).
3.1 Study characteristics
The characteristics of including literature were listed in Table 1. In Tao et al and Chiang et al only contained female patients. However, the patients in the study of Cardwell et al and Lee et al were man and woman. Three studies[9–11] provided the risk of lung cancer on alendronate. All included studies were cohort studies and provided adjusted RR/ OR/HR and 95%CI.
Table 1 -
Detailed characteristics of included studies in this meta-analysis
|Author and published year
||Adjusted RR/ OR /HR (95% CI)
||Type of BPs
||70.0 ± 11
||Case: 4.5 ± 2.6 Control: 4.4 ± 2.6
||BPs: 0.85 (0.7–1.03)
||Age, sex, general practice, BMI, cigarette smoking, alcohol intake, hormone therapy, NSAID use, Barrett's esophagus, GERD, H2 receptor antagonist use, proton pump inhibitor use
||Treatment: 2.92 Control: 3.04
||Alendronate: 1.47 (1–2.17)
||Smoking habits, alcohol consumption, body-mass index, socioeconomic status, and family history of cancer
||BPs: 0.91 (0.8–1.04) Alendronate: 0.89 (0.77–1.02)
||BPs, Alendronate, Risedronate
||Adjusted for baseline age, ethnicity, education, smoking status, number of cigarettes per day, duration of regular smoking in years, alcohol use status, body mass index, physical activity, total calcium intake, total vitamin D intake, statins use, and hormone treatment status and stratified on WHI study component.
||73.4 ± 8.4
||4.3 ± 2.5
||Alendronate: 1.17 (0.95–1.43)
||Adjusted for age and gender
BMI = body mass index, BPs = bisphosphonates, F = female, GERD = gastroesophageal reflux disease, M = man, NA = not available, NSAID = non-steroidal anti-inflammatory drug.
3.2 Bisphosphonate and lung cancer
No significant relevance was found between the use of BPs and the risk of lung cancer (OR 1.02, 95%CI 0.85–1.24, I2 71%) (Fig. 2). The sensitivity analysis was performed by excluded 1 study in this group at a time, and the result was stable. We did not find publication bias through the Egger test.
3.3 Alendronate and lung cancer
Three studies[9–11] provided the risk of lung cancer with alendronate in included literature. In our study, we found that the use of alendronate might increase the risk of lung cancer. The pooled estimate showed that there was no relevant association between alendronate and lung cancer (OR 1.10, 95%CI 0.84–1.45, I2 77%) (Fig. 3). However, we performed sensitivity analysis in this group, and found that when we excluded Tao et al the heterogeneity disappeared and the result have changed which indicated that the use of alendronate would increase the risk of lung cancer(OR 1.23, 95%CI 1.02–1.49, I2 4.1%). We did not find publication bias through the Egger test.
3.4 Female and mixed gender
There was no relationship between BPs and the risk of lung cancer in the mix gender group (OR 1.09, 95%CI 0.64–1.86, I2 83.7%) or female group (OR 1.02, 95%CI 0.80–1.30, I2 75.7%). (Fig. 4)
3.5 Patient with smoking history
Only 1 study was included in this group. We found that the risk of lung cancer decreased in female bisphosphonate users who never smoke (OR 0.57, 95%CI 0.39–0.84). But there was no evidence showing that the risk of lung cancer decreased in female bisphosphonate users who ever smoke (OR 0.96, 95%CI 0.83–1.11). (Fig. 5)
This is the first multifaceted analysis between BPs and lung cancer. There was no publication bias in our analysis. The Included literature was assessed by the NOS, and the quality of these studies was high. Four studies were included in our analysis, which included a total of 284,605 bisphosphonate users.
In our analysis, we could not find a significant relevance between the use of BPs or alendronate and the risk of lung cancer. But there was an interesting thing that in the group of alendronate, we performed a series of sensitivity analyses, when the study Tao et al was excluded, the heterogeneity disappeared and the result changed which indicated that the use of alendronate would increase the risk of lung cancer (OR 1.23, 95%CI 1.02–1.49, I2 4.1%). It means that alendronate might increase the risk of lung cancer. However, there were only 2 studies of alendronate group after excluding the study Tao et al. It could not provide a strong evidence to prove that alendronate could increase the risk of lung cancer, so future studies should focus on this topic.
We found that the risk of lung cancer decreased in female bisphosphonate users who never smoke (OR 0.57, 95%CI 0.39–0.84). But no evidence showed that the risk of lung cancer decreased in female bisphosphonate users who ever smoke (OR 0.96, 95%CI 0.83–1.11). However, this group had a limitation, which was only 1 literature was included. Individual studies cannot yield reliable conclusions, so more research is needed to figure out this confusion. There was high heterogeneity in our analysis, but we could not find the heterogeneous source due to the restriction number of included literature and available data from the original literature.
Our study has multiple strengths:
- (1) This is the first multifaceted analysis between BPs and lung cancer.
- (2) We conducted a comprehensive search strategy and no language restriction in our search strategy.
- (3) The sensitivity analyses were performed in our analysis to examine the stability of the results.
- (4) Previously, it was believed that BPs can be used in lung cancer and can effectively prevent bone metastasis of lung cancer, but few people mentioned whether BPs could be a risk factor for carcinogenesis.
Therefore, our study provided a new research direction for BPs.
Whereas, there are some limitations to our study:
- (1) All included studies tried to control for the confounding variables, but not all the confounding variables could be controlled in each literature.
- (2) There was high heterogeneity in our analysis, but we could not find the heterogeneous source due to the restriction number of including studies and available data from the original literature.
- (3) We could not find out the effect of BPs on different histologic types of lung cancer.
- (4) Only 4 studies were included in our analysis.
More studies are needed to confirm our findings.
In our analysis, we could not find significant relevant between the use of BPs and the risk of lung cancer. The use of alendronate might increase the risk of lung cancer. The future studies should focus on whether alendronate would increase the risk of lung cancer, and whether the risk of lung cancer decreased in female bisphosphonate users who never smoke.
Conceptualization: Chengnong Guan.
Data curation: Muyan Zhong.
Formal analysis: Minghao Li, Chengnong Guan.
Funding acquisition: Minghao Li, Chengnong Guan.
Investigation: Minghao Li, Muyan Zhong.
Methodology: Minghao Li, Muyan Zhong.
Project administration: Chengnong Guan.
Resources: Minghao Li.
Software: Minghao Li, Muyan Zhong.
Supervision: Chengnong Guan.
Validation: Chengnong Guan.
Visualization: Minghao Li.
Writing – original draft: Minghao Li, Muyan Zhong.
Writing – review & editing: Minghao Li.
. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67:7–30.
. Center JR, et al. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet 1999;353:878–82.
. Bliuc D, et al. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA 2009;301:513–21.
. Giusti A, Hamdy NA, Papapoulos SE. Atypical fractures of the femur and bisphosphonate therapy: a systematic review of case/case series studies. Bone 2010;47:169–80.
. de Groen PC, et al. Esophagitis associated with the use of alendronate. N Engl J Med 1996;335:1016–21.
. Tosteson AN, et al. Early discontinuation of treatment for osteoporosis. Am J Med 2003;115:209–16.
. Parfitt JR, Driman DK. Pathological effects of drugs on the gastrointestinal tract: a review. Hum Pathol 2007;38:527–36.
. MacLean C, et al. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008;148:197–213.
. Tao MH, et al. Oral bisphosphonate use and lung cancer incidence among postmenopausal women. Ann Oncol 2018;29:1476–85.
. Lee WY, et al. A higher dosage of oral alendronate will increase the subsequent cancer risk of osteoporosis patients in Taiwan: a population-based cohort study. PLoS One 2012;7:
. Chiang CH, et al. Oral alendronate use and risk of cancer in postmenopausal women with osteoporosis: a nationwide study. J Bone Miner Res 2012;27:1951–8.
. Cardwell CR, et al. Exposure to oral bisphosphonates and risk of cancer. Int J Cancer 2012;131:E717–25.
. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2005;3:Cd003474.
. Thosani N, et al. Reduced risk of colorectal cancer with use of oral bisphosphonates: a systematic review and meta-analysis
. J Clin Oncol 2013;31:623–30.
. Gnant M, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009;360:679–91.
. Andrici J, Tio M, Eslick GD. Meta-analysis
: oral bisphosphonates and the risk of oesophageal cancer. Aliment Pharmacol Ther 2012;36:708–16.
. Seo GH, Choi HJ. Oral bisphosphonate and risk of esophageal cancer: a nationwide claim study. J Bone Metab 2015;22:77–81.
. Vogtmann E, et al. Oral bisphosphonate exposure and the risk of upper gastrointestinal cancers. PLoS One 2015;10:e0140180.
. Li M, Zhong M. Bisphosphonates and risk of oesophageal cancer: a meta-analysis
. GastroHep 2020;2:123–32.
. Stroup DF, et al. Meta-analysis
of observational studies in epidemiology: a proposal for reporting. Meta-analysis
of observational studies in epidemiology (MOOSE) group. JAMA 2000;283:2008–12.
. Lichtenstein MJ, Mulrow CD, Elwood PC. Guidelines for reading case-control studies. J Chronic Dis 1987;40:893–903.
. Higgins JP, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557–60.
. DerSimonian R, Laird N. Meta-analysis
in clinical trials. Control Clin Trials 1986;7:177–88.
. Egger M, et al. Bias in meta-analysis
detected by a simple, graphical test. BMJ 1997;315:629–34.