Oral bisphosphonate use and colorectal cancer incidence in the Women’s Health Initiative

Abstract

Bisphosphonates are widely-prescribed to increase bone density in postmenopausal women with osteopenia or osteoporosis. Amino-bisphosphonates have numerous anticancer properties and reduce bone-metastases in cancer patients. Several studies, including the Women’s Health Initiative (WHI), have found that use of oral bisphosphonates is associated with reduced risk of developing breast cancer, but less is known about associations with other common malignancies in women such as colorectal cancer (CRC). A few case-control and retrospective cohort studies have reported decreased risk of CRC among bisphosphonate users. In contrast, a prospective cohort study found no association. We evaluated the association between oral bisphosphonate use and CRC incidence in 156,826 postmenopausal women, ages 50–79, who participated in WHI clinical trials and observational study. A detailed health interview was conducted at baseline, and bisphosphonate use was ascertained from an inventory of regularly-used medications at baseline and over follow-up. A total of 1,931 women were diagnosed with incident invasive CRC during a median follow-up of 12 years. Alendronate was the most commonly used bisphosphonate, accounting for >90% of the total person-years of use. The association between oral bisphosphonate use and CRC risk did not reach statistical significance (hazard ratio [HR] from multivariable-adjusted models, 0.88; 95% confidence interval [CI], 0.72–1.07; P=0.19). Furthermore, we did not observe greater risk reductions for women with longer duration of use. Uncontrolled confounding may explain why previous studies have observed an association.

Introduction

Bisphosphonates are widely-used to treat bone loss, with over 150 million prescriptions dispensed in the United States between 2005–2009.⁽¹⁾ Amino-bisphosphonates prevent the attachment of osteoclasts to bone by inhibiting farnesyl-pyrophosphate synthase,⁽²⁾ and experimental studies have demonstrated their ability to promote apoptosis and suppress growth and angiogenic factors.⁽³⁾ Bisphosphonates prevent bone metastases,⁽⁴⁾ but it is unclear if they play a role in the primary prevention of cancer. Use of bisphosphonates has been found to be associated with ~30% reduced risk of breast cancer in several studies,^(5,6) including the Women’s Health Initiative (WHI).⁽⁷⁾ Studies of bisphosphonates and the risk of developing other hormone-related cancers such as colorectal cancer (CRC) have been inconsistent.

The Molecular Epidemiology of Colorectal Cancer (MECC) case-control study reported nearly 60% reduced risk of CRC for postmenopausal women who used bisphosphonates for ≥1 year (odds ratio [OR], 0.41; 95% confidence interval [CI], 0.25–0.67).⁽⁸⁾ More modest inverse associations were observed in two studies nested within the United Kingdom General Practice Research Database (GPRD)^(9,10) (OR, 0.87; CI, 0.77–1.00 and OR, 0.74; CI, 0.60–0.91), and one from the Manitoba Drug Program Information Network⁽¹¹⁾ (OR, 0.78; CI 0.65–0.94, specific to risedronate). Analyses using the Danish National Prescription Database are conflicting; one reported an inverse association (hazard ratio [HR], 0.69; CI, 0.60–0.79),⁽¹²⁾ but another suggested no association (HR, 1.16; CI, 0.93–1.45).⁽¹³⁾ The later study, however, noted a reduced risk of CRC in those taking the highest doses that was not apparent for those with the highest cumulative exposure.⁽¹³⁾ To date, the only prospective data comes from the Nurses’ Health Study (NHS), which observed no association (HR, 1.04; CI, 0.82–1.33).⁽¹⁴⁾ Given the varied findings of previous studies, we investigated the association between oral bisphosphonate use and CRC incidence in participants of the WHI clinical trials (WHI-CT) and observational study (WHI-OS).

Materials and Methods

Study Population

WHI enrolled 161,808 postmenopausal women, 50–79 years of age, from 40 clinical centers across the United States between 1993–1998.⁽¹⁵⁾ WHI-OS participants were generally similar to those of WHI-CT, but were ineligible or unwilling to be included in a randomized trial. Study eligibility and implementation details have been extensively documented.⁽¹⁶⁾

Measurement of Health Characteristics and Oral Bisphosphonate Use

All women were interviewed on general health information at baseline. Total calcium and vitamin D intake were estimated from two sources: 1) diet using a semi-quantitative food frequency questionnaire; and 2) from an inventory of medications and supplements. An inventory of all current, regularly-used medications, including bisphosphonates, was taken at baseline and at 1, 3, and 6 years after randomization for WHI-CT components. The same inventory was performed at baseline and 3 years after for WHI-OS. Participants were instructed to bring medication bottles/packaging for drugs taken at least twice per week during the previous 2 weeks. All medications were matched to the Medi-Span (Indianapolis, IN) Master Drug Data Base (MDDB) to ascertain detailed ingredient information.

Follow-up for Colorectal Cancer Diagnoses

Clinical outcomes, including diagnoses of CRC, were reported by participants every 6 months for WHI-CT and annually for WHI-OS. Study physicians adjudicated case reports by reviewing medical records and pathology reports.⁽¹⁷⁾ Participants reported receipt of colorectal exams for any indication, including hemoccult test, sigmoidoscopy, and colonoscopy. Diagnoses of colorectal polyps were also documented, but these were not physician-adjudicated.

The estrogen-progestin trial was stopped in 2002,⁽¹⁸⁾ the estrogen-alone trial was stopped in 2004,⁽¹⁹⁾ and the primary study period for all other components ended in 2005, after which time 115,400 participants re-consented to be followed for additional outcomes including diagnoses of CRC.

Study Exclusions

We excluded 5 women who had not turned 50 years old at baseline, 946 with a personal history of colon, rectal, bowel, or intestinal cancer, 1,760 with a personal history of ulcerative colitis, and 2,271 who reported ever having part of their intestine removed. Among the eligible 156,826 women, a total of 2,070 reported a diagnosis of CRC during follow-up through August 2009. We did not count 139 diagnoses as outcomes (N=70 that could not be adjudicated and N=69 that were adenocarcinoma in situ), leaving 1,931 with CRC.

Statistical Analyses

We calculated descriptive statistics at baseline and also for any use during the first 3 years of the study. HRs and CIs comparing bisphosphonate users to non-users were estimated using proportional hazards regression. Bisphosphonate use was treated as a time-varying never/ever variable by updating baseline use at Years 1, 3, and 6 for women in WHI-CT and at Year 3 for WHI-OS (non-users could become users over time, but users could not become non-users). All models stratified the baseline hazard by study component and randomization arm for the estrogen-alone trial, estrogen-progestin trial, and calcium/vitamin D trial. The proportional hazards assumption was assessed by testing for interactions with log-transformed time-on-study.

Regression models included adjustment for covariates measured at baseline (not time-varying) as categorized in Table 1: age, race, education, body mass index (BMI), smoking status, alcohol consumption, physical activity, aspirin and other nonsteroidal anti-inflammatory drug (NSAID) use, first-degree family history of CRC, estrogen-only use, estrogen-progestin use, mammography history, lower endoscopy (sigmoidoscopy or colonoscopy) history, total calcium intake, total vitamin D intake, and 5-year fracture probability as predicted by the model developed by Robbins et al.⁽²⁰⁾ This fracture probability is based on 11 factors: age, race, weight, height, self-reported health, diabetes, physical activity, bone fracture after age 54, parental hip fracture, smoking, and corticoidsteroid use, and has been shown to correlate well with bone mineral density (BMD).⁽⁷⁾ We also explored associations with bisphosphonate type and duration of use as time-varying variables. Analyses were performed using SAS 9.2 (SAS Institute, Inc.; Cary, NC). P-values are two-sided with P≤0.05 considered statistical significant.

Table 1.

Characteristics of WHI women according to use of oral bisphosphonates.

	Oral Bisphosphonate User at Baseline				Oral Bisphosphonate User at Baseline, Year 1, or Year 31
	No (N = 153,782)		Yes (N = 3,044)		No (N = 133,304)		Yes (N = 10,031)
Characteristic at Baseline	N	%	N	%	N	%	N	%
Study components2
WHI-OS	88,131	57	2,224	73	75,333	57	6,794	68
WHI-CT: Calcium/Vitamin D	35,134	23	347	11	32,317	24	1,514	15
WHI-CT: Dietary Modification	47,172	31	573	19	41,590	31	2,289	23
WHI-CT: Hormones
Placebo	13,026	9	155	5	11,463	9	693	7
Estrogen-alone	5,069	3	45	2	4,482	3	181	2
Estrogen-progestin	8,215	5	94	3	7,413	6	329	3
Age (years)
Mean (SD)	63.1	(7.2)	67.2	(6.4)	63.0	(7.2)	66.1	(6.9)
50–59	51,998	34	393	13	45,558	34	1,747	17
60–69	68,890	45	1,423	47	59,957	45	4,953	49
≥ 70	32,894	21	1,228	40	27,789	21	3,331	33
Race/ethnicity
White	126,641	82	2,752	90	110,628	83	9,068	90
Black/African American	14,137	9	39	1	11,922	9	194	2
Hispanic/Latino	6,203	4	83	3	5,016	4	222	2
Asian/Pacific Islander	3,968	3	136	4	3,353	3	413	4
American Indian/Alaska Native/Other/Unknown	2,833	2	34	1	2,385	2	134	1
Education
High school/vocational/less	50,032	32	846	28	43,129	33	2,706	27
Some college/college graduate	59,070	39	1,116	37	51,299	39	3,773	38
Graduate/professional	43,539	29	1,052	35	37,912	29	3,467	35
Body mass index (kg/m2)
Mean (SD)	28.0	(5.9)	25.4	(4.9)	28.1	(5.9)	25.3	(4.8)
< 25	52,946	35	1,659	55	45,264	34	5,467	55
25 to < 30	53,026	35	967	32	46,334	35	3,154	32
≥ 30	46,446	31	398	13	40,547	31	1,324	13
Smoking
Never	77,550	51	1,598	53	67,787	52	5,268	53
Former	63,559	42	1,272	42	55,016	42	4,149	42
Current	10,663	7	131	4	8,849	7	482	5
Alcohol consumption
Never	16,707	11	386	13	14,404	11	1,085	11
Former	28,529	19	513	17	24,271	18	1,596	16
Current < 1 drink/week	50,352	33	930	31	43,782	33	3,115	31
Current 1 to < 7 drinks/week	39,243	26	811	27	34,238	26	2,853	29
Current ≥ 7 drinks/week	17,794	12	381	13	15,646	12	1,323	13
Recreational physical activity (MET-hours/week)
Mean (SD)	12.4	(13.7)	14.4	(14.1)	12.5	(13.7)	14.0	(13.9)
0 – < 5	54,114	37	857	28	46,493	37	2,913	30
5 – < 10	25,405	17	512	17	21,995	17	1,711	17
10 – < 30	52,075	36	1,290	43	45,334	36	4,099	42
≥ 30	14,947	10	361	12	12,992	10	1,149	12
Regular NSAID use	29,309	19	608	20	25,660	19	1,785	18
Regular aspirin use	32,941	21	789	26	28,674	22	2,449	24
Family history of CRC in first-degree relatives	23,061	16	488	18	19,963	16	1,583	17
Estrogen-alone use
Never	99,053	64	2,124	70	85,244	64	6,960	69
< 5 years	20,350	13	399	13	17,586	13	1,290	13
5 to < 10 years	10,855	7	165	5	9,582	7	556	6
≥ 10 years	23,519	15	356	12	20,888	16	1,225	12
Estrogen-progestin use
Never	113,574	74	2,158	71	97,800	73	7,241	72
< 5 years	20,323	13	450	15	17,880	13	1,376	14
5 to < 10 years	10,953	7	200	7	9,740	7	710	7
≥ 10 years	8,927	6	236	8	7,879	6	704	7
Mammogram in prior two years	124,109	83	2,669	91	108,105	84	8749	90
Last colorectal endoscopy
Never had endoscopy	72,325	50	1,101	37	62,458	50	3,877	40
< 5 years ago	45,866	32	1,330	44	39,796	32	4,038	41
≥ 5 years ago	27,493	19	578	19	23,830	19	1,909	19
Last hemoccult test
Never had hemoccult test	37,054	26	471	16	31,667	25	1,676	17
< 5 years ago	80,861	56	2,031	68	70,399	56	6,528	67
≥ 5 years ago	27,585	19	490	16	23,853	19	1,609	16
Ever had colon polyps removed	11,993	8	368	12	10,222	8	1,051	11
Total calcium intake3 (mg/day)
Mean (SD)	1,161.9	(739.8)	1,589.8	(869.3)	1,162.2	(741.4)	1,405.5	(786.9)
< 800	54,749	36	463	15	47,208	35	2,305	23
800 to < 1,200	37,423	24	583	19	32,691	25	2,169	22
≥ 1,200	61,465	40	1,997	67	53,285	40	5,551	55
Total vitamin D intake3 (IU/day)
Mean (SD)	365.7	(277.6)	499.3	(313.7)	365.8	(276.8)	444.7	(298.2)
< 400	87,123	57	1,134	37	75,550	57	4,436	44
400 to < 600	37,793	25	824	27	32,771	25	2,759	28
≥ 600	28,705	19	1,084	36	24,851	19	2,828	28
History of osteoporosis	9,443	6	2,166	72	8,525	6	2,024	71
5-year predicted probability of hip fracture,4 %
< 0.5	109,410	71	1,239	41	95,939	72	5,054	50
0.5 to 1	23,835	16	767	25	20,450	15	2,305	23
≥ 1	20,537	13	1,038	34	16,915	13	2,672	27

¹Among those remaining at risk of CRC at Year 3.

²Percentages do not sum to 100% due to overlap of study components. Hormone trials had separate control groups; the two placebo groups have been combined here.

³Intake from diet, supplements, and medications.

⁴Predicted probability based on Robbins et al.⁽²⁰⁾

Abbreviations: CRC, colorectal cancer; MET, metabolic equivalent of task; NSAID, nonsteroidal anti-inflammatory drug; SD, standard deviation; WHI-CT, Women's Health Initiative Clinical Trials; WHI-OS, Women's Health Initiative Observational Study

Results

Bisphosphonate use was low at baseline (N=3,044 users, 2%), but became increasingly common over the course of follow-up (N=10,349 users at Year 3, 7% of those remaining at risk of CRC; of whom N=3,373 used <1 year). Consistent with the indication for use, 72% of baseline users reported a physician-diagnosis of osteoporosis, compared to only 6% of non-users (Table 1). Baseline users were more likely to be older, White, of lower BMI, non-smokers, and to have recently undergone a cancer screening test. Users also had higher total calcium intake, vitamin D intake, and 5-year probability of hip fracture. Women who reported use anytime during the first 3 years of the study (including baseline) were generally similar to baseline users, but, on average, were slightly younger, had lower calcium, vitamin D, and 5-year probability of hip fracture – trends that likely reflect the prescription of bisphosphonates to a broader patient population. Over the course of the study, use of the amino-bisphosphonate alendronate accounted for >90% of the total person-time of bisphosphonate use.

Based on a multivariable-adjusted model, the estimated HR of CRC risk comparing bisphosphonate users to non-users was not different from the null at the α=0.05 level of significance (HR, 0.88; CI, 0.72–1.07; P=0.19; Table 2). This fully-adjusted estimate was attenuated from an age-only adjusted estimate. Because alendronate use predominated, type-specific estimates for risedronate and other types (etidronate and tiludronate) were not very precise. The magnitude of the association was strongest for recent adopters of bisphosphonates than for longer-term users. We explored whether the association between CRC risk and bisphosphonate use depended on BMI, family history of CRC, hormone use by type, vitamin D and calcium intake, cancer screening tests, and indication for bisphosphonate use. The strongest associations were among women with low vitamin D intake (< 400 IU/day; HR, 0.67; CI, 0.49–0.92) and who had family history of CRC (HR, 0.59; CI, 0.34–1.00). Neither interaction, however, achieved statistical significance with consideration of multiple tests (P-interaction=0.05 and 0.16, respectively). Replacing the 5-year predicted probability of hip fracture with all of its components as actual adjustment variables also did not substantially alter estimates.

Table 2.

Relative risk of developing CRC comparing oral bisphosphonate users to non-users.

			Age-adjusted		Multivariable-adjusted
Oral bisphosphonate use1	Person-years at risk	N CRC events	HR2 (95% CI)	P	HR2,3 (95% CI)	P
Any use
No	1,555,268	1,805	1.00 (Reference)		1.00 (Reference)
Yes	111,538	126	0.81 (0.67, 0.97)	0.02	0.88 (0.72, 1.07)	0.19
Type
Alendronate sodium	102,219	115	0.78 (0.64, 0.95)	0.01	0.84 (0.68, 1.04)	0.11
Risedronate sodium	5,666	7	0.91 (0.43, 1.91)	0.80	0.93 (0.42, 2.09)	0.86
Other4	3,653	4	0.78 (0.29, 2.08)	0.62	0.72 (0.23, 2.23)	0.57
Duration of use
< 1 year	36,692	29	0.64 (0.45, 0.91)	0.01	0.70 (0.49, 1.02)	0.06
1 to 3 years	44,206	59	0.89 (0.68, 1.18)	0.42	0.89 (0.65, 1.20)	0.43
≥ 3 years	30,640	38	0.79 (0.56, 1.12)	0.19	0.95 (0.67, 1.35)	0.78

¹Users reported at least 2 weeks of use; non-users include never users and those who used for < 2 weeks. Baseline oral bisphosphonate use updated at Years 1, 3, and 6 for women in WHI-CT and updated at Year 3 for WHI-OS.

²Baseline hazard stratified by WHI study component and randomization assignment within the hormone trials and calcium/vitamin D trial.

³Adjusted for age, race, education, BMI, smoking status, alcohol consumption, physical activity, NSAID use, aspirin use, family history of CRC, estrogen-only use, estrogen-progestin use, history of endoscopy, history of mammography,, total calcium intake, total vitamin D intake, and 5-year hip fracture probability (all measured at baseline).

⁴Other includes etidronate disodium and tiludronate disodium.

Abbreviations: BMI, body mass index; CI, confidence interval; CRC, colorectal cancer; HR, hazard ratio; NSAID, nonsteroidal anti-inflammatory drug; WHI-CT, Women's Health Initiative Clinical Trials; WHI-OS Women's Health Initiative Observational Study.

Discussion

We did not find sufficient evidence to conclude that there was a meaningful association between bisphosphonate use and CRC risk in WHI. If any association exists, it may be smaller than what our study could detect. If bisphosphonates reduced CRC risk, we would expect the relation to be stronger for women using for longer durations. This was not reflected in our data. Instead, any apparent risk reduction may be the consequence of recent physician contact.

Our results are consistent with those of Khalili et al., where no association was observed over 10 years of follow-up in NHS (HR, 1.04; CI, 0.82–1.33).⁽¹⁴⁾ There are, however, some differences between their analysis and ours. WHI was twice as large (1,931 CRC cases among 156,826 women, compared to 801 CRC cases among 86,277 women at risk in NHS) and confirmed bisphosphonate use, type, and non-intravenous preparation via assessments of medication bottles and not simply from self-reported questionnaire. Among other variables, we adjusted HRs for a predicted fracture probability (BMD surrogate), recent physician contact at mammography, education, and hormone type, which were not part of the NHS analysis. Khalili et al., however, adjusted for some exposures that we did not, including regular statin use, folate intake, red meat intake, and personal history of colorectal polyps beyond receipt of endoscopy.

In contrast to our findings, several previous case-control and retrospective studies have observed a reduced risk of developing CRC among users.^(8–13) Analyses from pharmacy databases generally have limited ability to adequately control for confounding. The Danish studies did not adjust for BMI, calcium, or vitamin D. One GPRD study adjusted for calcium and vitamin D, but included only prescription sources. None, including MECC, measured calcium and vitamin D intake from diet.

Our study is not without limitations. WHI began around the time bisphosphonates first started being commonly prescribed. Use was low at baseline (2%) and half of these women were users for <1 year. Although the prevalence of use increased during follow-up, of the women who developed CRC, fewer than 150 had ever used bisphosphonates during the first 6 years of the study. Given that nearly all users were taking alendronate, we had very little power to detect associations for other types. Consequently, we could not confirm the previously reported inverse association specific to risedronate.⁽¹¹⁾ It is possible that any benefits of bisphosphonates for CRC prevention require higher doses or longer durations than that used by women in WHI. We did not evaluate dose, and could not account for continued compliance between medications assessments. Further studies may provide a more complete evaluation.

Despite the promising experimental evidence of the antiproliferative action of amino-bisphosphonates, our study lends further support to the conclusion that use of bisphosphonates does not meaningfully alter the risk of developing CRC. Women who are prescribed bisphosphonates may have bone loss that results from factors that are also associated with CRC risk, including lifetime hormonal exposures. Any anti-proliferative action of bisphosphonates may be offset by the increased risk of CRC in these women. Our results suggest that uncontrolled confounding may explain why previous studies have observed decreased risk of CRC among bisphosphonate users.