Download Qualified Health Claims for Calcium and Colorectal, Breast, and

Nutrition and Cancer, 61(2), 157–164
Copyright © 2009, Taylor & Francis Group, LLC
ISSN: 0163-5581 print / 1532-7914 online
DOI: 10.1080/01635580802395741
Qualified Health Claims for Calcium and Colorectal, Breast,
and Prostate Cancers: The U.S. Food and Drug
Administration’s Evidence-Based Review
Claudine J. Kavanaugh, Paula R. Trumbo, and Kathleen C. Ellwood
Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park,
Maryland, USA
In 2003, the United States Food and Drug Administration (FDA)
received a health claim petition for calcium supplements and reduced risk of colorectal, breast, and prostate cancers. Health claims
characterize the relationship between a substance (food or food
component) and disease (e.g., cancer or cardiovascular disease) or
health-related condition (e.g., hypertension) and require premarket approval for the labeling of conventional foods and dietary
supplements by the FDA. This review describes how the FDA used
the evidence-based review system to evaluate the scientific evidence
for these proposed health claims. FDA found no credible evidence
to support health claims for calcium and a reduced risk of breast
and prostate cancers. The agency did find limited evidence for the
relationship between calcium intake and colorectal cancer risk.
INTRODUCTION
Emerging evidence on nutrition and health relationships in
the late 1980s sparked the enactment of the Nutrition Labeling and Education Act (NLEA) of 1990 (1). NLEA allowed
the United States Food and Drug Administration (FDA or the
agency) to authorize health claims. Prior to 1990, no claims
about disease were allowed on the food label. Health claims
characterize the relationship between a substance (food or food
component) and disease (e.g., cardiovascular disease) or healthrelated condition (e.g., hypertension) and require premarket
approval for the labeling of conventional foods and dietary
supplements by the FDA. NLEA allowed the agency to authorize health claims that met the significant scientific agreement
standard. The significant scientific agreement standard provides
strong evidence for the substance–disease relationship, is supported by the totality of publicly available data, and agreed on
Submitted 26 November 2007; accepted in final form 13 March
2008.
Address correspondence to Claudine J. Kavanaugh, U. S. Food
and Drug Administration, Center for Food Safety and Applied Nutrition, HFS-830, 5100 Paint Branch Parkway, College Park, MD
20740. Phone: 301-436-1847. Fax: 301-436-2636. E-mail: claudine.
[email protected]
among qualified experts that the relationship is valid. In contrast to a significant scientific agreement (authorized) health
claim, qualified health claims rely on less scientific evidence
and are accompanied by disqualifying language to reflect the
level of science supporting the claim. Qualified health claims
were issued for the labeling of dietary supplements after several court decisions regarding First Amendment issues and later
expanded to conventional foods due to a major initiative by the
FDA in 2003 (2). In the 1999 court ruling, Pearson v. Shalala
(3) concluded that the First Amendment protection of commercial speech does not permit the agency to reject health claims
that it determines to be potentially misleading. The agency may
add a disclaimer statement to the health claim (i.e., qualified
health claim) to reflect the level of science unless the agency
also reasonably determines that no disclaimer would eliminate
the potential deception (4). Both authorized and qualified health
claims require an extensive scientific review of the evidence.
In July 2007, the agency released the draft guidance document, http://www.cfsan.fda.gov/∼dms/hclmgui5.html (5), outlining the evidence-based review system for health claims. The
evidence-based review system is a systematic process for evaluating the scientific evidence for proposed health claims. This
review demonstrates how the agency evaluated the scientific evidence using this system for the proposed qualified health claims
for supplemental calcium intake and risk of colorectal, breast,
and prostate cancers.
BACKGROUND
Colorectal, breast, and prostate cancers are 3 of the most
commonly diagnosed forms of cancer in the United States (6).
Nutrition and diet are thought to play a significant role in reduction of these types of cancer (6), and many nutrients including
calcium have been evaluated for their potential protective effect. Increased calcium intake is associated with decreased risk
of colorectal cancer as well as breast cancer in epidemiological,
cellular, and animal studies (7–10). Calcium has been associated
with increasing cellular differentiation and apoptosis in both
normal and tumor cells (7). For colorectal cancer, calcium may
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C. J. KAVANAUGH ET AL.
bind bile and fatty acids in the intestinal tract and thereby keep
these compounds from damaging the intestinal mucosa. It has
been hypothesized that calcium may affect cancer risk through
the metabolism of vitamin D, particularly in breast cancer (8).
In contrast to colorectal and breast cancer, some epidemiological evidence has suggested that calcium may actually increase
prostate cancer risk (11).
In December 2003, the FDA received a petition for qualified
health claims regarding calcium from dietary supplements and
a reduced risk of colorectal, breast, and prostate cancers from
a dietary supplement manufacturer. This review outlines how
the agency evaluated the scientific evidence for the proposed
qualified health claims.
THE QUALIFIED HEALTH CLAIM PETITION PROCESS
Qualified health claim petitions submitted to the agency must
follow specific rules outlined in the Code of Federal Regulations
(ref 101.14 and 101.70). These requirements include defining
the substance(s), diseases, or health-related conditions; summary of the scientific data (both positive and negative); copies
of all computerized literature searches performed by the petitioner; all information relied on to support the proposed health
claim; as well as any data reporting adverse consequences. The
agency acknowledges receipt of the petition within 15 days.
Within 45 days of receipt, the FDA will file the petition, thereby
making the contents of the petition public. At the time of filing,
FDA will post the petition on the FDA Web page for a 60-day
public comment period. During this time, written comments
may be submitted to the agency. On or before 270 days after receipt of the petition, a final decision will be sent to the petitioner
in the form of a letter as to whether the FDA intends to exercise
enforcement discretion with respect to a qualified health claim
or deny the petition. The letter will be posted on the FDA’s Web
site and in the docket. When a letter of enforcement discretion
has been issued, the FDA does not intend to object to the use
of the claim specified in the letter provided that the products
that bear the claim are consistent with the stated criteria. Extensions beyond 270 days can be granted upon mutual agreement
between the petitioner and the agency.
EVIDENCE-BASED REVIEW SYSTEM
In 2007, the FDA published draft guidance on the evidencebased review system for the scientific review of health claims
(5). The evidence-based system reviews and rates the scientific evidence for a given substance–disease relationship (health
claim). The FDA reviews studies submitted in petitions seeking health claims, and the petitioner is required to provide all
evidence related to the health claim (e.g., supportive and not
supportive). Through a literature search, the agency identifies
any additional studies that are considered to be relevant to the
petitioned health claims. The FDA focuses its review on reports
of human intervention and observational studies. In addition to
individual reports of human studies, the agency also consid-
ers other types of data and information in its review such as
meta-analyses, review articles, and animal and in vitro studies.
These other types of data and information may be useful to assist the agency in understanding the scientific issues about the
substance, the disease or health-related condition, or both but
cannot by themselves support a health claim relationship.
The FDA evaluates the individual reports of human studies
to determine whether any scientific conclusions can be drawn
from each study. The absence of critical criteria, such as a control
group or statistical analysis, means that scientific conclusions
cannot be drawn from the study (12). Studies from which the
FDA cannot draw any scientific conclusions about the health
claim relationship are eliminated from further review. Because
health claims involve reducing the risk of a disease in people
who do not already have the disease that is the subject of the
claim, the FDA considers evidence from studies in individuals
diagnosed with the disease that is the subject of the health claim
only if it is scientifically appropriate to extrapolate to individuals
who do not have the disease.
The FDA rates the remaining human intervention and observational studies for methodological quality. This quality rating
is based on several criteria related to study design (e.g., use
of a placebo control vs. a nonplacebo controlled group), data
collection (e.g., type of dietary assessment method), the quality
of the statistical analysis, the type of outcome measured (e.g.,
disease incidence vs. validated surrogate endpoint), and study
population characteristics other than relevance to the U.S. population (e.g., selection bias and whether important information
about the study subjects—e.g., age, smoker vs. nonsmoker—
was gathered and reported).
Finally, the FDA evaluates the results of the remaining studies
and the strength of the total body of publicly available evidence.
The agency conducts this rating evaluation by considering the
study type (e.g., intervention, prospective cohort, case control,
cross-sectional), the methodological quality rating previously
assigned, the quantity of evidence (number of the various types
of studies and sample sizes), whether the body of scientific
evidence supports a health claim relationship for the U.S. population or target subgroup, whether study results supporting the
proposed claim have been replicated(13), and the overall consistency (14) of the total body of evidence. Based on the totality
of the scientific evidence, the FDA determines whether such
evidence is credible to support the substance–disease relationship. If there is credible evidence, the agency determines the
qualifying language that reflects the level of scientific evidence
to support the relationship.
SURROGATE ENDPOINTS FOR CANCER
Both significant scientific agreement and qualified health
claims are directed toward risk reduction in the healthy U.S.
population or a specific subpopulation (e.g., the elderly). The
FDA uses surrogate markers for disease risk when they have
been appropriately validated and are recognized by the National
QUALIFIED HEALTH CLAIMS FOR CALCIUM AND COLORECTAL, BREAST, AND PROSTATE CANCERS
Institutes of Health or the FDA Center for Drug Evaluation
and Research. The FDA has identified the following markers to
use in identifying risk reduction for purposes of a health claim
evaluation involving colorectal, breast, and prostate cancers: incident cases of the particular cancer being studied and recurrent
colorectal polyps as a surrogate marker of colorectal cancer.
DIETARY CALCIUM AND CANCER RISK
Several observational studies have specifically evaluated supplemental calcium intake and colorectal, breast, and or prostate
cancer risk. However, most observational studies have calculated calcium intake from the diet or water and then measured
the risk of cancer.
The proposed claim is for a relationship between calcium
from dietary supplements and a reduced risk of colorectal,
breast, and prostate cancers. In observational studies that calculate nutrient intake from food, measures of calcium consumption are based on recorded dietary intake methods such as food
frequency questionnaires, diet recalls, or diet records in which
the type and amount of foods consumed are estimated. A common weakness of observational studies is the limited ability to
ascertain the actual nutrient intake for the population studied.
Furthermore, the nutrient content of foods can vary [e.g., due to
demographics (soil composition), food processing/cooking procedures, or storage (duration, temperature)]. Thus, it is difficult
to ascertain an accurate amount of the nutrient consumed based
on reports of dietary intake of foods. In addition, conventional
foods contain not only calcium but also other nutrients that may
be associated with the metabolism of calcium or the pathogenesis of colorectal, breast, or prostate cancers. Because foods
consist of many nutrients and substances, it is difficult to study
the nutrient or food components in isolation (15). Therefore,
observational studies that have calculated calcium from dietary
sources were not considered in the review of the substance and
disease relationship for these qualified health claims.
COLORECTAL CANCER
Intervention Studies
The petitioner identified intervention studies that evaluated
the relationship between calcium intake and colorectal cancer.
However, most of these studies have not provided information
from which scientific conclusions could be drawn for one or
more of the following reasons:
1. Many intervention studies have used subjects that were diagnosed with colorectal cancer. Health claims characterize the
relationship between a substance and a reduction in risk of
contracting a particular disease in healthy people. The FDA
may consider evidence from studies in individuals already
diagnosed with a disease if it is scientifically appropriate
to extrapolate to individuals who do not have the disease;
however, this was not the case for subjects diagnosed with
colorectal cancer.
159
2. The studies have not measured a validated surrogate endpoint for colorectal cancer and therefore have not provided
evidence for colorectal cancer risk reduction. Several studies have measured fatty acid, bile acid, or water content of
feces; ornithine decarboxylase activity; or colon/rectal cell
proliferation. These have not provided evidence for the risk
reduction of colorectal cancer.
3. Intervention studies have used supplemental calcium in combination with other vitamins (selenium, vitamin E, vitamin
C, and β-carotene) or have used dairy products in lieu of
supplemental calcium as the intervention. Foods and multinutrient dietary supplements contain not only calcium but also
other nutrients that may be associated with the metabolism
of calcium and/or the pathogenesis of colon/rectal polyp recurrence or colorectal cancer. Therefore, no scientific conclusions could be drawn from them about the relationship
between calcium supplements and colorectal cancer.
4. Studies have been a republication or reanalysis of a study
already being used to evaluate the proposed claim; therefore,
these studies have provided no new scientific data.
5. Statistical analysis has not been conducted in the studies to
determine if there was a difference between the treatment
group and the control group. Statistical analysis is critical
because it provides the comparison between subjects consuming calcium and those not consuming calcium to determine whether there is a reduction in cancer risk. Thus, when
statistics have not been conducted, it is not possible to determine if there was a difference between the treatment and
control groups.
Two intervention studies have evaluated the relationship between calcium intake and reduced risk of colorectal cancer
(16,17). Both studies have received high methodological quality
study ratings. The Calcium Polyp Prevention Study was a randomized double-blind intervention trial on 930 subjects with a
recent history (previous 3 mo) of colon/rectal polyps (16). The
mean age of the subjects was 61 ± 9 yr, and 70% of the subjects
were men. Of the 930 subjects that underwent randomization,
832 completed the study follow-up of two colonoscopies, at one
and four years after enrollment. After a 3-mo placebo run-in period, the subjects were randomized to receive 3 g/day of calcium
carbonate (1.2 g/day of elemental calcium) or placebo until the
completion of the study. The relative risk for developing a polyp
between the first and second endoscopy while consuming the
calcium supplement was 0.81 [with 95% confidence interval
(CI) = 0.67–0.99], indicating a significant decrease.
Bonithon-Kopp et al. (17) was a randomized, double-blind,
intervention trial on 665 subjects with a recent history of
colon/rectal polyps. There were 3 groups in the study: subjects that received calcium gluconolactate and carbonate daily
(2 g/day elemental calcium) (n = 218), subjects that received
3.5 g of fiber per day (n = 226), and subjects that received a
placebo (n = 221). Approximately 60% of the subjects were
males, and the average age for the intervention groups was
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C. J. KAVANAUGH ET AL.
approximately 59 yr. Both the calcium and placebo groups had
a similar number of subjects complete the study: 176 for calcium
and 178 for placebo. The adjusted relative risk for calcium supplementation and polyp recurrence in this study was 0.66 (95%
CI = 0.38–1.17). Calcium supplementation did not significantly
reduce colorectal polyp recurrence in this study.
Observational Studies
Most observational studies that have evaluated calcium and
the risk of colorectal cancer have estimated calcium intake from
either dietary or water intake. Scientific conclusions could not be
drawn from these studies regarding supplemental calcium and
colorectal cancer risk for the reasons discussed in the Dietary
Calcium and Cancer Risk section.
Six prospective cohort studies have evaluated the relationship
between supplemental calcium and risk of colon/rectal cancer
(18–23). All 6 studies were considered to be of high methodological quality.
The Flood et al. (18) study followed a cohort of 45,354 U.S.
women for approximately 8.5 yr and identified 482 cases of
colon/rectal cancer during the follow-up. Calcium supplement
consumption (>800 mg/day) was associated with a decreased
risk of colon/rectal cancer (relative risk of 0.76, 95% CI =
0.56–0.98) (18).
The Cancer Prevention Study II Nutrition cohort consisted
of approximately 126,000 U.S. males and females who completed a detailed questionnaire regarding different lifestyle and
dietary habits in 1992–1993 (19). After 4 to 5 yr of follow-up,
683 cases of colorectal cancer were identified in the cohort.
Calcium supplement use was associated with a reduced risk of
developing colon/rectal cancer with a relative risk of 0.69 (95%
CI = 0.49–0.96). However, when the cohort was stratified by
gender, calcium supplementation had no significant effect on
colon/rectal cancer incidence.
The Nurses Health Study and Health Professionals Followup study (87,988 females and 47,344 males, respectively) evaluated calcium intake and colon/rectal cancer risk over 10 to
16 years of follow-up, identifying 1,025 colon/rectal cancer
cases (20). Current calcium supplement use was associated
with a decreased risk of distal colon cancer incidence in a
combined cohort analysis (relative risk of 0.69, 95% CI =
0.51–0.94 compared to nonsupplement users). When the cohorts were stratified by gender, calcium supplementation had no
significant effect on distal colon cancer incidence. Calcium supplementation was not specifically evaluated in proximal colon
cancer; however, total calcium intake (supplemental and dietary calcium combined) did not demonstrate any reduction in
risk.
A cohort of 35,216 women from Iowa assessed calcium intake and colon cancer risk (21). The women completed a questionnaire regarding dietary and supplemental sources of calcium
in 1986 and were followed for 9 yr, with 241 colon cancer cases
identified. Supplemental calcium use was associated with a sig-
nificantly reduced risk of colon cancer incidence (relative risk
of 0.6, 95% CI = 0.4–0.9) in women without a family history of
colon cancer. There was no beneficial relationship between calcium supplementation and colon/rectal cancer in women with a
family history of colon cancer.
Two prospective studies have evaluated the association between calcium supplementation and polyp recurrence (22,23).
Martinez et al. (22) was a secondary analysis of an intervention study initially designed to evaluate fiber intake and polyp
recurrence. The primary intervention had no effect on polyp recurrence. The study followed 1,304 males and females for 3 yr.
Calcium supplement use had no association with polyp recurrence (relative risk of 0.94, 95% CI = 0.67–1.33). Hyman et al.
(23) performed a secondary analysis of an intervention trial designed to evaluate different antioxidant compounds (β-carotene,
vitamins C and E) and polyp recurrence. The intervention had
no effect on polyp recurrence. The study followed 864 subjects
for 4 yr. There was no association between calcium supplement use and polyp recurrence (relative risk of 0.76, 95% CI =
0.42–1.38).
Five case-control studies of moderate methodological quality
have evaluated the relationship between calcium supplement use
and colon/rectal cancer risk (24–28). Marcus and Newcom (24)
conducted a case-control study in 678 controls and 512 female
colon/rectal cancer cases from the United States. Supplemental
calcium intake had no significant association with colon or rectal cancer risk [odds ratio (OR) = 1.0, 95% CI = 0.7–1.6, and
OR = 0.8, 95% CI = 0.5–1.6, respectively). White et al. (25)
found no significant association between calcium supplement
use and colon cancer risk in 444 cases and 427 controls from
the United States. Neugut et al. (26) performed two different
case-control studies in one publication; the first study compared
297 subjects newly diagnosed with polyps to 505 controls. There
was no association between calcium supplement use and polyp
occurrence (OR = 0.9, 95% CI = 0.2–4.0). The second casecontrol study contained 297 subjects with recurrent polyps and
347 controls (without recurrent polyps but have a history of
polyps). There was no association between calcium supplement
use and polyp recurrence (OR = 2.9, 95% CI = 0.6–9.5). Whelan et al. (27) conducted a case-control study with 183 subjects
diagnosed with recurrent colon/rectal polyps and 265 subjects
without recurrent colon/rectal polyps. Supplemental calcium intake was associated with a decreased risk of polyp recurrence
(OR = 0.51, 95% CI = 0.27–0.96). Peleg et al. (28) found no
relationship between prescribed calcium supplement use and
colon/rectal cancer risk in 93 colorectal carcinoma cases, 113
colorectal adenocarcinoma cases, and 186 or 226 controls from
the United States (OR = 1.93 and 0.68, 95% CI = 0.81–4.62
and 0.24–1.89, respectively).
In summary, there were two intervention studies and six
prospective observational studies that provided information
about the relationship between supplemental calcium intake
calcium and colon/rectal cancer risk reduction (Table 1). One
intervention study reported a significant reduction in recurrent
QUALIFIED HEALTH CLAIMS FOR CALCIUM AND COLORECTAL, BREAST, AND PROSTATE CANCERS
161
TABLE 1
Studies reviewed for the qualified health claim for calcium supplements and a reduced risk of colorectal cancera
Author and
Year Publication
(Ref. No.)
Study Type
Baron et al., 1999 (16)
Intervention
United
States
Bonithon-Kopp et al.,
2000 (17)
Intervention
Europe
Flood et al., 2005 (18)
Cohort
Sellers et al., 1998 (21)
Cohort
United
States
United
States
409 calcium
supplements, 423
placebo controls
221 calcium
supplements, 221
placebo control
482 cases, 45,354
women
212 cases, 35,216
women
McCullough et al., 2003
(19)
Wu et al., 2002 (20)
Cohort
United
States
United
States
683 cases, 60,866 males,
66,883 females
1,025 cases, 47,344
males, 87,988 females
Hyman et al., 1998 (23)
Cohort
United
States
Martinez et al., 2002
(22)
Cohort
United
States
Marcus and Newcom,
1998 (24)
Case control
United
States
260 cases (polyp
recurrence), 864
subjects
639 cases (polyp
recurrence), 1,304
subjects
348 colon cancer cases,
164 rectal cancer
cases, 678 controls
Neugut et al., 1996 (26)
Case control
United
States
193 recurrent polyps,
347controls, 297
newly diagnosed
polyps, 505 controls
Whelan et al., 1999 (27)
Case control
United
States
White et al, 1997 (25)
Case control
United
States
448 subjects with a
history of adenoma,
183 recurrent
adenoma, 265 no
recurrence
444 colon cancer cases,
427 Controls
a
Cohort
Study
Location
No. Cases
and Control
Subjects
Abbreviations are as follows: RR, relative risk; CI, confidence interval; OR, odd ratio.
Results/Dose
Adjusted RR for calcium supplementation
and polyp recurrence = 0.81, 95% CI =
0.67–0.99
Adjusted RR for calcium supplementation
and polyp recurrence = 0.66, 95% CI =
0.38–1.17
>800 mg calcium supplements per day,
adjusted RR = 0.76 (95% CI = 0.56–0.98)
>500 mg calcium supplements per day,
adjusted RR for women with no family
history colon cancer = 0.6 (95% CI =
0.4–0.9); adjusted RR for women with a
family history of colon cancer = 1.0 (95%
CI = 0.5–2.1)
>500 mg calcium supplements per day,
adjusted RR = 0.56 (95% CI = 0.49–0.96)
Compared never users to current users of
supplemental calcium, adjusted RR for
distal colon cancer = 0.69 (95% CI =
0.51–0.94)
No calcium supplement use compared to
some use, adjusted RR = 1.25 (95% CI =
0.78–2.01)
>200 mg calcium supplements per day,
adjusted RR = 0.94 (95% CI = 0.67–1.33)
≥800 mg calcium supplements per day,
adjusted OR for colon cancer = 1.0 (95%
CI = 0.7–1.6); adjusted OR for rectal
cancer = 0.8 (95% CI = 0.5–1.6)
Calcium supplement users versus non users;
recurrent polyp adjusted OR males = 1.3
(95% CI = 0.6–2.8), females = 1.9 (95%
CI = 1.0–3.8); incidence polyp adjusted
RR males = 0.7 (95% CI = 0.3–1.6),
females = 1.3 (95% CI = 0.8–2.1)
Calcium supplement use vs. nonusers for
adenoma recurrence, adjusted OR = 0.51
(95% CI = 0.271–0.962)
Compared non–calcium-supplement users to
subjects consuming >100 mg/day,
adjusted RR = 0.78 (95% CI = 0.52–1.18)
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C. J. KAVANAUGH ET AL.
colon/rectal polyps after supplementation with 1.2 g/day of calcium (16). In contrast, the intervention study by Bonithon-Kopp
et al. (17) reported no significant benefit of calcium supplementation. The Baron et al. (16) study included more subjects and
had a longer follow-up time than Bonithon-Kopp et al. (17),
which may have provided the study with more power (e.g.,
ability to detect a difference) to find a significant beneficial effect of supplemental calcium on colon/rectal cancer risk. Of the
six prospectively designed observational studies, four reported
some type of significant association between calcium supplements and the risk reduction of colon/rectal cancer (18–21),
whereas two studies reported no association (22,23). The studies that have reported protective associations for supplemental
calcium were the cohorts with the largest number of subjects
that contained both genders and a broad age range of subjects.
The effect of calcium intake on decreased colon/rectal cancer
risk was modest, and the effect did not seem to increase after a
threshold of calcium intake was achieved (20), thereby suggesting that larger study populations are needed to find a modest
reduction in risk. Of the four case-control studies, three studies
reported no association between calcium intake and colon/rectal
cancer (24–26), and one study reported a protective association between calcium and colon/rectal cancer risk (27). Based
on the above evidence, the FDA concluded that there was a
low level of comfort that a relationship exists between supplemental calcium intake and a reduced risk of colon/rectal
cancer.
BREAST CANCER
Intervention Studies
The FDA did not identify any intervention studies that evaluated the relationship between calcium and breast cancer risk.
Observation Studies
The FDA identified eight observational studies on calcium
and risk of breast cancer, consisting of two prospective cohort
studies (29,30) and six case-control studies (31–36). Seven of
these studies measured calcium intake from estimated intake
of foods. Scientific conclusions could not be drawn from these
studies regarding supplemental calcium and breast cancer risk
for the reasons discussed in the Dietary Calcium and Cancer
Risk section above.
One cohort study evaluated the relationship between calcium
supplements and breast cancer (29) and received a high methodological quality rating. The cohort study evaluated calcium supplement intake in 88,691 pre and postmenopausal female nurses,
with 3,482 cases identified during follow-up. Calcium supplement use was not significantly associated with breast cancer
incidence in either group of nurses. Premenopausal women consuming greater than 900 mg/day of supplemental calcium had
a relative risk of 1.10 (95% CI = 0.81–1.50) for developing
breast cancer compared to women not consuming supplements.
Postmenopausal women consuming greater than 900 mg/day
of supplemental calcium had a relative risk of 0.93 (95% CI =
0.81–1.08) for developing breast cancer compared to women not
consuming calcium supplements. When supplemental calcium
intake was stratified by dietary calcium intake, no significant
association between supplemental calcium intake and breast
cancer was found. The FDA concluded that there was no credible evidence to support a qualified health claim for supplemental
calcium intake and breast cancer risk.
PROSTATE CANCER
Intervention Studies
One intervention study was found by the agency relating
to calcium supplementation and prostate cancer risk (37). The
report was designed to specifically evaluate the effect of supplemental calcium intake on colon/rectal polyp recurrence. Prostate
cancer incidence was a secondary endpoint of the study. Because
the study did not screen for prevalent cases of prostate cancer
at the onset of the study, the results may be biased due to an
uneven distribution of prevalent cases in the treatment vs. the
placebo group. Because uneven distribution of important patient
or disease characteristics between groups may lead to mistaken
interpretation (12), scientific conclusions could not be drawn
from this study about the relationship between calcium and reduced risk of prostate cancer.
Observational Studies
The FDA identified 13 observational studies on the relationship between calcium intake and prostate cancer. Ten studies
estimated dietary calcium intake from food or water consumption (38–47) and scientific conclusions could not be drawn
for the reasons discussed above in the Dietary Calcium and
Cancer section.
One prospective cohort study evaluated the relationship between calcium intake and prostate cancer and was of high
methodological quality (48). The cohort followed 47,781 men
for 8 yr and evaluated the effect of supplemental calcium use in
a stratified analysis with dietary calcium intake. During followup 1,792 incident prostate cancer cases were identified. This
study reported that the group consuming the least amount of
dietary calcium (<600 mg/day) and the highest calcium supplement intake (>900 mg/day) was associated with a significant
increase in the risk of metastatic prostate cancer (relative risk
of 3.6, 95% CI = 1.5–8.8). No stratified analysis of supplemental and dietary calcium use for total prostate cancer (metastatic
and nonmetastatic prostate cancer) was evaluated. However, total calcium intake (supplemental and dietary combined) at the
highest intake level (greater than 2 g/day) was significantly associated with an increased risk of prostate cancer.
Two case-control studies of high methodological quality
evaluated the relationship between supplemental calcium intake and prostate cancer risk (49,50). Kristal et al. (49) was
QUALIFIED HEALTH CLAIMS FOR CALCIUM AND COLORECTAL, BREAST, AND PROSTATE CANCERS
a case-control study that included 697 incident prostate cancer cases and 666 controls from the Seattle, Washington area.
Calcium supplement use was not significantly associated with
prostate cancer risk, even at the highest quartile of intake (OR =
1.25, 95% CI = 0.73–2.17). Kristal et al. (50) was a case control
study with 605 cases of cancer and 592 controls that evaluated
calcium intake from supplements in a stratified analysis with dietary calcium intake. Calcium intake from supplements did not
significantly affect prostate cancer risk. Because there were no
studies that supported the proposed qualified health claim, the
FDA concluded that there was no credible evidence to support a
relationship between the consumption of supplemental calcium
and prostate cancer risk.
SUMMARY AND CLAIMS
The FDA concluded that there was no credible evidence
to support qualified health claims about supplemental calcium
intake and a reduced risk of breast or prostate cancers. However,
FDA concluded that there was limited credible evidence for a
qualified health claim about supplemental calcium intake and
colon/rectal cancer, provided that the qualified health claim was
appropriately worded so as to not mislead consumers. Thus, the
agency issued a letter of enforcement discretion for the use of
the following claim:
Some evidence suggests that calcium supplements may reduce
the risk of colon/rectal cancer, however, FDA has determined that
this evidence is limited and not conclusive.
New Research
Since the FDA issued a letter of enforcement discretion on
calcium supplements and reduced risk of colorectal and breast
cancers in 2005, several studies have been published (51–53).
Grau et al. (51) continued to follow subjects from the Calcium
Polyp Prevention Study [Baron et al. (16)] and reported a reduced risk in the recurrence of colorectal polyps existed in subjects receiving calcium supplements 5 yr after the intervention
was stopped. A study by Lappe et al. (52) evaluated colon and
breast cancer incidence as a secondary endpoint for an intervention study evaluating calcium supplement intake and fracture
incidence in postmenopausal women. Because colon or breast
cancer were secondary endpoints (52), the study would be similar to Baron et al. (37) that was discussed above and therefore
would not be included in a future review. McCullough et al. (53)
evaluated calcium supplement use and the risk of breast cancer
in a cohort of 68,000 women and reported no association. These
studies have not been evaluated using the FDA’s evidence-based
review system; however, based on preliminary appraisal, they do
not seem to contradict the conclusions made by the FDA based
on the credible evidence used to evaluate the qualified health
claims for calcium supplements and reduced risk of colorectal
and breast cancers.
163
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