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Health Claims: Letter of Denial - Alkaline and Earth Alkaline Citrates Minimizing the Risk of Osteoporosis

Back to Health Claims Meeting Significant Scientific Agreement (SSA)

October 30, 2007

(Docket Number 2007P-0301)

Dr. Wulf Dröge
Senior Vice-President Research & Development
Immunotec Inc.
300 Joseph Carrier
Vaudreuil-Dorion (Quebec)
Canada J7V-5V5

RE: Petition for a Health Claim Stating that Alkaline and Earth Alkaline Citrates Minimize the Risk of Osteoporosis (Docket Number 2007P-0301)

Dear Dr. Dröge:

This letter responds to your health claim petition received on April 23, 2007, by the Food and Drug Administration (FDA or the agency). You submitted this petition pursuant to section 403(r)(5)(D) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 343(r)(5)(D)), and requested that the agency authorize health claims characterizing the relationship between the consumption of alkaline and earth alkaline citrate(s) and a reduced risk of osteoporosis. This petition proposed the following model health claims for dietary supplements:

"Potassium citrate alone or in combination with calcium citrate reduces the risk of osteoporosis."

"Potassium citrate inhibits bone resorption, the typical cause of osteoporosis."

"A daily dose of 4.3 g potassium citrate was shown to inhibit bone resorption."

"A dose of calcium citrate and/or potassium citrate sufficient to increase the urine PH to 6.3-6.7 may have the effect of reducing the risk of osteoporosis."

"Potassium citrate alone or in combination with other alkaline or earth alkaline citrate salts at a dose sufficient to increase the urine PH to 6.3-6.7 may have the desired effect of decreasing the risk of osteoporosis."

"Potassium citrate alone or in combination with other alkaline or earth alkaline citrates and in combination with high protein diets or protein supplements may reduce the risk of osteoporosis."

"Potassium citrate alone or in combination with calcium citrate and in combination with high protein diets or protein supplements may reduce the risk of osteoporosis."

In letters dated January 31, 2007 and March 8, 2007, the agency informed you that it was unable to acknowledge receipt of health claim petitions you submitted to the agency about the relationship between alkaline and earth alkaline citrates and osteoporosis because they were incomplete. On March 23, 2007, you participated in a conference call with FDA concerning your health claim petition submissions. During that conference call, FDA explained the type of analytical methods and data that were needed in order to have a complete petition. FDA also sought further clarification of the substances that were the subject of the petition and discussed other types of claims (i.e., structure/function claims and qualified health claims) that could be used in the labeling of dietary supplements containing alkaline and earth alkaline citrates in relation to bone strength or a reduction in risk of osteoporosis. During the conference call, you stated that you would submit additional analytical data, clarified the nature of the substances, and indicated that you were only interested in a health claim authorized by FDA via regulation (memorandum to the administrative record, Docket No., 2007P-0301, M1).

You subsequently submitted the information necessary to complete one of your petitions. In a letter dated May 3, 2007, FDA acknowledged your petition and initiated the agency's preliminary review of the petition. In that letter, FDA also informed you that the date by which FDA would either file or deny the petition was August 1, 2007. FDA filed your petition on that date.

FDA issues a regulation authorizing a health claim only when it determines, based on the totality of publicly available scientific evidence (including evidence from well-designed studies conducted in a manner which is consistent with generally recognized scientific principles), that there is significant scientific agreement (SSA), among experts qualified by scientific training and experience to evaluate such claims, that the claim is supported by such evidence (21 CFR 101.14(c)). This letter sets forth the agency's conclusion that the proposed health claims for use in the labeling of dietary supplements do not meet the SSA standard in 21 CFR 101.14(c). The agency is thus denying your petition for a regulation authorizing a health claim characterizing a relationship between potassium citrate alone or in combination with other alkaline or earth alkaline citrates and a reduced risk of osteoporosis.

I. Overview of Data and Eligibility for a Health Claim

A health claim characterizes the relationship between a substance and a disease or health-related condition (21 CFR 101.14(a)(1)). The substance must be associated with a disease or health-related condition for which the general U.S. population, or an identified U.S. population subgroup is at risk (21 CFR 101.14(b)(1)). Health claims characterize the relationship between the substance and a reduction in risk of contracting a particular disease.(1)

In a review of a health claim, the agency first identifies the substance and disease or health-related condition that is the subject of the proposed claim and the population to which the claim is targeted. FDA considers the data and information provided in the petition, in addition to other written data and information available to the agency, to determine whether the data and information could support a relationship between the substance and the disease or health-related condition.(2) The agency then separates individual reports of human studies from other types of data and information. FDA focuses its review on reports of human intervention and observational studies.(3)

In addition to individual reports of human studies, the agency also considers other types of data and information in its review, such as meta-analyses,(4) review articles,(5) 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 both, but cannot by themselves support a health claim relationship. Reports that discuss a number of different studies, such as meta-analyses and review articles, do not provide sufficient information on the individual studies reviewed for FDA to determine critical elements such as the study population characteristics and the composition of the food or food substances used. Similarly, a lack of detailed information on studies summarized in meta-analyses and review articles would prevent FDA from determining whether the studies are flawed in critical elements such as design, conduct of studies, and data analysis. FDA must be able to review the critical elements of a study to determine whether any scientific conclusions can be drawn from it. Therefore, FDA uses meta-analyses, review articles, and similar publications(6) to identify reports of additional studies that may be useful to the health claim review and as background about the substance-disease relationship. If additional studies are identified, the agency evaluates them individually.

FDA uses animal and in vitro studies as background information regarding mechanisms of action that might be involved in any relationship between the substance and the disease. The physiology of animals is different than that of humans. In vitro studies are conducted in an artificial environment and cannot account for a multitude of normal physiological processes such as digestion, absorption, distribution, and metabolism that affect how humans respond to the consumption of foods and dietary substances (IOM, 2005, Chapter 7). Animal and in vitro studies can be used to generate hypotheses or to explore a mechanism of action but cannot adequately support a relationship between the substance and the disease.

FDA evaluates the individual reports of human studies to determine whether any scientific conclusions can be drawn from each study. The absence of critical factors such as a control group or a statistical analysis means that scientific conclusions cannot be drawn from the study (Spilker, 1991, Chapters 8 and 70; Federal Judicial Center, 2000). Studies from which FDA cannot draw any scientific conclusions do not support the health claim relationship and these 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, 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. That is, the available scientific evidence must demonstrate that: (1) the mechanism(s) for the mitigation or treatment effects measured in the diseased populations are the same as the mechanism(s) for risk reduction effects in non-diseased populations; and (2) the substance affects these mechanisms in the same way in both diseased people and healthy people. If such evidence is not available, the agency cannot draw any scientific conclusions from studies that use diseased subjects to evaluate the substance-disease relationship.

Next, FDA evaluates the remaining human intervention and observational studies for methodological quality. FDA considers criteria related to study design (e.g., use of a placebo control versus a non-placebo 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 versus 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. non-smoker - was gathered and reported). If the scientific study adequately addressed all or most of the above criteria, it would receive a high methodological quality rating. Moderate or low quality ratings would be given based on the extent of the deficiencies or uncertainties in the quality criteria. Studies that are so deficient that scientific conclusions cannot be drawn from them cannot be used to support the health claim relationship, and these are eliminated from further review.

Finally, FDA evaluates the strength of the total body of publicly available evidence. The agency conducts this 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 various types of studies and sample sizes), whether the body of evidence supports a health claim relationship for the U.S. population or target subgroup, whether study results supporting the proposed claim have been replicated,(7) and the overall consistency(8) of the total body of evidence. Based on the totality of the scientific evidence, FDA determines whether such evidence supports the substance/disease relationship.

A. Substance

A health claim characterizes the relationship between a substance and a disease or health-related condition (21 CFR 101.14(a)(1)). A substance means a specific food or component of food regardless of whether the food is in conventional form or a dietary supplement (21 CFR 101.14(a)(2)). The petition sought authorization of a health claim in the labeling of dietary supplements for potassium citrate or a combination of potassium citrate and calcium citrate. The petition also identified the combination of potassium citrate, calcium citrate, and magnesium citrate and the combination of potassium citrate, calcium citrate, magnesium citrate, and sodium citrate as ‘desirable' substances. The petition described these substances as desirable because, according to the petitioner, the bone conserving effect of these alkaline and earth alkaline citrates is believed to result from the reduction in net acid load.

Potassium, calcium, magnesium, and sodium are components of foods (IOM, 2004, Chapter 5; IOM, 1997, Chapter 4; IOM, 1997 Chapter 6; and IOM, 2004, Chapter 6). Therefore, pure preparations of the citrate salts of potassium, calcium, magnesium, and sodium meet the definition of substance in the health claim regulation (21 CFR 101.14(a)(2)). Therefore, they could be the subject of a health claim in the labeling of a dietary supplement.

B. Disease or Health Related Condition

A disease or health-related condition means damage to an organ, part, structure, or system of the body such that it does not function properly or a state of health leading to such dysfunctioning (21 CFR 101.14(a)(5)). The petition identified osteoporosis as the disease that is the subject for all but one of the proposed health claims. According to the NIH Consensus Statement "Osteoporosis Prevention, Diagnosis, and Therapy" (hereafter, 2000 NIH Consensus Statement), osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture (NIH, 2000). Thus, the agency concludes that osteoporosis is a disease and therefore the petitioner has satisfied the requirement in 21 CFR 101.14(a)(5).

The following model health claim proposed in the petition, "A daily dose of 4.3 g potassium citrate was shown to inhibit bone resorption," is about the impact of a substance on bone resorption. A health claim as defined in 21 CFR 101.14 is any claim made on the label or in labeling of a food, including a dietary supplement, that expressly or by implication characterizes the relationship of any substance to a disease or health-related condition (21 CFR 101.14(a)). Bone resorption is not a disease or health-related condition (21 CFR 101.14(a)(5)). Thus, the proposed claim "A daily dose of 4.3 g potassium citrate was shown to inhibit bone resorption" does not meet the requirements in 21 CFR 101.14(a)(5) for a health claim, and we did not review the scientific support for the claim.

C. Safety

Under 21 CFR 101.14(b)(3)(ii), if the substance is to be consumed at other than decreased dietary levels, the substance must be a food or a food ingredient or a component of a food ingredient whose use at levels necessary to justify a claim must be demonstrated by the proponent of the claim, to FDA's satisfaction, to be safe and lawful under applicable food safety provisions of the Act.

FDA evaluates whether the substance is "safe and lawful" under the applicable food safety provisions of the Act. For dietary supplements, the applicable safety provisions require, among other things, that the dietary ingredient not present a significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling or, if no conditions of use are suggested or recommended in the labeling, under ordinary conditions of use (section 402(f)(1)(A) of the Act (21 U.S.C. 342(f)(1)(A))). Further, a dietary supplement must not contain a poisonous or deleterious substance which may render the supplement injurious to health under the conditions of use recommended or suggested in the labeling (section 402(f)(1)(D) of the Act (21 U.S.C. 342(f)(1)(D))).

It is not necessary for FDA to make a determination about the safety of potassium citrate alone or in combination with other alkaline or earth alkaline citrates in this letter because the agency is denying the petition for the proposed health claims because they do not meet the SSA standard, as discussed in sections II and III below.

II. The Agency's Consideration of a Health Claim

FDA has identified the incidence of osteoporosis as the disease endpoint to use in identifying osteoporosis risk reduction for purposes of a health claim evaluation. FDA has also identified bone mineral density (BMD) or bone mineral content (BMC) as valid surrogate endpoints for predicting risk of osteoporosis in the proposed health claim evaluation.

According to a 2000 NIH Consensus Statement, osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture (NIH, 2000). Bone strength is dependent upon bone density and bone quality. Bone density is determined by peak bone mass and amount of bone loss (NIH, 2000). Bone quality is a function of architecture, turnover, damage accumulation (e.g., micro fractures) and mineralization (NIH, 2000). The most common measures of overall bone strength are those for bone mass, namely BMD(9) and BMC. BMC is the amount of mineral at a particular skeletal site such as the femoral neck, lumbar spine, or total body; whereas BMD is BMC divided by the area of the scanned region (IOM, 1997, Chapter 4). One of the proposed claims, "A daily dose of 4.3 g potassium citrate was shown to inhibit bone resorption," does not meet the requirements of a health claim as discussed in section 1B of this letter. Bone resorption is not a disease, health-related condition or, a surrogate endpoint; therefore, scientific evidence to support this proposed claim was not reviewed.

The petition cited 13 publications as evidence to substantiate the relationship for the proposed claims. These publications consisted of: one letter, one book chapter about spectrophotometry and light-scattering methods, four studies that did not evaluate the substance and disease relationship (Dawson-Hughes et al., 2002; Rapuri et al., 2003; Alexy et al., 2005; Kerstetter et al., 2005), and 7 articles on human intervention or observational studies that evaluated the substance/disease relationship. In addition to the studies referenced in the petition, FDA identified from a literature search two additional intervention studies that evaluated the relationship between potassium citrate consumption and risk of osteoporosis (Jehle et al., 2006, Vescini et al., 2005).

A. Assessment of Background Materials

"Background materials" here refers to review articles, letters, and description of products. Although useful for background information, these materials do not contain sufficient information on the individual studies that they reviewed. Therefore, FDA could not draw any scientific conclusions from this information. FDA could not determine factors such as the study population characteristics or the composition of the products used (e.g., food, dietary supplement). Similarly, the lack of detailed information on studies summarized in these materials prevents FDA from determining whether the studies are flawed in critical elements such as design, conduct of studies, and data analysis. FDA must be able to review the critical elements of a study to determine whether any scientific conclusions can be drawn from it. As a result, the background materials supplied by the petitioner do not provide information from which scientific conclusions can be drawn regarding the substance/disease relationship claimed by the petitioner.

B. Assessment of the Intervention Studies

FDA identified six human intervention studies for its evaluation of the relationship between potassium citrate and risk of osteoporosis. Scientific conclusions could not be drawn from any of these six studies regarding the substance/disease relationship for one or more of the following reasons.

Potassium citrate

Three studies did not measure incidence of osteoporosis or a valid surrogate endpoint of osteoporosis (BMD or BMC) (Sakhaee et al., 2005; Sellmeyer et al., 2002; Marangella et al., 2004). Although two of the studies measured BMD at the start of the study, BMD was not measured after the intervention (Sakhaee et al., 2005; Marangella et al., 2004). Because these studies did not measure incidence of osteoporosis or a surrogate endpoint after the intervention, scientific conclusions about the relationship between consumption of potassium citrate and reduced risk of osteoporosis cannot be determined.

Two studies did not include a control group for comparison to the relative effects of potassium citrate consumption (Pak et al., 2002; Vescini et al., 2005). It could not be determined if the changes in the endpoint of interest were due to potassium citrate consumption or to unrelated or uncontrolled extraneous factors (Spilker, 1991, Chapter 8). Therefore, no scientific conclusions about the relationship between consumption of potassium citrate and reduced risk of osteoporosis can be determined from these studies.

One study did not perform statistical analysis between the intervention and control group (Marangella et al., 2004). Statistical analysis of the relationship is a critical factor because it provides the comparison between subjects consuming potassium citrate and those not consuming potassium citrate, to determine whether there is a reduction in risk of osteoporosis. When statistics are not performed on the specific substance/disease relationship, it cannot be determined whether there is a difference between the two groups (Spilker, 1991, Chapter 70). Therefore, no scientific conclusions about the relationship between consumption of potassium citrate and reduced risk of osteoporosis can be determined from this study.

Finally, one study evaluated the effects of potassium citrate on BMD in a population that included some women with osteoporosis (Jehel et al., 2006). The investigation assessed the effect of taking dietary supplements containing potassium citrate on BMD in postmenopausal women and included women with normal bone mass, low bone mass, and osteoporosis (T score -1 to -4).(10) The investigators reported that lumbar spine BMD increased significantly in the potassium citrate group, whereas a progressive decrease in BMD was observed in the potassium chloride group (control), resulting in an intergroup difference of 1.87 ± 0.50% (P<0.001). Data from this study were not stratified based on the subject's bone mass status. Without stratification based on whether the subjects had osteoporosis at the start of the study, it was not possible to determine whether potassium citrate consumption increased bone mass in subjects who already had established osteoporosis and/or those who had low or normal bone mass.

Health claims characterize the relationship between a substance and a reduction in risk of contracting a particular disease.  As a result, FDA considers evidence from studies in individuals already diagnosed with a disease only if it is scientifically appropriate to extrapolate to individuals who do not have the disease.  The available scientific evidence must demonstrate that: (1) the mechanism(s) for the mitigation or treatment effects measured in the diseased populations are the same as the mechanism(s) for risk reduction effects in non-diseased populations and (2) the substance affects these mechanisms in the same way in both diseased people and healthy people.

Available science shows that the normal progression of osteoporosis (loss of BMD) may be slowed with adequate intake of certain nutrients (e.g., calcium, vitamin D) and other lifestyle factors (e.g., weight-bearing exercise) (NIH, 2000; Dawson-Hughes, 2006). However, there are no studies to demonstrate that the mechanism for maintaining or increasing BMD in response to potassium citrate consumption is the same for both osteoporotic individuals and those with low or normal bone mass. Furthermore, no studies have demonstrated whether potassium citrate supplementation can effectively treat or reverse loss of BMD in osteoporotic individuals.  

Because it is not known whether potassium citrate intake can reverse bone loss and/or improve BMD in individuals with osteoporosis, it cannot be determined whether it is valid to extrapolate to individuals with osteoporosis in evaluating the role of potassium citrate in reducing the risk of osteoporosis in individuals who do not have the disease. Therefore, no scientific conclusions about the relationship between consumption of potassium citrate and reduced risk of osteoporosis can be determined from this study. 

Potassium citrate and calcium citrate

The one intervention study submitted to support a health claim for a combination of potassium citrate and calcium citrate did not measure incidence of osteoporosis or a validated surrogate endpoint of osteoporosis (BMD or BMC) (Sakhaee et al., 2005). Although BMD was measured at the start of the study, BMD was not measured after the intervention. Because this study did not measure incidence of osteoporosis or a surrogate endpoint after the intervention, scientific conclusions about the relationship between consumption of potassium citrate and calcium citrate and osteoporosis cannot be determined. The agency could not identify any additional relevant intervention studies from an independent literature search it conducted.

Potassium citrate, calcium citrate and magnesium citrate

No intervention studies were submitted by the petitioner relating consumption of potassium citrate, calcium citrate and magnesium citrate and osteoporosis. Furthermore, the agency could not identify any relevant intervention studies from an independent literature search it conducted.

Potassium citrate, calcium citrate, magnesium citrate and sodium citrate

No intervention studies were submitted by the petitioner relating consumption of potassium citrate, calcium citrate, magnesium citrate and sodium citrate and osteoporosis. Furthermore, the agency could not identify any relevant intervention studies from an independent literature search it conducted.

C. Assessment of the Observational Studies

Potassium citrate

FDA identified three observational studies for its evaluation of the relationship between potassium citrate and risk of osteoporosis. However, scientific conclusions could not be drawn from any of these three studies regarding the substance/disease relationship for the reasons discussed below.

The three observational studies evaluated the relationship between dietary potassium intakes on BMD (Tucker el al., 1999; Macdonald et al., 2005; New et al., 2004). However, these studies did not measure potassium citrate intake. Food composition databases do not provide the potassium citrate content of foods (e.g., USDA Nutrient Database for Standard Reference). Therefore, it is not possible to evaluate the relationship between potassium citrate and BMD based on these three observational studies.

Furthermore, even if the agency were to consider these three studies for the purposes of evaluating whether a relationship exists between potassium citrate and the risk of osteoporosis, no scientific conclusions regarding the validity of the proposed health claims could be drawn from them because they focused on consumption of conventional foods, not specific nutrients. The proposed health claim for the labeling of dietary supplements would characterize the relationship between potassium citrate and a reduced risk of osteoporosis, not between conventional foods containing potassium or potassium citrate and a reduced risk of osteoporosis. In observational studies that calculate nutrient intake from conventional food, measures of specific nutrient or food substance (e.g., potassium citrate) intake 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 such as the three at issue here is the limited ability to ascertain the actual intake of a particular food substance for the population studied. Thus, it is difficult to ascertain an accurate amount of the nutrient or food substance consumed based on reports of dietary intake of foods.

In addition, conventional foods (such as fruits and vegetables) contain not only potassium citrate, but also other nutrients (i.e., vitamin K, magnesium, zinc and fiber), that may be associated with the metabolism of potassium citrate or the pathogenesis of osteoporosis, BMD, or BMC. Because foods consist of many nutrients and substances, it is difficult to study the nutrient or food components in isolation (Sempos et al., 1999). For instance, dietary fiber can affect potassium balance by increasing the fecal excretion of potassium (IOM, 2004, Chapter 5). (See Sempos et. al., (1999), Willett (1990), and Willett (1998) regarding the complexity of identifying the relationship between a specific nutrient within a food and a disease.) For studies based on recorded dietary intake of such foods, it is not possible to accurately determine whether any observed effects of potassium citrate on reducing the risk of osteoporosis were due to: 1) potassium citrate alone; 2) interactions between potassium citrate and other substances; 3) other food substances acting alone or together; or, 4) decreased consumption of other substances contained in foods displaced from the diet by the increased intake of potassium-rich foods.

In fact, evidence demonstrates that in a number of instances, epidemiological studies based on the recorded dietary intake of conventional foods may indicate a benefit for a particular food substance with respect to a disease, but it is subsequently demonstrated in an intervention study that the nutrient-containing dietary supplement does not confer a benefit or actually increases risk of the disease (Lichtenstein and Russell, 2005). For example, previous epidemiological studies reported an association between fruits and vegetables high in beta-carotene and a reduced risk of lung cancer (Peto et al., 1981). However, subsequent intervention studies, the Alpha-Tocopherol and Beta Carotene Prevention Study (ATBC) and the Carotene and Retinol Efficiency Trial (CARET), demonstrated that beta-carotene supplements increase the risk of lung cancer in smokers and asbestos-exposed workers, respectively (The ATBC, 1994; Omenn et al., 1996). These studies illustrate that the effect of a nutrient provided as a dietary supplement exhibits different health effects compared to when it is consumed among many other food components. Furthermore, these studies demonstrate the potential public health risk of relying on results from epidemiological studies, in which the effect of a nutrient is based on recorded dietary intake of conventional foods as the sole source for concluding that a relationship exists between a specific nutrient and disease risk; the effect could actually be harmful.

Therefore, observational studies in conventional foods seldom provide any scientifically valid evidence for a claim about risk reduction for a particular nutrient or food substance because, in fact, the nutrient or substance in supplement form may decrease, have no effect, or actually increase risk of the disease or health related condition. For the above reasons, FDA concludes that scientific conclusions cannot be drawn from observational studies on conventional foods for the proposed claim for potassium citrate.

Potassium citrate and calcium citrate

No observational studies were submitted by the petitioner relating consumption of potassium citrate and calcium citrate and osteoporosis. Furthermore, the agency could not identify any relevant observational studies from an independent literature search it conducted.

Potassium citrate, calcium citrate and magnesium citrate

No observational studies were submitted by the petitioner relating consumption of a dietary supplement containing potassium citrate, calcium citrate and magnesium citrate and osteoporosis. Furthermore, the agency could not identify any relevant observational studies from an independent literature search it conducted.

Potassium citrate, calcium citrate, magnesium citrate and sodium citrate

No observational studies were submitted by the petitioner relating consumption of a dietary supplement containing potassium citrate, calcium citrate, magnesium citrate and sodium citrate and osteoporosis. Furthermore, the agency could not identify any relevant observational studies from an independent literature search it conducted.

III. Strength of the Scientific Evidence

Finally, the agency evaluates the strength of the total body of publicly available evidence. The agency conducts this evaluation by considering the study type (e.g., intervention, prospective cohort, case-control, cross-sectional), the methodological quality, the quantity of evidence (number of various types of studies and sample sizes), whether the body of evidence supports a health claim relationship for the U.S. population or target subgroup, whether study results supporting the proposed claim have been replicated,(11) and the overall consistency (12) of the total body of evidence. Based on the totality of the publicly available scientific evidence, FDA then determines under 21 CFR 101.14(c) whether there is significant scientific agreement among qualified experts that the claim is supported by such evidence.

As discussed in section II of this letter, none of the publicly available scientific evidence (intervention or observational studies) supports a relationship between consumption of potassium citrate alone or in combination with other alkaline or other earth alkaline citrates and osteoporosis. Furthermore, because the publicly available scientific evidence does not support a relationship between potassium citrate alone or in combination with other alkaline or earth alkaline citrates and osteoporosis, there cannot be a consensus among qualified experts that the proposed health claims are supported by such evidence.

Therefore, FDA concludes that the proposed claims for the relationship between alkaline and earth alkaline citrate(s) and a reduced risk of osteoporosis do not meet the SSA standard.

V. Conclusions

Based on FDA's consideration of the scientific evidence submitted with your petition, and other pertinent scientific evidence, FDA concludes that the proposed health claims for potassium citrate alone or in combination with other alkaline or earth alkaline citrates and reduced risk of osteoporosis do not meet the significant scientific agreement standard in 21 CFR 101.14(c). Thus, FDA is denying your petition for a health claim based on the following proposed claims:

"Potassium citrate alone or in combination with calcium citrate reduces the risk of osteoporosis."

"Potassium citrate inhibits bone resorption, the typical cause of osteoporosis."

"A dose of calcium citrate and/or potassium citrate sufficient to increase the urine PH to 6.3-6.7 may have the effect of reducing the risk of osteoporosis."

"Potassium citrate alone or in combination with other alkaline or earth alkaline citrate salts at a dose sufficient to increase the urine PH to 6.3-6.7 may have the desired effect of decreasing the risk of osteoporosis."

"Potassium citrate alone or in combination with other alkaline or earth alkaline citrates and in combination with high protein diets or protein supplements may reduce the risk of osteoporosis."

"Potassium citrate alone or in combination with calcium citrate and in combination with high protein diets or protein supplements may reduce the risk of osteoporosis."

Please note that there is a separate process for petitioning the agency for qualified health claims.(13) However, based on the scientific evidence reviewed in evaluating your current petition, there is no credible evidence to support qualified claims for potassium citrate alone or in combination with other alkaline or earth alkaline citrates and reduced risk of osteoporosis. Neither a disclaimer nor qualifying language would suffice to prevent consumer deception from the proposed health claims.

Finally, please note that scientific information is subject to change, as are consumer consumption patterns. FDA intends to evaluate new information that becomes available to determine whether it necessitates a change in this decision. For example, scientific evidence may become available that will support significant scientific agreement.

Sincerely,

Barbara O. Schneeman, Ph.D.
Director
Office of Nutrition, Labeling, and Dietary Supplements


References

Alexy, U., Remer, T., Manz, F., Neu, C.M. and Schoenau, E. Long-term protein intake and dietary potential renal acid load are associated with bone modeling and remolding at the proximal radius in healthy children. American Journal of Clinical Nutrition, 82: 1107-1114, 2005.

The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. New England Journal of Medicine, 330: 1029-1035, 1994.

Dawson-Hughes, B. Osteoporosis. In: Shils, M., Shike, M., Ross, A., Caballero, B., and Cousins, R. (Eds) Modern Nutrition in Health and Disease. Tenth Edition, Lippincott Williams & Wilkins, pp 1339-1352. 2006.

Dawson-Hughes, B. and Harris, S.S. Calcium intake influences the association of protein intake with rates of bone loss in elderly men and women. American Journal of Clinical Nutrition, 75: 773-779, 2002.

Federal Judicial Center, Reference Manual on Scientific Evidence. Second Edition, pp. 93, 343, 2000.

IOM (Institute of Medicine of the National Academies). Calcium. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. National Academy Press, Washington, D.C., Chapter 4, 1997.

IOM (Institute of Medicine of the National Academies). Magnesium. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. National Academy Press, Washington, D.C., Chapter 6, 1997.

IOM (Institute of Medicine, National Academy of Sciences). Potassium. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride and Sulfate. National Academy Press, Washington, D.C., Chapter 5, 2004.

IOM (Institute of Medicine of the National Academies), Sodium and Chloride. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride and Sulfate. National Academy Press, Washington, D.C., Chapter 6, 2004.

IOM (Institute of Medicine of the National Academies), Dietary Supplements: A Framework for Evaluating Safety, Categories of Scientific Evidence - In Vitro Data. National Academy Press, Washington, D.C., Chapter 7, 2005.

Jehle, S., Zanetti, A., Muser, J., Hulter, H.N. and Krapf, R. Partial neutralization of the acidogenic western diet with potassium citrate increases bone mass in postmenopausal women with osteopenia. Journal of American Society of Nephrology, 17: 3213-3222, 2006.

Kerstetter J.E., O'Brien, K.O., Caseria, D.M., Wall, D.E. and Insogna, K.L. The impact of dietary protein on calcium absorption and kinetic measures of bone turnover in women. The Journal of Clinical Endocrinology and Metabolism, 90: 26-31, 2005.

Lichtenstein, A.H. and Russell, R.M. Essential Nutrients: Food or Supplements? Journal of American Medical Association, 294: 351-358, 2005

Macdonald, H.M., New, S.A., Fraser, W.D., Campbell, M.K., and Reid, D.M. Low dietary potassium intakes and high dietary estimates of net endogenous acid production are associated with low bone mineral density in premenopausal women and increased markers of bone resorption in postmenopausal women. American Journal of Clinical Nutrition, 81: 923-933, 2005.

Marangella, M., Di Stefano, M., Casalis, S., Berutti, S., D'Amelio, P., and Isaia, G.C. Effects of potassium citrate supplementation on bone metabolism. Calcified Tissue International, 74: 330-335, 2004.

New, S.A., MacDonald, H.M., Campbell, M.K., Martin, J.C., Garton, M.J., Robins, S.P. and Reid, D.M. Lower estimates of net endogenous noncarbonic acid production are positively associated with indexes of bone health in premenopausal and perimenopausal women. American Journal of Clinical Nutrition, 79: 131-138, 2004.

NIH. Osteoporosis Prevention, Diagnosis, and Therapy. NIH Consensus Statement Online (http://consensus.nih.gov/2000/2000Osteoporosis111html.htm,) 17(1): 1-36. March 27-29. 2000. Date accessed, April 17, 2007.

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Notes

(1) See Whitaker v. Thompson, 353 F.3d 947, 950-51 (D.C. Cir.) (upholding FDA's interpretation of what constitutes a health claim), cert. denied, 125 S. Ct. 310 (2004).

(2) For brevity, "disease" will be used as shorthand for "disease or health-related condition" in the rest of the section.

(3) In an intervention study, subjects similar to each other are randomly assigned to either receive the intervention or not to receive the intervention, whereas in an observational study, the subjects (or their medical records) are observed for a certain outcome (i.e., disease). Intervention studies provide the strongest evidence for an effect.

(4) A meta-analysis is the process of systematically combining and evaluating the results of clinical trials that have been completed or terminated (Spilker, Meta-Analysis: in Guide to Clinical Studies. Raven Press, New York, Chapter 104, 1991).

(5) Review articles summarize the findings of individual studies.

(6) Other examples include book chapters, abstracts, letters to the editor, and committee reports.

(7) Replication of scientific findings is important for evaluating the strength of scientific evidence (Wilson E.B., An Introduction to Scientific Research. Dover Publications, 1990; pages 46-48).

(8) Consistency of findings among similar and different study designs is important for evaluating causation and the strength of scientific evidence (Hill A.B. The environment and disease: association or causation? Proceedings of the Royal Society of Medicine. 1965; 58:295-300); see also Evidence Report/Technology Assessment No. 47, Systems to Rate the Strength of Scientific Evidence, Agency for Healthcare Research and Quality.

(9) Bone Mineral Density (BMD) is often measured by a dual-energy-X-ray (DXA) and is compared to an established norm or peak BMD of a healthy 30 year old adult (standard) in order to give a T-score. The T-score is defined as the number of standard deviations (SD) above or below the average BMD values for young healthy women. The World Health Organization has established the following definitions based on bone mass measurement at the spine, hip, or wrist in white postmenopausal women: Normal: T-score between +1 and -1; low bone mass (osteopenia): T-score between -1 and -2.5; osteoporosis: T-score at or below -2.5. The greater the negative number, the more severe the osteoporosis. (NIH. Bone mass measurements: what the numbers mean, http://www.niams.nih.gov/Health_Info/Bone/Bone_Health/bone_mass_measure.asp, revised June 2006. Date accessed: April 4, 2007.)

(10) See supra, note 9.

(11) See supra, note 7.

(12) See supra, note 8.

(13) "Interim Procedures for Qualified Health Claims in the Labeling of Conventional Human Food and Human Dietary Supplements" (July 10, 2003). .