May 17, 2004

J. Craig Rowlands, Ph.D./DABT

Food and Drug Administration

CFSAN

5 100 Paint Branch Parkway

HFF-830

College Park, MD 20740-3835

Dear Dr. Rowlands:

I am responding to your request to submit comments about a petition for
a qualified health claim for supplemental calcium and kidney/urinary
stones by 5/17/04. I am an associate professor and the University of
Texas Southwestern Medical Center at Dallas. My clinical and research
focus over the last decade is the prevention of kidney stones, a disease
that afflicts up to 12% of men and which recurs in 50% of them. Over the
last three decades, we have seen over 2500 kidney stone formers in our
center for this purpose. Based on my clinical experience and my thorough
review of the available pertinent clinical studies, I am concerned that
treatment of active kidney stone formers with calcium may exacerbate
stone disease rather than ameliorate the risk. I will try summarize the
key data below with the potential positives and negatives of calcium
supplementation in regards to stone formation.

For intuitive reasons, dietary calcium restriction was strongly
advocated for many years. The vast majority of kidney stones contain
calcium.^1^ Among the identified physiologic risk factors for stone
recurrence, high urinary calcium is the most important. Curhan recently
showed that urinary calcium directly correlates with the risk stone
formation better than other stone risk factors.^2^ High urinary calcium
also diminishes the protection of protein inhibitors against stone
formation.^3^ Moreover, treatment with either thiazide diuretics or
indapamide, agents with lower urinary calcium, reduced stone recurrence
in several placebo-controlled trials.^4^ Finally, dietary calcium raises
urinary calcium, and this is accentuated in patients with high urinary
calcium.^5^ For these reasons, dietary calcium restriction was expected
to reduce kidney stone risk despite the absence of any prospective
trials.

Urinary calcium is affected by many other factors other than dietary
calcium. Sodium, animal protein and glucose may raise urinary calcium,
whereas phosphate and alkali intake may lower it.^6-9^ In fact, the
combination of high sodium intake and high animal protein intake will
raise urinary calcium more than high calcium intake. The reason is that
only a net of 100 to 300 mg of calcium is absorbed from the
intestine/day. In contrast, 10,000 mg of calcium is filtered and 9,700
to 9,900 mg is reabsorbed by the kidney. Since sodium and animal protein
inhibit calcium reabsorption by the kidney, it is not surprising that
they affect urinary calcium substantially.

Recently several studies have counterintuitively suggested that higher
calcium intake prevents kidney stones. In 1993, Curhan published
convincing data that higher calcium intake protects against first stone
formation (-32%) in men.^10^ In 1997, a similar protection against the
first stone formation was demonstrated in women.^11^Despite careful
adjustment for expected confounders, these large observational studies
could not adjust for intake of two dietary factors with probably impact
on stone disease- alkali and oxalate. After the 2^nd^ study was
published, I saw three patients in 1 month whose stone disease became
much more aggressive after their urologist treated them with
supplemental calcium.

The most convincing study was published by Borghi et al in the New
England Journal in 2002.^12^ In a 5-year prospective clinical trial, the
authors compared normal calcium intake to low calcium intake, and
demonstrated that the higher calcium diet prevented kidney stones much
more effectively. However, even this study did not prove that higher
calcium diet is more effective than low calcium diet at reducing stone
recurrence. Unfortunately, there were other differences between diets.
Only the high calcium group was additionally subjected to a diet
restricted in sodium and animal protein and enriched in potassium (a
source of alkali) and fiber (which binds dietary calcium). Thus, this
otherwise well-done study did not directly compare the effect of dietary
calcium alone.

The data relating supplemental calcium to stone risk is even less
abundant. There is no prospective clinical trial. One epidemiologic
trial found that supplemental calcium increased the risk of kidney
stones by 20%.^11^ Unlike calcium supplements, dairy, the key source of
dietary calcium, may have factors that prevent the rise in urinary
calcium including citrate and phosphate.

In summary, the data that dietary calcium prevents kidney stones is
still controversial. That concerning calcium supplements is even less
convincing. There is no trial that has directly compared higher calcium
intake to lower calcium intake. On the other hand, it is possible that
the higher calcium intake may cause more harm than good. Until this
matter is more settled, it would be unwise to allow labeling suggesting
that calcium supplements reduce stone risk.

1\. Mandel NS, Mandel GS: Urinary tract stone disease in the United
States veteran population: II. Geographical variation in composition. J
Urol 1989;142:1516-1521.

2\. Curhan GC, Willett WC, SPeizer FE, Stampfer MJ. Twentry-four-hour
urine chemistries and the risk of kidney stones among women and men.
Kidney Int 2001;59:2290.

3\. Zerwekh JE, Hwang TIS, Poindexter J, Hill K, Wendell G, Pak CYC:
Modulation by calcium of the inhibitor activity of citrate, chondroitin
sulfate and urinary glycoprotein against calcium oxalate
crystallization. Kidney Int 1988;33:1005-1008.

4\. Pearle MS, Roehrborn CG, Pak CyC. Meta-analysis of randomized trials
for medical prevention of claium oxalate nephrolithiasis. J Endourol
1999;13:679.

5\. Lemann J Jr. Calcium and phosphate metabolism: An overview in health
and in calcium stone formers. In Coe FL, Favus MJ, Pak CYC, Parks JH,
Preminger GM (eds): "Kidney Stones: Medical and Surgical Management,"
1^st^ ed. Philadelphia: Lippincott-Raven, pp 259-288, 1996.

6.Breslau NA, MCGuire JL, Zerwekh JE, Pak CYC. The role of dietary
sodium on renal excretion and intestinal absorption of calcIum and on
vitamin D metabolism. J Clin Endocrinol Metab 1982;55:369-373.

7 Breslau NA, Heller HJ, Reza-Albarran AA, Pak CYC. Physiological effect
of a slow release potassium phosphate for absorptive hypercalciuria: a
randomized double-blind trial. J Urol 1998;160:664-668.

8 Lemann J Jr, Litzow JR, Lennon EJ. Studies of the mechanism by which
chronic metabolic acidosis augments urinary Ca excretion in man. J Clin
Investig 1967;46:1318-1328.

9 Heller HJ. The role of calcium in the prevention of kidney stones. J
Am Coll Nutr 1999;18:373S-378S.

10 Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of
dietary calcium and other nutrients and the risk of symptomatic kidney
stones. N Engl J Med 1993;328:833-838.

11 Curhan GC, WIlett WC, Speizer FE, Spiegelman D, Sttampfer MJ.
Comparison of dietary calcium with supplemental calcium and other
nutrients as factors affecting the risk for kidney sotne s in women. Ann
Intern Med 1997;126:497-504.

12\. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for
the prevention of recurrent stoens in idiopathic hypercalciuria. N Engl
J Med 2002;346:77-83.