To the Editor: The increased incidence of nephrolithiasis amongpatients taking supplemental calcium carbonate that was reportedby Jackson et al. (Feb. 16 issue)1 might have been avoided ifcalcium citrate had been given. It has been shown that urinarycalcium oxalate crystals that form in the presence of hypercalciuriaand hyperoxaluria develop into clinically important stones onlyafter aggregation into larger particles. This aggregation isinhibited by citrate at physiologic concentrations.2,3
The data in Table 3 in the report suggest that calcium and vitaminD reduced the incidence of hip fracture more in older patientsthan in younger patients, which is not unexpected, given thepathophysiological differences between perimenopausal bone lossand senile bone loss.4 Measurement of parathyroid hormone levelsto assess the adequacy of vitamin D intake might have helpedin the interpretation of these findings.5,6 The dose of supplementaryvitamin D used in this study, assuming it was the sole or majorsource of vitamin D, may have been too low to have had a moredramatic effect in either age group.
Susan Terris, M.D., Ph.D. 25 Coleman Ave. Red Bank, NJ 07701
References
Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683. [Erratum, N Engl J Med 2006;354:1102.] [Free Full Text]
Glauser A, Hochreiter W, Jaeger P, Hess B. Determinants of urinary excretion of Tamm-Horsfall protein in non-selected kidney stone formers and healthy subjects. Nephrol Dial Transplant 2000;15:1580-1587. [Free Full Text]
Hess B, Jordi S, Zipperle L, Ettinger E, Giovanoli R. Citrate determines calcium oxalate crystallization kinetics and crystal morphology -- studies in the presence of Tamm-Horsfall protein of a healthy subject and a severely recurrent calcium stone former. Nephrol Dial Transplant 2000;15:366-374. [Free Full Text]
Kinyamu HK, Gallagher JC, Rafferty KA, Balhorn KE. Dietary calcium and vitamin D intake in elderly women: effect on serum parathyroid hormone and vitamin D metabolites. Am J Clin Nutr 1998;67:342-348. [Abstract]
Holick MF, Siris ES, Binkley N, et al. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 2005;90:3215-3224. [Free Full Text]
To the Editor: Although Jackson and coworkers conclude thatcalcium and vitamin D supplementation did not significantlyreduce fracture rates among women 50 to 79 years of age, theirobservations can be interpreted to provide support for a differentconclusion. Since it has been well established that bone mineraldensity (BMD) decreases progressively in postmenopausal womenwho are not treated for bone loss, one is struck by the authors'finding that the mean BMD for the total spine and the wholebody in the control subjects increased steadily over the nineyears of the study, and that the BMD for the total hip remainedessentially unchanged, as shown in Figure 2 of the article byJackson et al. This phenomenon was almost surely influencedby the large proportion of control subjects who were alreadytaking calcium or vitamin D at "therapeutic" doses. One wouldexpect improved BMD to be associated with fewer fractures; theinvestigators did, in fact, find fracture rates for both controlsubjects and treated subjects to be less than half the ratehistorically anticipated. It is also not surprising that theadministration of additional calcium and vitamin D to treatedsubjects further reduced hip fractures only to a limited degree,particularly since the optimal intakes of both are unknown.
Gerson T. Lesser, M.D. Mount Sinai School of Medicine New York, NY 10029 glesser{at}jhha.org
To the Editor: The results of the Women's Health Initiative(WHI) trial of calcium with vitamin D reveal that calcium andvitamin D supplementation (1000 mg of calcium carbonate with400 IU of vitamin D) did not lower fracture rates but did increasethe risk of kidney stones in calcium-replete postmenopausalwomen (mean intake, 1150 mg per day) whose intake of vitaminD was insufficient (serum 25-hydroxyvitamin D, 48 nmol per liter).How should these results influence clinical practice? They shouldhave no effect on the evidence-based recommendation that postmenopausalwomen, who typically consume 600 mg of elemental calcium perday, should increase their calcium intake to 1200 mg per day.1Similarly, the results should not deter physicians from recommending800 IU of vitamin D per day — the amount the average postmenopausalwoman needs to raise her serum 25-hydroxyvitamin D level tothat needed to lower the risk of fracture (75 nmol per liter).2Finally, the increased risk of kidney stones among the womenin the study who were consuming a mean of 2150 mg per day ofcalcium (usual mean intake plus supplement), as compared withthose consuming 1150 mg per day, should not be assumed to applyto women who increase their intake to 1200 mg per day. It isimportant that the WHI trial not be used to sanction the inadequateintake of calcium and vitamin D that is so widespread amongpostmenopausal women today.
Bess Dawson-Hughes, M.D. Tufts University Boston, MA 02111 bess.dawson-hughes{at}tufts.edu
Dr. Dawson-Hughes reports having received an honorarium fromGlaxoSmithKline.
References
Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary reference intakes: for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington, D.C.: National Academy Press, 1997.
Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int 2005;16:713-716. [CrossRef][Web of Science][Medline]
The authors reply: Dr. Terris notes that use of supplementalcalcium citrate, instead of calcium carbonate, may lessen therisk of kidney stones observed in the WHI calcium with vitaminD trial, and we agree. However, calcium carbonate, perhaps becauseof its greater affordability, is still the most common formof calcium supplementation used in the United States. The presentstudy did not have the power to examine changes in parathyroidhormone levels among women with hip fracture and controls, becausestored specimens were available after randomization for a subsampleof the trial population that consisted of only 6 percent ofthe subjects.
Dr. Lesser attributes the low rate of hip fracture in the placebogroup to the already high levels of calcium intake at baseline.As we report, there are other powerful fracture-lowering factorsthat probably also contributed, including high levels of hormoneuse and body-mass index and the enrollment of fewer women over70 years of age than expected. Nonetheless, we believe thatthe trial results provide several indications that calcium intakedoes reduce the risk of hip fracture. Calcium and vitamin Dsupplementation reduced the risk of hip fracture by 29 percentamong women with an adherence of 80 percent or more, 21 percentamong those 60 years of age or older at enrollment, and 30 percentamong those not taking other calcium supplements during thetrial (all 95 percent confidence intervals for the correspondinghazard ratios exclude 1). In fact, we believe that these datasupport current recommendations for adequate calcium intake.
Two other clarifications are important to make in the interpretationof the trial results. First, the increased risk of kidney stoneswas not associated with high baseline calcium intake. Our preliminaryanalyses indicated no interaction with baseline calcium intakeand, in fact, a somewhat greater risk among women with a lowertotal calcium intake at baseline. The factors contributing toan increase in the risk of kidney stones are under investigation.Second, some have disregarded the greater effects of the calcium-plus-vitamin-Dintervention in older women as being uninterpretable, claimingthat the randomization was no longer intact in subgroups definedaccording to age. In fact, the randomization of women in allthe WHI trials was stratified according to age in order to ensurethat measured and unmeasured characteristics would be balancedwithin the age groups. There are other caveats associated withsubgroup analysis (e.g., multiple comparisons and lack of power),but in the WHI trials, age-specific analyses are protected fromconfounding by the randomized design.
Rebecca D. Jackson, M.D. Ohio State University Columbus, OH 43210 jackson.20{at}osu.edu
Andrea Z. LaCroix, Ph.D. Fred Hutchinson Cancer Research Center Seattle, WA 98109
Correction
to
Jackson et al., 
75 nmol per liter).2 Finally, the increased risk of kidney stones among the women in the study who were consuming a mean of 2150 mg per day of calcium (usual mean intake plus supplement), as compared with those consuming 1150 mg per day, should not be assumed to apply to women who increase their intake to 1200 mg per day. It is important that the WHI trial not be used to sanction the inadequate intake of calcium and vitamin D that is so widespread among postmenopausal women today. 
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