NUTRITION, EXERCISE, AND LIFESTYLE IN OSTEOPOROSIS (C WEAVER AND S FERRARI, SECTION EDITORS)

Calcium Supplementation: Is Protecting Against OsteoporosisCounter to Protecting against Cardiovascular Disease?

Connie M. Weaver

Published online: 27 March 2014# Springer Science+Business Media New York 2014

Abstract Calcium is the dominant mineral in bone and is ashortfall nutrient in the diet. For those consuming inadequatedietary calcium, calcium supplements have been a standardstrategy for prevention of osteoporosis. Recently, calciumsupplementation has been linked to both increased and de-creased cardiovascular disease risk creating considerable un-certainty. Moreover, recent reports have shed uncertainty overthe effectiveness of calcium supplements to reduce risk offracture. The evidence for calcium supplementation effectsto both reduce risk of fracture and increase coronary heartdisease and mortality are reviewed. Although the importanceof good calcium nutrition is well known, determining theadvantage of calcium supplementation to either bone or hearthealth has been hampered by poor subject compliance andstudy design flaws. At present, the current RecommendedDietary Allowances for calcium still appear to be a good targetwith potential risks for chronic disease if intakes fall too shortor greatly exceed these recommendations.

Keywords Calcium .Cardiovascular disease . Osteoporosis .

Vascular calcification .Myocardial infarction

What is the Controversy?

Good nutrition and dietary habits are associated with the pre-vention and treatment of many chronic diseases includingosteoporosis and cardiovascular disease. Lifestyle choices aremodifiable factors, unlike age and genotype, and therefore, diet,physical activity, smoking, and alcohol use recommendations

are a main component of public health messaging and healthcare provider counseling.

Although bone is a living tissue, and thus, requires allessential nutrients, the key nutrients involved in bone massdevelopment andmaintenance that are most often deficient arecalcium and vitamin D. Aging is associated with increasedparathyroid hormone release and increased bone resorption,which is suppressed with dietary calcium. 1,25-dihydroxyvitamin D regulates synthesis of calcium bindingproteins that facilitate calcium absorption across the intestinalepithelium. Because much of the world’s population receivesless dietary calcium and vitamin D input than is recommend-ed, the medical community has been promoting the use ofcalcium supplements for the last couple of decades and vita-min D more recently [1]. Even funding agencies such as theNational Institutes of Health have expected clinical trials toinclude calcium and vitamin D supplementation rather than atrue placebo as the current standard of care. However, recentsecondary analyses of randomized, controlled trials (RCTs)have challenged calcium and vitamin D supplementation orcalcium alone supplementation because of increased risk ofheart attacks [2, 3•, 4]. The response of the research commu-nity to assessing the relationship between calcium and cardio-vascular disease (CVD) risk has been enormous. Meanwhile,concern over cardiovascular risk of heart attack has led to adecrease in the number of U.S. consumers who take calciumsupplements; for example, supplement use decreased from22 % in 2011 to 17 % in 2012 [5]. Among women aged≥60 years, 60 % of women take calcium supplements and56 % take vitamin D [6]. Furthermore, milk intake, the mainsource of dietary calcium and vitamin D in the U.S.A. con-tinues to fall. The controversy has not been resolved and thedebate continues [7–11].

This article discusses the strength of the evidence forcalcium intake, and specifically supplementation, for bothosteoporosis and cardiovascular disease risk. The effect of

C. M. Weaver (*)Department of Nutrition Science, Purdue University, 700 W StateStreet, West Lafayette, IN 47907, USAe-mail: weavercm@purdue.edu

Curr Osteoporos Rep (2014) 12:211–218DOI 10.1007/s11914-014-0208-1

diet on chronic disease risk is difficult to determine becauseosteoporosis and cardiovascular disease are long latency dis-eases and single nutrient effects are usually small. Studies onthe benefit or risk of supplements are practically relativelyshort, compared with development of the disease. They areoften small, nonrepresentative of a general population, and arerarely designed as a dose response trial. Moreover, they rarelyuse background nutrient intake or status as an exclusioncriteria; therefore, many participants may be above the thresh-old for effect. This article will conclude with a call for a wayforward to resolve the controversy.

Strength of Evidence for Calcium Supplementationand Osteoporosis

Calcium is the dominant mineral in the bone mineral contentand is essential for bone mass accrual and maintenance.Homeostatic mechanisms maintain serum calcium within anarrow range and when dietary calcium is inadequate toreplace obligatory losses, bone is resorbed to meet the de-mand. Excessive bone resorption from chronically low calci-um intakes can lead to osteopenia and ultimately fracture.

The question of whether calcium supplementation protectsagainst fracture depends on calcium intake from the diet.Calcium is a threshold nutrient meaning that above a certainlevel for each individual, surplus calcium is excreted. Thus, ifcalcium supplements merely increase intakes that are near orabove the plateau, there would be no benefit to bone.Recommended calcium intakes for bone outcomes for adultsare 1000 to 1200 mg/d for North America and the FAO/WHOthat are intended to include a margin of safety (typically 2standard deviations above the estimated average requirementsfor a population) [12, 13]. The actual threshold calcium intakefor a physiological affect is uncertain. Small daily chronicdeficits of calcium balance below the threshold can take a tollon bone. For a personwith a bone calcium content of 1000 g, anet calcium loss of ~30 mg/d would lead to an annual boneloss of ~1.2 %.

Few of the RCTs targeted participants who had calcium (orvitamin D) intakes below the threshold (or deficient status).The largest and longest RCT for calcium supplementation andfracture was part of theWomen’s Health Initiative [10, 14] andthis trial dominates meta-analyses. The intervention was1000 mg calcium as calcium carbonate and 400 IU of vitaminD3 or placebo daily. The enrollment was less than the originalrecruitment goals (36,282 vs 45,000 postmenopausal women)andwere younger than the original recruitment goal withmorein the 50–59 years age range and less in the oldest group of70–79 years. Most (83 %) of the women were white and 37 %were obese. At baseline the mean calcium intake approachedthe Recommended Dietary Allowance (RDA) for calcium andthe mean intake of vitamin D was ~367 IU/d as women were

not excluded from taking their own calcium and vitamin Dlevels, except at high levels. Thus, baseline intakes were muchhigher than average intakes for women age 51–70 years fordiet alone, ie, 788±23 mg/d for calcium and 156 IU/d forvitamin D [15]. The initial report after an average of 7.0±1.4 years intervention was that although hip bone mineraldensity was higher (P<0.01) in the supplemented group inthe subset measured, there was no significant reduction of hipfracture (Hazard Ratio, HR=–0.82, 95 % CI, 0.72–1.08),except in adherent to intervention (>80 %) women takingsupplements for 5 or more years (HR for hip fracture 0.71,95 % CI, 0.52 compared with 0.97) [10]. In a subsequentanalysis of women in the trial plus 68,717 postmenopausalwomen aged 50–79 years in the WHI ProspectiveObservational Study in the same catchment, Prentice et al[16•] reported HRs for a number of health benefits and risks(Fig. 1) and still saw no significant benefit to reducing hipfracture. However, in adherent women in the trial only, takingsupplements 5 ormore years, there was a significant beneficialeffect of calcium and vitamin D supplementation with a HRfor hip fracture of 0.62 (95 % CI, 0.38–1.00) [16•]. In womennot taking supplements at baseline (42.2 %), the HR for hipfracture after 5 or more years of intervention was 0.24 (95 %CI, 0.07–0.84) (Fig. 2). After 11 years (4.9 years past-intervention) in the 29.862 women (86 %) followed in theWHI, the incidence of hip fracture continued to be similar inthe supplemented and placebo groups (HR=0.95, 95 % CI,0.78–1.15), but vertebral fractures were lower in the supple-mented group (H=0.87, 95 % CI, 0.76–0.98) [17]. In a meta-analysis of 4 RCTs of calcium supplementation alone (800–1200 mg/d) in postmenopausal women, the relative risk forhip fracture was 1.64 (95 % CI, 1.02–2.64) for intention totreat compared with a RR of 1.42 (95%CI, 0.81–2.49) using aper-protocol analysis [18]. It would be speculative to conclude

Fig. 1 HRs (Mean ±95 % CI) for women in the WHI calcium andvitamin D RCT plusWHI Observational Study Data taken from Prentice,et al [16•]

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that the difference between this meta-analysis showing nobenefit of calcium supplementation alone and the benefit ofcalcium and vitamin D supplementation, at least in adherentwomen in the WHI, were due to the addition of vitamin D inthe WHI given that the number of hip fractures and totalnumber of subjects were so much greater in the WHI(31,282 vs 6504) and none of the studies in the meta-analysis were greater than 5 years. Some meta-analyses ofcalcium and vitamin D supplementation have also shownreductions in fracture risk. For example, a 12 % reduction intotal fractures was concluded from a meta-analysis of 17RCTs [19]. Others found no significant effect of supplemen-tation on fracture reduction [20–22]. There are meta-analysesof other types of studies, including prospective cohort studies[18] but observational studies are typically confounded ascharacteristics of supplement users are different than non-users [16•].

Not all groups recommend vitamin D and calcium supple-ments to prevent fractures. For example, Moyer et al [23•]from the U.S. Preventative Services Task Force (USPSTF)concluded from 2 systematic reviews and a meta-analysis onvitamin D with and without calcium that the evidence wasinsufficient to assess the balance of benefits and harms ofsupplementation for primary prevention of fractures in pre-menopausal women or men and recommended with moderatecertainty (Grade D) against daily supplementation with≤400 IU vitamin D3 and ±1000 mg calcium in noninstitution-alized postmenopausal women with insufficient evidence forgreater amounts. This report has been criticized [24] and theimplications are far reaching because health care providerswill not be required to assist patients in achieving adequatecalcium and vitamin Dwith the aid of supplements. In a recentfeature article, Bauer [25] said the USDSTF did not addresssupplementation specifically in persons with inadequate die-tary intake. The evidence for a benefit of calcium supplements

has been criticized on the basis that the strongest evidencecomes from subgroup analysis in adherent patients. Seeman[26] determined a 24 % reduction (P<0.0001) for compliant(>80 % adherent) studies compared with nonsignificant forpoorly compliant studies. However, per protocol analysis is aconcern because sub-analysis jeopardizes the assumptions ofrandomization. Moreover, he cautions that the studies did notrecruit for calcium deficiency so efficacy is uninterpretable.For now, the best evidence we have is the subgroup analysis ofthe WHI [16•] that supports calcium and vitamin D supple-mentation for those not receiving adequate intakes from diet.

Strength of Evidence for Calcium Supplementationand Cardiovascular Disease Risk

Historically, calcium supplementation has been associatedwith protection against cardiovascular disease, largely byimproving blood lipid profiles [27] reducing blood pressure,and altering calciotropic hormones, etc, but this evidence wasbased on intermediate outcomes. The initial secondary analy-ses of RCT that reported an adverse effect of calcium supple-mentation on cardiovascular disease risk [2, 3•] have beencriticized because of confounding that occurs with secondaryanalyses, lack of consistency of outcome measures, and use ofcomposite end points, lack of control for confounding factors,too much weight on data sets given to nonadjusticated events,lack of plausible mechanism, and no observable dose response[9, 28, 29].

Many subsequent studies have attempted to determine therelationship between calcium supplementation or intake andcardiovascular outcomes and to address some of the criticismsof the hypothesis. These reports can be grouped as RCTs,observational studies, and mechanistic studies. The RCTs andobservational studies have been recently reviewed for both

Fig. 2 HRs (Mean ±95 % CI) forwomen adherent to calcium andvitamin D supplementation in theWHI trial and not taking personalsupplements at baseline. Datataken from Prentice et al [16•]

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protective effects and risks for CVD, coronary heart disease,and stroke [30••]. The authors summarized 5 prospectivestudies on calcium supplementation and total CVD, 7 onCHD, and 5 on stroke as well as 8 prospective studies on totalCVD, 11 on CHD, and 13 on stroke for effect of dietarycalcium. They reported on 7 RCTs of calcium supplementa-tion and CVD. The results were highly mixed. The primaryknowledge gap is that there is no RCTspecifically designed toinvestigate the effect of calcium supplements on CVD, andtherefore, no definite conclusion can be drawn.

More studies have been reported since the review byRautiainen et al [30••]. Although none are the needed primaryRCT, there have been some impressive studies that have ad-dressed the topic. One large study adds further confusionbecause they found sex differences. High calcium intake ofsupplemental calcium, but not dietary calcium was associatedwith increased CVD death in men (RR=1.20, 95 % CI, 1.05–1.36), but not with women and not with cerebrovascular diseasein either sex in the 388,229 participants in the NationalInstitutes of Health—AARP Diet and Health Study [31]. Thehighest quartile of calcium intake (>1565 mg/d) compared withthe lowest quartile was not significantly (P=0.084) associatedwith total or cardiovascular mortality. Three important abstractswere presented at the 2013 American Society for Bone andMineral Research (ASBMR), all of which found no significanteffect of calcium supplementation on risk of CVD. The firstwas a report of a meta-analysis of RCTs of calcium supplemen-tation with or without vitamin D on cardiovascular safety inpostmenopausal women [32]. This analysis included the recentre-analysis of the RCT of the WHI [16•]. It is an improvementover the initial meta-analysis that raised the concern of safety ofcalcium supplementation [3] by being both larger (4646 deathsfrom 59,844 participants vs. 1094 deaths from 11,921 partici-pants) and adjudicated. The trial level RR was 0.96 (95 % CI,0.91–1.02, P=0.18) for total deaths and for myocardial infarc-tion (RR=1.09 (95 % CI, 0.89–1.33 P=0.21) and for ischemicheart disease, RR=1.02 (05 % CI, 0.–10.9, P=0.53). Thesecond report at ASBMR was a 17.7 year prospective studyin 407 men and women, which showed higher dietary calciumintake was associated with decreased vertebral fracture, main-tenance of hip BMD, and decreased abdominal aortic calcifi-cation [33]. The third studymined the data from theDietary andSupplemental Calcium Intake and the Risk of Mortality inOlder Men (the MrOS Study) with 5967 participants followedfor 10 years [34]. Neither total calcium intake, supplementintake, nor combined intake were associated with total orcardiovascular mortality.

These studies support the recent published report that cal-cium intake and serum calcium concentration were not relatedto a cardiovascular death in 20,024 people evaluated inNHANES III [35]. Thus, the overall observational and trialevidence does not constitute a strong case for a concern forcalcium supplementation on CHD or CVD.

Role of Vitamin D Supplementation

The independent and combined with calcium supplementationeffects of vitamin D on CVD risk are challenging to assessbecause the large RCTs used to assess the relationship haveused combined interventions. One effort funded by theAmerican Heart Association and the National Heart, Lungand Blood Institute resulted in a systematic review andmeta-analysis of RCTs and prospective cohort studies [36].The authors found no significant effects of supplementationwith either nutrient alone or in combination on CVD risk, butconcluded there may be a slight benefit of vitamin D supple-mentation at moderate to high doses. Benefit of vitamin D useappears strongest in patients receiving dialysis. In a mousemodel of chronic kidney disease (CKD), 1 ,25-hydroxyvitamin D reduced PTH and osteoblastic gene expres-sion in the aorta, which is normally elevated in CKD and isassociated with vascular calcification [37]. But in these trans-genic knock-out mice, protection against aortic calcificationwas also associated with increased bone osteoblast stimulationand increased bone formation rates.

Mortality and Quality of Life

Some reports focusing on the association of calcium andvitamin D supplementation and mortality have already beenpointed out. Nevertheless, discussion of the priority of healthoutcomes is warranted. Osteoporotic fractures can lead toassisted living and even death; 20 % of patients who sufferhip fracture go to nursing homes and odds of dying in the first3 months following fracture increase as much as 4-fold [1].Perhaps the decrease in quality of life in the majority of hipfracture cases with associated pain and immobility duringconvalescence is more relevant in decisions about lifestylechoices. Reduced cardiovascular function and debilitatingstroke can also result in decreased quality of life. Each indi-vidual may have their own set of priorities for quality of lifeand length of life depending on the degree of loss of qualityand the extent to which life can be extended. A pooled analysisof 70,528 elderly patients and a meta-analysis of 24 RCTs with88,097 participants [38] offers a perspective on priority deci-sions. Calcium and vitamin D supplementation (but not vita-min D supplementation alone) decreasedmortality over 3 yearsby 7 % (95 % CI, 1 %–12 %). The RECORD trial [39] wasincluded in this analysis, which provided over one-half of thepatients in the analysis by Bolland et al [3•], which reported the30 % increase in myocardial infarction. This apparent discrep-ancy between an increase in myocardial infarction and de-creased mortality was explained by the authors as attributableto the small contribution of myocardial infarction to overallmortality and the protective effect of calcium and vitamin Dsupplementation on other causes of death such as including

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colorectal cancer. These authors assume that there is a risk ofcalcium supplementation to cardiovascular risk.

The influence of calcium intake on mortality is undoubt-edly related to dose. Both low and high calcium intakes havebeen associated with increased risk of mortality (Fig. 3). In the9033 participants of the Canadian Multicenter OsteoporosisStudy (CaMos), increase in calcium intake as diet or supple-ments up to 1000 mg per day was associated with a statisti-cally significant decrease in mortality with too few data above1000 mg/d to make any conclusions [40]. More recently, in aprospective longitudinal study of 61,433 women followed for19 years, women consuming over 1400mg/d had a higher HRfor mortality (HR=1.40, 95 % CI, 1.17–1.67) compared withwomen consuming less than 1 g/d [41]. The study reported aU-shaped relationship of calcium intake and mortality.Similarly, in the large AARP Diet and Health Study describedearlier, a U-shaped relationship was observed between calci-um intake and CVD mortality, but only in men with the nadiroccurring at about the recommended intake of 1200 mgcalcium/d [30••]. The increase in mortality at the high end ofcalcium intake was above 1500 mg/d. A Swedish studyshowed a positive association between calcium intake andall-cause mortality on high calcium intakes of an average of1953mg/d [42]. Also, combined use of calcium and vitaminDsupplements and anti-osteoporosis drugs was associated withthe highest survival rate in a retrospective cohort of 23,615 hipfracture patients from a national Finnish data base, though the1-year mortality HR for just the dietary supplements was animpressive 0.74 (95 % CI, 0.67–0.81) [43].

Dietary calcium intake, in contrast to supplements, has eitherbeen associated with a protective effect or no effect on CVDrisk although the evidence has been considered inconclusive[28, 44]. In the large AARP Diet and health Study, dietarycalcium intake was unrelated to CVD death in either men orwomen [30••]. Individual constituents in dairy products such asselected milk fats, vitamin D, calcium, magnesium, and whey

proteins may be involved in protecting against cardiometabolicsyndrome [45]. Even though full fat dairy products containsaturated fatty acids, dairy intake was not associated withincidence of myocardial infarction implying that the wholefood matrix is more impactful than a single constituent [46].Interestingly, yogurt but no other dairy products was associatedwith lower common carotid artery intima-media thickness in1080 elderly Australian women [47]. Thus, evidence to dategives reassurance that meeting calcium needs through diet is asafe and recommended approach to meeting calcium needs.

Mechanism of Calcium Supplementation and CVD Risk?

Those who promote that calcium supplementation poses a riskfor CVD suggest that bolus doses elevate serum calcium levelsalbeit to high levels within the normal range, and thereby,predispose calcification of coronary abdominal arteries [8]. Itis true that serum calcium rises and serum PTH declinesmeasurably after an overnight fast with bolus doses of calciumof 300 mg or higher. Milk, yogurt, and calcium carbonate at500 mg calcium produced similar peak increases in serumionized calcium levels in the first hour, but returned to baselinewith the milk after ~3 hours and was still slightly and similarlyelevated, after a yogurt or supplement test meal at 4 hours [48].Skim milk powder enriched with calcium carbonate or milkcalcium resulted in slightly higher elevations in serum calciumwith both sources and lower serum PTHwith the salt [49]. Thetransient increases in serum calcium are not represented byin vitro studies that show elevated calcium levels within thenormal range alter blood coagulation [50].

Increasing serum mineral levels would have little effect onpassive calcium deposition in arteries because the increasedserum calcium level is still well below saturation. Calciumdeposition occurs through a highly coordinated cell-mediatedprocess possibly through signaling induced by calcium

Fig. 3 Calcium intake andmortality risk referenced toDietary Reference Intakes set bythe Institute of Medicine [12]

Curr Osteoporos Rep (2014) 12:211–218 215

sensing receptors. Increased serum calcium upregulates fibro-blast growth factor-23 (FGF-23) promoter activity [37].Theoretically, this could form the basis for a mechanismbecause higher levels of FGF-23 are associated with higherrates of cardiovascular and all-cause mortality.

In clinical studies, the evidence to date is against bolusdoses of calcium stressing cardiovascular health. Single dairymeals had no effect on markers of inflammation or atherogen-esis in overweight adults [51]. An acute dose of 1 g of calciumas calcium citrate elevated serum calcium and suppressedserum PTH, decreased arterial wave reflection and increasedmyocardial perfusion by pulse wave analysis [52]. Thus,cardiovascular function is not adversely affected by a rise inserum calcium, at least acutely. In the prospective cohortFramingham Study, higher habitual calcium intakes were notassociated with increased coronary artery calcification mea-sured by computed tomography [53].

Conclusions and Future Directions

RCTs provide the strongest evidence because they give insightinto causal relationships. We have not had clear evidence forthe relationships between calcium supplementation and eitherrisk of fracture or cardiovascular disease or mortality.Regarding the former, there have been many RCTs, but resultsdepend on habitual calcium intakes and compliance. Whenbaseline calcium intakes already approach the threshold formaintenance of bonemineral content, more cannot be achievedwith calcium supplementation. Even so, when only adherentpatients are considered, the largest RCT showed dramaticlowering of risk and hip fracture [16•]. This is the strongestevidence to date. Yet, these results are considered inconclusiveas the assumptions of randomization are not met with sub-analysis. For the relationship of calcium supplementation andcardiovascular disease risk, there have been no RCTs wherethat was the primary question. Some argue that such a specif-ically designed trial is necessary for definitive evidence [26].

Is it possible to have a RCT of sufficient size and durationfor chronic diseases to develop in participants who are insuf-ficient in any nutrient who will comply>80% for any nutrientand any disease outcome? Historical results suggest that it isvery difficult. Even the best designed trials have poor ability toassess calcium status and dietary intake, which is more rele-vant to bone health than compliance with supplementation.Better methods for diet assessment that are influenced less byhuman error are greatly needed. Moreover, it is difficult tostudy mechanisms in humans as imaging is still too crude todetect early changes. My laboratory recently reported use ofan animal model and new approach for detecting early chang-es in coronary artery calcium [54–56].

Animal models have the advantage of being able to be fedcontrolled diets for sufficiently long periods to develop chronic

disease. We used the Ossabaw miniature swine that developdiet-induced atherosclerosis similar to humans. We adminis-tered a rare isotope 41Ca, that can be detected at 10-18M con-centrations by Accelerator Mass Spectrometry, in order to de-termine early coronary artery calcium deposition. High calciumdiets approaching the equivalent of the Upper Level for humansfrom neither calcium carbonate supplements nor dairy calciumneither increased coronary artery calcification nor decreasedendothelial function. This raises doubt about calcium supple-mentation risking CVD. Complications with other disease con-ditions such as chronic kidney disease require further investiga-tion. Calcium supplementation has been associated with a mod-est increase in urinary stones [16•] though the USPSTF assessedthe harm as small [23•]. Further investigation with appropriateanimal models should be continued to investigate mechanisticeffects of diet/supplementation on all relevant tissues.

Even considering all of the flaws with studies examining therelationship of calcium supplementation and chronic disease,an examination of Figure 3 suggests that meeting the RDA of1200 mg/d and staying below the UL is healthful for bothbones and heart. Meeting calcium recommendations by diet isprudent because many nutrients and possibly healthful bioac-tive constituents are also part of the package. Dairy productsprovide the majority of calcium in most diets. A cup of milk oryogurt contains about 300 mg. There are a few calcium forti-fied foods, mostly beverages that provide bioavailable calciumas alternatives to dairy. The Dietary Guidelines for Americas[57] recommend 3 servings of dairy products or calciumfortified foods daily. For every serving of dairy product orequivalent short of 3 servings, 300mg calcium as a supplementis advised to meet the recommended calcium intakes.

Compliance with Ethics Guidelines

Conflict of Interest C. M. Weaver declares that she has no conflicts ofinterest.

Human andAnimal Rights and InformedConsent All studies by theauthor involving animal and/or human subjects were performed afterapproval by the appropriate institutional review boards. When required,written informed consent was obtained from all participants.

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