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RESEARCH: Tania Winzenberg, Kelly Shaw, Jayne Fryer, and Graeme Jones Effects of calcium supplementation on bone density in healthy children: meta-analysis of randomised controlled trials BMJ 2006; 333: 775 [Abstract] [Full text]

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To the Editor:

Robert P. Heaney, Connie M. Weaver   (26 September 2006)

The Changing Face of Hypercalcaemia

Ali I Al-bahrani, William DFraser , Eilleen Manning, L Ranganth, Trevor Hine   (27 September 2006)

In reply

Graeme Jones, Tania Winzenberg   (3 October 2006)

Role of calcium supplementation is very limited in improving bone mineral density in all age groups

Jai B Sharma MD MRCOG, Sameer Chadha , Medical Student , MAM College New Delhi, Shikha Mehta, Medical student, MAM College, New Delhi   (13 October 2006)

Adequate calcium intake plus high physical activity may be useful for bone health in children

Toshihiro Sugiyama   (14 October 2006)

Take account of calcium excretion

Clare M Hamon   (14 October 2006)

Effect size at the end of supplementation period in terms of g/cm2

Tanis R Fenton, Michael Eliasziw, David A. Hanley   (20 April 2007)

To the Editor: 26 September 2006
Robert P. Heaney, John A. Creighton University Professor Creighton University, Omaha, NE 68178, Connie M. Weaver Send response to journal: Re: To the Editor:	A meta-analysis of calcium supplementation in children in a recent issue of the Journal reported a positive effect, but deemed it too small to be useful (1). Service, in a Perspective on meta-analysis, noted that many meta-analytic teams lack members with content expertise in the area being summarized (2). As a consequence, while the meta-analyses may be rigorous with respect to methodologic issues, they can overlook important biological flaws in the studies concerned or pool studies that are incommensurable. The publication by Winzenberg et al. (1) constitutes a good case in point. Among several biologic errors in this meta-analysis, two in particular stand out: the use of bone mineral density (BMD) as the outcome variable and the failure to ensure that all studies included a low calcium control group. Both issues have been explored extensively elsewhere and are treated in depth in at least one standard reference book (3–6). Briefly, during growth, bone expands in three dimensions. BMD, as measured (and by design), eliminates the increase in mass associated with two of those dimensions. Thus BMD change misses most of the actual change in bone mass during growth. (And when true density can be measured, it misses mass change entirely.) In this instance, the meta-analysis found a significant aggregate positive effect, but the authors concluded that it was too small to be useful. They were apparently unaware 1) that changes in bone mass during growth are typically several times larger than changes in BMD; and 2) that bone strength is directly related to mass and size, and only indirectly to BMD. Furthermore, use of BMD explicitly precludes finding an effect of the intervention on bone size. The latter point is not simply a theoretical objection, as several investigations have suggested that high calcium intakes, in addition to improving bone mineral acquisition, can increase bone size as well (7,8). Thus BMD is precisely the wrong outcome measure for nutritional effects during growth. Calcium, like iron, vitamin D, and many other nutrients, exhibits threshold behavior, i.e., effects accrue up to only a certain threshold intake value, above which further increases in intake produce no additional effect (4,5). Studies without a low calcium intake contrast group are not capable of testing whether calcium produces skeletal (or other) benefits. Several of the studies included by Winzenberg et al. exhibited precisely that problem. The fact that the investigators in the studies assembled in this meta- analysis had themselves made these same mistakes does not justify their inclusion. One of the points of a meta-analysis is to weed out flawed studies – flawed not just because of poor randomization or blinding, but because of inapposite methods and poorly posed biological questions. In both their title and their conclusions the authors are careful to use the term “healthy children”, a designator which would logically include the notion that their diets were adequate in all essential nutrients. In that sense, therefore, one cannot disagree with the conclusion that more calcium does not produce much benefit. But since that point has been shown many times over and is implicit in the notion of a threshold nutrient, one wonders why this analysis was done or published in the first place. It is likely that the message for the average reader would be that calcium intake in children is not important. That would be not only wrong, but potentially dangerous, as well. Robert P. Heaney, M.D. Creighton University, Omaha, Nebraska, USA Connie M. Weaver, Ph.D. Purdue University, West Lafayette, Indiana, USA References 1. Winzenberg T, Shaw K, Fryer J, Jones G. Effects of calcium supplementation on bone density in healthy children: meta-analysis of randomized controlled trials. BMJ 2006; 2. Service FJ. Idle thoughts from an addled mind. Endocr Prac 2002;8:135- 136. 3. Prentice A, Parsons TJ, Cole TJ. Uncritical use of bone mineral density in absorptiometry may lead to size-related artifacts in the identification of bone mineral determinants. Am J Clin Nutr 1994;60: 837-842. 4. Heaney RP. Design considerations for clinical investigations of osteoporosis. In: Osteoporosis, 3rd Ed. Marcus R, Feldman D, Nelson D, Rosen C, eds. Elsevier Inc., San Diego, CA (in press) 2007. 5. Heaney RP, Bachmann GA. Interpreting studies of nutritional prevention. A perspective using calcium as a model. J Women’s Health 2005;14:990-897, 2005. 6. Heaney RP. BMD: The problem. Osteoporos Int 2005;16:1013-1015. 7. Prentice A, Ginty F, Stear SJ, Jones SC, Laskey MA, Cole TJ. Calcium supplementation increases stature and bone mineral mass of 16-18 year old boys. J Clin Endocrinol Metab 2005;90:3153-3161. 8. Bonjour J-P, Carrie AL, Ferrari S, Clavien H, Slosman D, Theintz G, Rizzoli R. Calcium-enriched foods and bone mass growth in prepubertal girls: a randomized, double-blind, placebo-controlled trial. J Clin Invest 1997;99:1287-1294. Competing interests: None declared
The Changing Face of Hypercalcaemia 27 September 2006
Ali I Al-bahrani, Senior Registrar Dept Clinical Biochemistry, Royal Liverpool University Hospital, Duncan Building, Liverpool L69 3GA, William DFraser , Eilleen Manning, L Ranganth, Trevor Hine Send response to journal: Re: The Changing Face of Hypercalcaemia	Over the last decade, the number of subjects diagnosed with hypercalcaemia has increased exponentially (5-fold) mainly because of laboratory automation and the introduction of plasma calcium determination in routine biochemical screening.1,2 Recent advances in our understanding of the pathophyisological changes in metabolic bone diseases (MBD) have resulted in increasing numbers of patients being treated with calcium and/or vitamin D supplements.3,4 Hypercalcaemia is a serious and not infrequent complication of malignant disease. Correct interpretation and recognition of the underlying cause has a major impact on the management and morbidity of these patients.5 We undertake this hospital- based survey to determine the causes and the biochemical profile in hypercalcaemic patients. 118286 calcium requests were received from 39360 patients between April 2003 and April 2004. Out of 118286 requests, the proportion with hypercalcaemia (Adjusted Calcium >2.60 mmol/L) was 10% (11702). The largest proportions were from subjects with chronic kidney disease (CKD), renal transplant (RTX) and osteoporosis(OP), 53%, 21% and 6.7%, respectively. The next commonest causes of hypercalcaemia from this survey were malignancy followed by primary hyperparathyroidism (1o HPT), 11% and 3.5%, respectively. A characteristic pattern of hyperchloraemia and normal anion-gap was revealed in patients with 1o HPT. The likelihood of having 1o HPT was 3-5 fold higher in patients with Cl/PO4 ratio >129 compared to malignancy. This survey has revealed that hypercalcaemia is a common metabolic problem; iatrogenic factor is the commonest cause and need to be ruled out before embarking on expensive investigations. Combining Cl/PO4 ratio to the bone profile may help in the differentiation between 1oHPT and malignancy. References: 1. Fisken RA, Heath DA, Bold AM. Hypercalcaemia--a hospital survey. Q J Med. 1980;49:405-18 2. Bilezikian JP, Silverberg SJ. Clinical practice. Asymptomatic primary hyperparathyroidism. N Engl J Med. 2004; 22:1746-51. 3. Muhammedi MA, Piraino B, Rault R, Johnston JR, Puschett JB. Iatrogenic hypercalcemia in hemodialysis patients.Clin Nephrol. 1991;36:258-61. 4. Kato Y, Sato K, Sata A, Omori K, Nakajima K, Tokinaga K, Obara T, Takano K. Hypercalcemia induced by excessive intake of calcium supplement 5. Burkhardt E, Kistler HJ. [Hypercalcemia in hospitalized patients. Diagnostic and prognostic aspects] Schweiz Med Wochenschr. Competing interests: None declared
In reply 3 October 2006
Graeme Jones, Professor and Head, Musculoskeletal Unit, Menzies Research Institute Menzies Research Institute, Level2, 199 Macquarie St Hobart, Tasmania, Australia 7000, Tania Winzenberg Send response to journal: Re: In reply	Editor We welcome the chance to respond to the letter from Drs Heaney and Weaver. We disagree with their viewpoint in several areas. 1. The key question with calcium supplementation in children is whether this prevents fractures. There are no trials that have been large enough to answer this question in either younger or later life. The relationship between peak bone mass and fracture risk in later life appears substantial (1) but estimating an effect of calcium supplementation in children on fracture in later life would be at best a guess. The next question is which bone variable is the best surrogate marker of fracture in children. While the response from Drs Heaney and Weaver has some theoretical merit, this is not actually supported by hard data in children. In direct contrast to their assertion, we have recently reported that volumetric density (an estimate of true bone density) is the best correlate of fracture risk in children and is closely followed by areal BMD (2). The small change in bone size is of uncertain significance as there is little data relating it to fracture in children and BMC and bone area (which are the DXA variables that correlate most closely with bone size) were unable to discriminate children with fracture from controls (2). Furthermore, increasing bone size may actually be harmful as increased tibial cross-sectional area increases the risk of subsequent cartilage damage (3) which leads to cartilage loss (4) based on recent prospective MRI based studies from our institution. In the meta-analysis, we wanted to use volumetric density as the primary outcome but this was not reported in any studies. Areal BMD was, therefore, the next most valid measure. We also had data relating BMD to fracture as well as fracture incidence in children in our location (5) which allowed us to estimate the effect of calcium supplementation on fracture which was small. Other bone measures which are associated with fractures in children such as metacarpal index (6), skeletal age deviation (7) and heel ultrasound (G Jones, unpublished) may also be suitable for use as surrogate markers but again there is little data relating them to calcium intake. 2. The criticism about a lack of an appropriate control group is untenable. From a meta-analysis of calcium balance studies, Dr Heaney suggests around 1400 mg/day is needed (8), much more than the average 700 mg/day in the control groups, thus, according to this standard, all the studies in our review could be regarded as low intake. However, even restricting the analysis to the lowest quartile of supplementation (<582 mg/day) showed no beneficial effect even though three out of four studies in this subgroup had mean baseline intakes <400 mg/day. Our analysis showed that increasing intakes to levels suggested as necessary to maintain/increase calcium balance did very little casting doubt on the validity of the balance studies and, perhaps, indicating the body’s ability to adjust to much lower intakes. 3. We were disappointed and a little surprised that such well respected bone investigators seemed unaware of our group’s longstanding bone research program with its emphasis on children. The assumption that we lack content expertise is erroneous. Our review protocol was designed with content and methodological input. We would suggest that Dr’s Heaney and Weaver reassess their own viewpoints in the light of our results, rather than shooting the messenger when the data don’t support their position. References 1. Jones G. Relevance of peak bone mass to osteoporosis and fracture risk in later life. In Lane N, Sambrook P (eds). Osteoporosis and the osteoporosis of rheumatic diseases. Mosby, New York, 2006, p22-26. 2. Jones G, Ma D, Cameron F. Bone density interpretation and relevance in Caucasian children aged 9-17 years of age: insights from a population based fracture study. Journal of Clinical Densitometry 2006 9:202-9 3. Ding C, Cicuttini F, Scott F, Cooley H, Boon C, Jones G. Natural history of knee cartilage defects and factors influencing change. Archives of Internal Medicine 2006 166:651-8. 4. Ding C, Cicuttini F, Scott F, Boon C, Jones G. Prevalent and incident knee cartilage defects are associated with knee cartilage loss: a longitudinal study. Arthritis and Rheumatism 2005 12:3918-27. 5. Jones G, Cooley H. Symptomatic fracture incidence in those under 50 years of age in Southern Tasmania. Journal of Paediatrics and Child Health 2002 33:278-83. 6. Ma D, Jones G. The association between bone mineral density, metacarpal morphometry and upper limb fractures in children: a population based case- control study. Journal of Clinical Endocrinology and Metabolism 2003 88:1486-1491. 7. Jones G, Ma D. Skeletal age deviation assessed by the Tanner Whitehouse 2 method is associated with bone mass and fracture risk in children. Bone 2005 36:352-7. 8. Heaney RP, Abrams S, Dawson-Hughes B, et al. Peak bone mass. Osteoporos Int 2000;11:985-1009. Competing interests: None declared
Role of calcium supplementation is very limited in improving bone mineral density in all age groups 13 October 2006
Jai B Sharma MD MRCOG, Assistant Professor of Obstetrics and Gynaecology All India Institute of Medical Sciences , New Delhi, Sameer Chadha , Medical Student , MAM College New Delhi, Shikha Mehta, Medical student, MAM College, New Delhi Send response to journal: Re: Role of calcium supplementation is very limited in improving bone mineral density in all age groups	The meta-analysis on role of calcium supplementation in children by Winzenberg et al is an important meta-analysis to answer the role of calcium supplementation in improving bone mineral density (BMD) in children whether such a supplementation can prevent fractures in later life especially in postmenopausal women where osteoporosis is a significant problem especially post various recent studies on role of estrogen replacement therapy with negative results. There is a real need to find out alternatives to estrogens for management of osteoporosis a very big problem in menopausal women with high fracture rates especially in spine and hip. Calcium is one such alternative. Unfortunately Winzenberg's results are contrary. The calcium supplementation does not improve BMD in children especially in vertebral column and hip which really matter as these are the sites of fractures in later life. Moreover with prolonged calcium supplementation there is danger of hypercalcaemia with all its consequences. Hence calcium supplementation in children should be used with caution. However, in areas of calcium deficiency especially in developing countries like India, calcium should be given more liberally for its immediate actions. Competing interests: None declared
Adequate calcium intake plus high physical activity may be useful for bone health in children 14 October 2006
Toshihiro Sugiyama, Visiting research fellow The Royal Veterinary College, London NW1 0TU, UK Send response to journal: Re: Adequate calcium intake plus high physical activity may be useful for bone health in children	A meta-analysis by Winzenberg and colleagues (1) used areal bone mineral density (BMD) to evaluate the effects of calcium supplementation on the growing skeleton. However, bone material and structural properties strongly affect its strength (2). A recent first prospective cohort study including 6,213 children in southwest England showed that an increased risk of fracture was associated with lower areal BMD (OR per SD decrease = 1.12), lower volumetric BMD (1.89) and smaller bone size relative to body size (1.51) (3). Therefore, areal BMD would not be a good marker of fracture risk in children; analysis using this marker could underestimate the effects of calcium supplementation. The small positive effect of calcium supplementation on upper limb areal BMD may result in significant reduction of fracture risk in upper limbs, the most common fracture site in children (4). In addition, the positive effect on upper limb, but not hip or lumbar spine, areal BMD (1) appears to suggest that adequate calcium intake is required for bone gain at non-weight-bearing sites. Among 19 studies in their meta-analysis (1), the trials by Iuliano-Burns et al, Stear et al, Specker et al and Courteix et al found that calcium supplementation supported the exercise-induced site-specific increase in areal BMD, although subgroup analysis by level of physical activity showed no effect modification (1). Bone strain from mechanical loads is an important factor to control the skeleton, and bone mineralization in children is much lower than that in adults. Thus, the lower material stiffness during growth would accelerate load-induced bone gain and calcium incorporation into bones could partly depend on their mechanical circumstances (5). In children, high physical activity with appropriate calcium intake is a candidate strategy for preventing fractures and it will be required to determine the optimum amount of daily calcium intake dependent on physical activity. Toshihiro Sugiyama, M.D., Ph.D. Department of Orthopaedic Surgery, Yamaguchi University School of Medicine, Yamaguchi 755-8505, Japan; and Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, London NW1 0TU, UK References 1. Winzenberg T, Shaw K, Fryer J, Jones G. Effects of calcium supplementation on bone density in healthy children: meta-analysis of randomized controlled trials. BMJ 2006;333:775-78. 2. Seeman E, Delmas PD. Bone quality: the material and structural basis of bone strength and fragility. N Engl J Med 2006;354:2250-61. 3. Clark EM, Ness AR, Bishop NJ, Tobias JH. Association between bone mass and fractures in children: a prospective cohort study. J Bone Miner Res 2006;21:1489-95. 4. Cooper C, Dennison EM, Leufkens HGM, Bishop N, van Staa TP. Epidemiology of childhood fractures in Britain: a study using the General Practice Research Database. J Bone Miner Res 2004;19:1976-81. 5. Sugiyama T, Taguchi T, Kawai S. Adaptation of bone to mechanical loads. Lancet 2002;359:1160. Competing interests: None declared
Take account of calcium excretion 14 October 2006
Clare M Hamon, GP Plymouth PL2 2JU Send response to journal: Re: Take account of calcium excretion	As far as I can see, this research does not address the issue of calcium loss through the kidneys, which must accompany the excretion of the metabolites of excessive protein. In Third World countries, average dietary protein intake is significantly lower than in the First World: my understanding is that this is a major factor in their relatively low incidence of osteoporosis. Dairy products have high levels of both calcium and protein, perfect for calves, but not necessarily so good for humans. Those of us who are vegans get most of our calcium from foods with lower levels of protein, such as green leafy vegetables, broccoli, swede, almonds, and brazils, as well as some from high-protein foods like tofu and fortified soya milk. I am uncomfortable about the way the dairy industry promotes their products as a good source of calcium, because, if the above is true, they are not so good at providing calcium which is retained by the human body. I would be very keen to see more research done in this field, specifically some which monitors protein as well as calcium intake. Competing interests: None declared
Effect size at the end of supplementation period in terms of g/cm2 20 April 2007
Tanis R Fenton, Professional Practice Leader, Clinical Nutrition Alberta Children's Hospital, T3B 6A8, Michael Eliasziw, David A. Hanley Send response to journal: Re: Effect size at the end of supplementation period in terms of g/cm2	To the Editor:             In the meta-analysis on role of calcium supplementation in children, Winzenberg et al (1) used standardised mean differences (SMD) to summarize their results and to base their conclusions.  Although the use of SMD is recognized as a valid approach in summarizing mean differences across trials in the Cochrane Review methodology (1), its primary purpose is for comparing variables with different units and measurement scales of different length (2). The SMD is calculated by dividing the group differences by the standard deviation.  This converts a variable which has units to a unitless score.  In other words, a variable which once had clinical meaning becomes clinically meaningless.             In Winzenberg et al.’s meta-analysis, all measurements of bone mineral density (BMD) were reported as grams per square centimetre (mg/cm2).  Under these circumstances, we believe that the use of SMDs is unnecessary.  An alternate approach is to summarize the treatment effects as absolute differences.  We have re-constructed Table 2 from the meta-analysis by calculating the effect size at the end of supplementation period in terms of g/cm2, the usual units of measurement for BMD.  We hope that our re-constructed Table will help clinicians better-appraise the magnitude of effect size for this meta-analysis.             In regards to interpreting the results from the Table, all bone sites show consistent increase in BMD at the end of a median calcium supplementation period of one year.  We disagree with Winzenberg et al.’s claim that the observed relative increase in upper limb body BMD is not clinically important.  Not only is this result statistically significant, but a yearly 0.007 g/cm2 increase (or a 1.8% relative increase) in BMD is a clinically meaningful change.  If this increase continued throughout childhood, it would likely translate to a substantial gain in bone strength.             We are concerned that the results of Winzenberg et al.’s meta-analysis could be construed to imply calcium is not important in childhood, even though the meta-analysis focused on the role of calcium supplementation and did not address calcium requirements. This interpretation of the results was promoted by the accompanying Editorial (3).  It was written by a member of the Physicians Committee for Responsible Medicine, a group that promotes vegan diets devoid of dairy products.  This thinking is at odds with the American Association of Clinical Endocrinologists (4), the National Institutes of Health Consensus Development Panel on Osteoporosis Prevention, Diagnosis and Therapy (5), the Institute of Medicine (6), and the Scientific Advisory Council of Osteoporosis Canada (7).  These groups recommend adequate intakes of calcium and vitamin D, combined with weight bearing physical activity, throughout childhood to promote the attainment of an optimal peak bone mass.  It is likely that calcium intake is a necessary but not sufficient condition for the development of a strong skeleton, as physical activity and calcium both play key roles in the attainment of a high peak bone mass (8).             Until we are absolutely certain about what the minimum and optimum combinations of calcium, vitamin D, foods from plant sources and physical activity are required to achieve a bone mass that will sustain the bones of individuals through their older ages without fragility fractures, it seems prudent to continue to follow the consensus-based recommendations for intakes of calcium and vitamin D. Sincerely, Tanis R. Fenton, PhD Candidate, RD Department of Community Health Sciences University of Calgary   Michael Eliasziw, PhD Department of Community Health Sciences University of Calgary Calgary AB, Canada   David A. Hanley, MD, FRCPC Departments of Medicine, Oncology and Community Health Sciences Division of Endocrinology and Metabolism University of Calgary       Effects of calcium supplementation on BMD at different sites (median treatment of one year) Bone Site Number of studies Number of Participants Mean BMD Control (g/cm2) Mean BMD Treatment (g/cm2) Mean BMD Difference (g/cm2) Relative Increase in BMD (%) P-value for Control versus Treatment Femoral neck 10 1073 0.798 0.810 0.012 1.5 0.055 Lumbar spine 11 1164 0.816 0.831 0.015 1.9 0.019 Upper limb 12 1579 0.390 0.397  0.007 1.8 0.003       References      1.   Winzenberg T, Shaw K, Fryer J, Jones G. Effects of calcium supplementation on bone density in healthy children: meta-analysis of randomised controlled trials. BMJ 2006; 333:775.    2.   Cohen J. Statistical Power Analysis for the Behavioral Sciences. New York: Academic Press; 1977.    3.   Lanou AJ. Bone health in children. BMJ 2006; 333:763-4.    4.   Hodgson SF, Watts NB, Bilezikian JP, Clarke BL, Gray TK, Harris DW et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract 2003; 9:544-64.    5.    Osteoporosis prevention, diagnosis, and therapy. JAMA 2001; 285:785-95.    6.   Institute of Medicine (IOM). Dietary Reference Intakes for calcium, phosphorus, magnesium, vitamin D and fluoride. The National Academies Press; 1997.    7.   Brown JP, Josse RG. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 2002; 167:S1-34.    8.   Courteix D, Jaffre C, Lespessailles E, Benhamou L. Cumulative effects of calcium supplementation and physical activity on bone accretion in premenarchal children: a double-blind randomised placebo-controlled trial. Int J Sports Med 2005; 26:332-8.     Competing interests: Until 2006, DAH served on a research grant review panel for the Dairy Farmers of Canada, and received an honorarium for this activity.