Web of industry, advocacy, and academia in the management of osteoporosisBMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h3170 (Published 21 July 2015) Cite this as: BMJ 2015;351:h3170
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Siddharth Bhatia’s arguments that academia-industry partnerships in the conduct of research should be encouraged in order to avoid duplication of effort, and that industry has no influence in the final outcome of research it funded are highly debatable, but not relevant to our paper. Our analysis focuses not on the generation of evidence, but on the influence of interactions between industry, advocacy organisations and academia in resisting the translation into clinical practice of strong evidence of lack of net benefit of calcium and/or vitamin D for fracture risk reduction in older adults. We agree with Bhatia that the magnitudes of the harms identified in clinical trials of calcium and/or vitamin D are small, but so are any reductions in fracture risk. Thus, the interventions may produce marginal benefit that is at least balanced by small harm, such that net benefit does not accrue. We don’t think patients should be advised to pursue treatments that do not produce net benefit to them.
We agree with Paolo Vercellini that academics should drive the revision of their relationships between with industry, as their primary responsibility is to the health of patients and the public.
We did not, as Spyridon Karras and colleagues contend, “claim that there is a lack of sufficient evidence for calcium/vitamin D on fracture risk reduction”. Nor did we argue that the generation of evidence in this area is industry-influenced. Instead, we argued that there is plenty of evidence, comprised of 14 large and 24 small randomised trials, supported predominantly by public-good funding. Collectively, these trials report marginal benefit that is balanced by modest harms for calcium supplements with or without vitamin D, and no benefit for vitamin D alone. Karras and colleagues’ claims of systematic flaws in the design and execution of the existing trials are both highly debatable and beside the point. If the existing evidence demonstrates that interventions do not benefit patients, those treatments should not be recommended.
We agree with Karras and colleagues that objective discussion is important. However, their implication that our work is prejudiced and descriptions of it as “politically correct” and designed to attract media attention suggest their evaluation lacks objectivity. Conflicts of interest may preclude objectivity. When a conflict of interest is present, it is not possible to be reassured that it has not influenced process(es) and outcome(s). Each of the two major osteoporosis advocacy organisations acknowledge that their existence depends on commercial sponsorship (http://www.iofbonehealth.org/news/iof-response-recent-report-questioning... http://commonhealth.wbur.org/2015/08/calcium-vitamin-d-commercial-influence). Our analysis suggests that, since calcium (supplements and food) and vitamin D (supplements and testing) are multi-billion dollar industries, the close relationships between industry, advocacy organisations, special societies and academia may be a reason why calcium and vitamin D are still widely recommended for older adults when strong evidence contradicts the practice. Organisations and individuals that proffer advice on medical practices should be free of conflicts of interest.
Competing interests: Andrew Grey is a shareholder in Auckland Bone Density, a company that provides bone densitometry services. Mark Bolland has no conflict of interest
We read with interest the article by Andrew Grey and Mark Bolland (1), regarding the role of calcium/vitamin D treatment in the field of osteoporosis. The authors raise significant scientific and ethical issues in their article, that warrant a statement reflecting the other side of this issue, a view that we think is held by many unprejudiced scientists working on this field worldwide.
Regarding the scientific part of this article, the authors claim that there is a lack of sufficient evidence for calcium/vitamin D supplementation on fracture risk reduction, and the main reasons for this phenomenon mainly lie on a complex association between ‘’big pharma’’ academic organization and media propaganda. In the end of their article, the authors classify results of many randomized controlled trials (RCTs) as beneficial, neutral or even harmful. without allowing for the challenges of conducting nutritional RCTs, many of which are unique to nutritional studies (2), and that could well confound their results. For example, an informative ‘’nutritional RCT’’ (that could be included in a systematic review) would use a single form of the nutrient, include a low exposure control group, ensure adequacy in dosing (by documenting therapeutic levels achieved), and optimization of co-nutrient status (3).
Based on the findings and interpretations of previous pioneer RCTs regarding
calcium/vitamin D supplements for osteoporosis (4-14), we would like to emphasize specific points that could affect interpretation of the portfolio of evidence in this field:
1) Trials have used different forms of vitamin D (D2 or D3) (4,5,11,13) , +/- calcium (4,5,9,10,13,14), and various routes of administration(4-10,13,14) . From a pharmacokinetic view, a large bolus of 50,000 or 100,000 IU of vitamin D would rapidly (in a few days) be absorbed, much would be excreted, and become undetectable in the serum (2,15), and several supplementation trials used this type of bolus administration, with further potential for reduction in efficacy due to induction of vitamin D catabolic mechanisms (16).
2) Most trials reported on the attained serum concentrations of 25-(OH) vitamin D post-supplementation (4, 5, 7-9, 11) as a surrogate marker in a small study cohort subgroup (in a total of 5-10% of study participants). Moreover, serum 25(OH)Ds were measured at a single time point and could not be considered as having attained therapeutic levels..
3) A low exposure group was absent in most studies (4, 5, 7-9, 11), though many scientists believe that supplementation with vitamin D in populations with lower baseline concentrations should be more effective, but supplementation of replete subjects (2, 3) will not.
4) Vitamin D efficacy depends on optimal provision of other relevant nutrients such as calcium, e.g. high calcium intakes prevent and heal rickets in vitamin D deficiency, even though vitamin D deficiency causes rickets; similarly, vitamins A and K, and magnesium intakes, affect vitamin D efficacy, but no RCTs examined adjusted for these variables .
5) It is crucial to underline the low adherence to intervention that often did not exceed 40-50% in previous RCTs. Using an ‘intent-to-treat’ analysis is of course the gold standard for evaluating the effectiveness of treatment, but we should mention that it gives no information on the efficiency per se of a molecule compared to a ‘per protocol’ analysis
Thus, RCTs can fail due to design problems and, by chance, as in any other field and in this context, a significant number of the trials cited by Grey and Bolland reported high dropout rates, which could well affect their outcomes. The potential benefits of supplementation with calcium and vitamin D operate through at least two different ways: i) beneficial calcium effects are not seen in serum values, but at the cellular level, with demonstrable increases in bone mineral density, an effect that has been established by a plethora of experimental (17) and clinical studies(18,19) so far.
ii) 25-OHVitamin D has to attain therapeutic levels, but these were not been attained at least not in most study participants, in most of the RCTs analysed in this article; similarly, many subjects had baseline values that demonstrated adequate nutrient status, so that supplementation trial outcomes might have been different in deficient populations, as exist in the majority of populations worldwide. Overall, we support the case that, in focusing on nutritional health effects, RCT interpretation needs to be made using 'nutritional' rather ‘’pharmaceutical’’ criteria and this stricture also applies to systematic reviews or meta-analyses (2,3) .
Regarding the ethical aspects of work on osteoporosis, we believe that the vast majority of researchers in this field have strong scientific, rather than financial, motivation. We would welcome discussion on any aspect of work in this difficult field, provided that it is accepted that it is studies and not research workers that are biased. We strongly favour continuing scientific debate that strives for carefully balanced views and avoids suggestions of personal lack of integrity, because we do not see the world in such stark terms – right versus wrong, since we think that the biology in this area is more complicated than is currently appreciated.
The debate should go beyond the politically correct and media-attractive phantasm of a scientific reasoning based mainly on conflicts of interest with the major financial groups rather than motivated by the quest for knowledge and health.The role of calcium and vitamin D supplements requires further investigation and we encourage further such work –just as we also appreciate the need for continued vigilance in ensuring correctly designed, objectively analysed, and fully reported, RCTs in this important area.
1.Grey A, Bolland MWeb of industry, advocacy, and academia in the management of osteoporosis. BMJ. 2015 Jul 21;351:h3170. doi: 10.1136/bmj.h3170
2.HeaneyRP,Guidelines for optimizing design and analysis of clinical studies of nutrient
effects Nutr Rev. 2014 Jan;72(1):48-54
3.Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrinol. 2012 Apr 1;4(2):95-100.
4. Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med 1996;124:400- 6.
5 .Meyer HE, Smedshaug GB, Kvaavik E, Falch JA, Tverdal A, Pedersen JI. Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. J Bone Miner Res 2002;17:709-15.
6. Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet 2005;365:1621-8.
7. Porthouse J, Cockayne S, King C, Saxon L, Steele E, Aspray T, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care. BMJ 2005;330:1003.
8. Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-83.
9. Prince RL, Devine A, Dhaliwal SS, Dick IM. Effects of calcium supplementation on clinical fracture and bone structure: results of a 5-year, double-blind, placebo-controlled trial in elderly women. Arch Intern Med 2006;166:869-75.
10. Reid IR, Mason B, Horne A, Ames R, Reid HE, Bava U, et al. Randomized controlled trial of calcium in healthy older women. Am J Med 2006;119:777-85.
11. Lyons RA, Johansen A, Brophy S, Newcombe RG, Phillips CJ, Lervy B, et al. Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation. Osteoporos Int 2007;18:811-8.
12. Salovaara K, Tuppurainen M, Karkkainen M, Rikkonen T, Sandini L, Sirola J, et al. Effect of vitamin D(3) and calcium on fracture risk in 65- to 71-year-old women: a population-based 3-year randomized, controlled trial--the OSTPRE-FPS. J Bone Miner Res 2010;25:1487-95.
13.Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C. Effect of annual intramuscular vitamin D on fracture risk in elderly men and women--a population-based, randomized, double-blind, placebo controlled trial. Rheumatology (Oxford) 2007;46:1852-7.
14. Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA 2010;303:1815-22.
15. Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ (2003) Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77:204–210
16. Heaney RP, Armas LA (2015) Quantifying the vitamin D economy. Nutr Rev 73(1):51–67
17. Feng Y, Zhou M, Zhang Q, Liu H, Xu Y, Shu L, Zhang J, Miao D, Ren Y. Synergistic effects of high dietary calcium and exogenous parathyroid hormone in promoting osteoblastic bone formation in mice. Br J Nutr. 2015 Mar 28;113(6):909-22
18. Zhu K, Devine A, Dick IM, Wilson SG, Prince RL. Effects of calcium and vitamin D supplementation on hip bone mineral density and calcium-related analytes in elderly ambulatory Australian women: a five-year randomized controlled trial. J Clin Endocrinol Metab. 2008 Mar;93(3):743-9.
19. Grados F, Brazier M, Kamel S, Duver S, Heurtebize N, Maamer M, Mathieu M, Garabédian M, Sebert JL, Fardellone P. Effects on bone mineral density of calcium and vitamin D supplementation in elderly women with vitamin D deficiency. Joint Bone Spine. 2003 Jun;70(3):203-8.
Competing interests: No competing interests
Kudos to The BMJ for bringing out this article and the authors for this exposure !
It needs a lot of commitment and courage to write and publish this type of article. As rightly pointed out, this nexus creates an artificial need of calcium and vitamin D. The dairy lobby is very strongly advocating milk consumption despite the fact that no other mammal ever consumes milk of other species. For a moment let us ignore the perils of high phosphate content of cattle milk and the disadvantages of animal protein consumption as this issue is controversial. Though data favoring calcium and vitamin D supplementation exist but a more robust data opposing this view also exist as pointed out by Bolland et al. As more calcium is absorbed in the bones, the production and activity of both osteoblasts and osteoclasts is increased (1). A higher amount of calcium in diet (dairy products) or supplements will lead to the rapid replacement of osteoblasts. As the number of times a cell can be replaced is finite, they are exhausted early. That is, calcium supplements will enhance bone loss. Out of a large intake of calcium how much is really useful that is also debatable as only about 200 mg is absorbed from gut irrespective of the amount ingested, but in calcium deficiency states it can be more(2)
1. Yudoh K, et al, Decreased cellular activity and replicative capacity of osteoblastic cells isolated from the periarticular bone of rheumatoid arthritis patients compared with osteoarthritis patients. Arthritis Rheum 2000 Oct;43(10):2178-88.
2. Kung AW, Age-related osteoporosis in Chinese: an evaluation of the response of intestinal calcium absorption and calcitropic hormones to dietary calcium deprivation. Am. J. Clin. Nutr. 1998 / 68 (6) / 1291-1297.
Competing interests: No competing interests
The web of financial interests involving industry, advocacy and academia in the management of osteoporosis described by Grey and Bolland,1 is paradigmatic of a situation characterising many medical specialties.2 However, the ethical implications regarding each component of this web seem different. Industry is a private enterprise, its goal is profit, and its managers are accountable to shareholders. Advocacy organisations are morally accountable to patients, but are supported mainly with private funds.3 Conversely, most European academics are public employees paid with citizens' taxes and are accountable to society at large. Academics appears to have here by far the highest ethical liability, as without their compliance neither industry nor advocacy organisations could alone catch medicine so effectively in this web of interests.
Academics influence prescription practices and, hence, impact on citizens' health and healthcare resources. Therefore, citizens not only should have the right to know which academics are paid by whom and how much, but should also be allowed to decide whether these financial ties are permissible. Collaboration between industry and academics is necessary, but should not imply payments to individual investigators. Money deriving from industry-supported research could be centralised in anonymous institutional funds. Academics have the moral duty of educating young generations according to the highest ethical standards. The possibility that teachers do not enable their medical students to objectively appraise the evidence must be prevented, also because students are intellectually vulnerable. Thus, universities should prohibit the establishment of financial ties between academics and private enterprises, including medical communication companies.4
In his last published words, Arnold Relman warned: "now, more than ever, it is important that leaders in academic medical centers set an example for students and faculty by concentrating on advancing the non-for-profit social purposes of these institutions. They cannot do this if they also have ties to pharmaceutical businesses".
1. Grey A, Bolland M. Web of industry, advocacy, and academia in the management of osteoporosis. BMJ 205;351:h3170.
2. Kassirer JP. Professional societies and industry support: what is the quid pro quo? Perspect Biol Med 2007;50:7-17.
3. Lenzer J. Many US medical associations and disease awareness groups depend heavily on funding by drug manufacturers. BMJ 2011;342:d2929.
4. Schwartz LM, Woloshin S. Medical communication companies and continuing medical education: clouding the sunshine? JAMA 2013;310:2507-2508.
5. Relman AS. Potential conflicts of interest for academic medical center leaders. JAMA 2014;312:558.
Competing interests: No competing interests
I thoroughly enjoyed reading this article but, with all due respect, I disagree with the overall conclusion that there should be reduced interaction between industry and academia.
On the contrary, it should be encouraged. Good research needs both funding and credential. While industry can provide the former, academia can provide the latter. If this partnership is reduced, there will be duplication of research, one by the industry and the other by academia. This will be highly undesirable as there will be considerable waste of resources, duplication of effort, and conflicting results. The regulatory authorities in many countries recommend industry sponsored research to be done by independent and reputable organisations as it brings quality, credibility and assurance to them as well as to the public.
So what is the issue here? The problem lies in the research question itself and in finding its answer. Some research questions are easily answered by good clinical research as the difference is quite obvious. Other research questions are complex, or the difference is so subtle that clear answer is difficult to obtain. An association of oral contraceptives and thromboembolism, increase in suicidal tendency in patients taking some anti-depressants, increased risk of cardiovascular death with use of over the counter NSAIDs are few of the examples.
As a researcher, I know that clinical trials are subject to chance, bias and confounding. Meta-analyses also are subject to publication bias and selection criteria chosen by authors. If the results are conflicting, it is extremely hard to accept one result and ignore the other. Most of the adverse events mentioned in the paper have Confidence Interval (CI) very close to 1 which makes them slightly statistically significant; however, the clinical consequences remain unknown.
As a physician, I rely on credible sources like Cochrane to provide me with the ‘ultimate’ answer. I will ‘blindly’ follow the recommendations in Cochrane as I will not have sufficient expertise to analyse all the evidence from worldwide literature. The fact that Cochrane currently recommend use of Vitamin D and calcium for prevention of fractures is testament that recent evidence is not concrete to make changes to the current recommendation.
The collaboration between industry and academia brings transparency and trust in research. The conduct of research is under high scrutiny from regulators and industry has no influence in the final outcome. We should acknowledge that decisions concerning public health are difficult to make and require robust evidence that may sometime be challenging to obtain as, perhaps, in this case.
Competing interests: No competing interests
Osteoporosis is usually due to zinc and magnesium deficiencies but not calcium deficiency.
The causes, prevention and treatment of osteoporosis have long been contentious issues. Epidemiological studies may help or mislead but each individual needs
biological tests to see what supplements are needed. Avoiding large doses of calcium supplements lowers the risk of renal stones and also possibly myocardial infarction.1 Adding calcium to drugs like biphosphonates would be unlikely to improve bone formation.2
The range of essential nutrients needed for bone formation include adequate intakes of zinc, magnesium, manganese, boron, vitamin D, vitamin
C, vitamin K, folic acid and Vitamin B6.3
In 1998 John McLaren-Howard, Stephen Davies, and I reported that among women with confirmed or suspected osteoporosis, those taking
HRT had abnormally higher serum copper levels and lower ALP activity compared with non-users with osteoporosis.3 HRT takers also had
significantly lower white cell zinc, lower red cell magnesium and lower serum bone ALP concentrations, and significantly higher mean serum phosphate levels, than other women with osteoporosis. Hormone takers also tended to have lower serum manganese, tartrate- resistant acid phosphatase (a measure of bone resorption), and vitamin C levels, and higher urinary
excretion of zinc and hydroxyproline. Serum calcium levels were normal. Repletion of these deficiencies and lowering of the elevated copper levels
were impaired unless progestogens and oestrogens were also discontinued.
None of the women tested in our studies were calcium deficient. Calcium deficiency is rare apart from in patients with parathyroid disease. Taking calcium can interfere with the absorption of zinc and iron and is not useful when the main problems are repleting zinc and magnesium deficiencies. 2-5
1 Bolland MJ, Avenell A, Baron JA et al. Effect of calcium
supplements on risk of myocardial infarction and cardiovascular events: meta-analysis.
BMJ 2010; 341: c3691
2 Cleland, J. G. F., Witte, K., Steel, S. Calcium supplements in people with osteoporosis. BMJ 2010; 341: c3856-c3856
3 McLaren-Howard J, Grant ECG, Davies S. Hormone Replacement Therapy and Osteoporosis: Bone Enzymes and Nutrient Imbalances. J Nutr Environ Med
1998; 8: 129-138.
4 Grant ECG. Zinc and magnesium supplements, not calcium
supplements, are needed in osteoporosis.
http://bmj.com/cgi/eletters/330/7498/1003#105438, 1 May 2005
5 Grant EC. Re: Oral bisphosphonates: prevention of osteoporotic fracture or disease mongering?
http://bmj.com/cgi/eletters/336/7648/784#193703, 15 Apr 2008
6 Grant EC. Bad medicine or rampant progestogen-induced
http://bmj.com/cgi/eletters/340/feb03_1/c643#231187, 11 Feb 2010
Competing interests: No competing interests