Placebo-Controlled Trials in Osteoporosis — Proceeding with Caution
N Engl J Med 2010; 363:1365-1367September 30, 2010
This article presents one viewpoint on the issues surrounding placebo-controlled trials in osteoporosis. The other Sounding Board article in this issue presents an opposing view. In a related interactive feature, the authors of each article give their Point of View about the other article. Participate in forming community opinion by choosing one of the viewpoints and, if you like, providing your reasons.
Effective treatments are now available to prevent osteoporotic fractures, but the process of approving new agents has been accompanied by a simmering controversy about the ethics of placebo-controlled trials for testing new drugs. This debate is often framed by the simple question of whether people who are highly susceptible to an osteoporotic fracture should be involved in a clinical trial and thereby risk random assignment to a placebo. However, the issue is more complex than this question and centers on multiple concerns that run the gamut from clinical equipoise (i.e., genuine uncertainty over whether or not the treatment will be beneficial) to informed consent to health care accessibility. Notwithstanding this debate, appropriate guidelines to exclude high-risk patients would allow placebo-controlled trials in osteoporosis to benefit some patients and inform investigators.
In the field of osteoporosis, the most prominent example of a well-executed placebo-controlled clinical trial is the Women's Health Initiative, which showed the antifracture efficacy of estrogen and progesterone but also illuminated critically important nonskeletal adverse events.1 More recently, investigators in a large, randomized, placebo-controlled trial of denosumab, the first of a new class of biologic agents, provided strong evidence of vertebral and nonvertebral antifracture efficacy but also reported unique side effects that have necessitated further study.2
The results of large, randomized, placebo-controlled trials, although convincing, are insufficient to promote universal acceptance of these drugs for the treatment of osteoporosis. In future studies, women at very high risk should not be allowed to enroll in a placebo-controlled trial of a new intervention when standard treatments are known to reduce the risk of a fracture by 30 to 50%. Who are such patients? We would argue that women with a history of a fragility fracture of the hip or spine, a very low bone mineral density (T score less than ?2.5), or both should be excluded, even if they express a willingness to participate. Of course, the choice ultimately rests with the individual woman, but high-risk patients must be encouraged to seek conventional therapeutic options. In addition, for such trials, a clinical trial investigator should not recruit his or her own patients who have osteoporosis.
Which women might we consider suitable for enrollment in such randomized trials? We would follow the recommendations of an expert panel that considered it appropriate to enroll patients with low bone mineral density in placebo-controlled trials if they had no history of fragility fractures or if radiologic imaging showed only asymptomatic morphometric vertebral fractures.3 Similarly, patients who had side effects from previous therapies or who did not have a response to conventional therapy might be considered. Inherent in these assumptions is the fact that few pure placebo-controlled trials involve patients with osteoporosis. Virtually all industry- and investigator-originated trials use an add-on approach in which one group receives calcium and vitamin D and another group receives calcium and vitamin D plus the active agent. For example, in another group of the Women's Health Initiative, the use of calcium plus 400 IU of vitamin D was associated with an increase in femoral bone mineral density and a reduction in the risk of hip fracture among older postmenopausal women.4 That trial empirically established the standard for a comparison group in studies of osteoporosis treatments.
In other circumstances, placebo-controlled trials inform us about new therapies in patients with a relatively low risk of fracture. The rates of absolute fracture among younger postmenopausal women with moderately reduced bone mass (i.e., T score greater than ?2.5) but no previous fractures are low. Trials that enroll these women are often designed to examine rates of bone loss, changes in surrogate indexes (such as biochemical markers of bone turnover), and critical safety indexes. Similarly, the comparison with a placebo-control group is particularly important for newer classes of drugs (e.g., a biologic agent such as denosumab) that would be difficult to contrast with other established drugs or historical control data.
There are certainly alternatives to placebo-controlled trials in osteoporosis. The most common alternatives are noninferiority and superiority trials in which a no-treatment group is replaced by a group that receives an established drug. These trials are much more difficult to carry out and require larger numbers of participants to prove noninferiority for a reduction in fracture risk. For example, in phase 3 fracture studies, 5000 to 8000 patients are generally required to achieve statistical power to assess group differences. In a noninferiority trial for antifracture efficacy, that number would increase and substantially more time would be required to conduct the trial. Furthermore, a trial that used alendronate as a comparison drug would necessitate the inclusion of patients who were at higher risk, since alendronate has not been shown to reduce fractures in women with T scores greater than ?2.0.5 Ultimately, any trial involving a comparison group would, given its necessarily larger size, result in more fractures over the duration of the trial than would be observed in a placebo-controlled study and, thus, it would offer no ethical advantage over the latter.6 Finally, these trials are also complicated by the issue of “assay sensitivity” (i.e., the level of accuracy in comparing a new drug with an established drug when the effect size is relatively small). Notwithstanding these issues, noninferiority studies can test surrogate markers for fracture (e.g., bone mineral density or bone-turnover markers), indexes that reduce the required number of study participants but do not directly address fracture outcomes, the most clinically important end point. However, the matter is complicated because changes in surrogate indexes, including bone mineral density, do not always predict the reduction of fracture risk during treatment.
Alternative approaches to recruitment could be considered; these include allowing patients to be randomly assigned to active drug or placebo if they are already receiving weaker agents such as a selective estrogen-receptor modulator or calcitonin. Another approach might be to improve decision making by subjects who are considering enrollment in clinical trials of new osteoporosis treatments by, for example, using the recently developed fracture risk assessment tool (FRAX) for screening subjects. The FRAX score provides the individual patient, in percentage terms, with an absolute risk of hip fracture or any osteoporotic fracture over the next 10 years, thereby allowing more informed decision making based on each patient's risk of fracture without active treatment.7 For example, in a 65-year-old woman with no fractures or other risk factors but a bone mineral density T score of ?2.5, the 10-year probability of a major fracture would be 13% and the 10-year probability of a hip fracture would be 2.8%. During a 3-year, randomized, controlled trial of a drug that would be predicted to reduce fractures by 40%, a total of 4.0% of subjects in a placebo group would sustain a fracture as compared with 2.4% of subjects in the treatment group. Providing these data to potential patients would inform decision making at all levels.
Guidelines from the European Medicines Agency8 that are quite similar to older (1994) guidelines from the U.S. Food and Drug Administration9 still promote the use of placebo-controlled trials to test new drugs in persons at risk for fractures. With that in mind, we believe that trial design and implementation should not supersede patient welfare or underestimate the potential for harm. To be ethical, the trial design first must answer the question being asked. It should provide potential participants with a high and clear standard of informed consent, including active review by an institutional review board and an independent data and safety monitoring board. Shared decision making must be a centerpiece of this process. The Declaration of Helsinki, which states that placebo trials are permissible when no major harm could be expected to come to trial participants as a result of delaying treatment, remains a major guideline for investigators.6 With the use of appropriate guidelines to exclude high-risk patients, placebo-controlled trials of osteoporosis treatments can benefit some patients and can inform investigators and the health care profession in a safe, transparent, and scientific manner.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Clifford J. Rosen, M.D.; Sundeep Khosla, M.D.
From the Maine Medical Center Research Institute, Scarborough (C.J.R.); and the College of Medicine, Mayo Clinic, Rochester, MN (S.K.).
References
1 Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 2003;290:1729-1738
2 Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756-765
3 Silverman SL, Cummings SR, Watts NB. Recommendations for the clinical evaluation of agents for treatment of osteoporosis: consensus of an expert panel representing the American Society for Bone and Mineral Research (ASBMR), the International Society for Clinical Densitometry (ISCD), and the National Osteoporosis Foundation (NOF). J Bone Miner Res 2008;23:159-165
4 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
5. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280:2077-2082
6. Fost N. Ethical issues in clinical research on fracture prevention in patients with osteoporosis. J Bone Miner Res 2003;18:1110-1115
7 Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int 2007;18:1033-1046
8 European Medicines Agency 2005. Guideline on the Evaluation of New Medicinal Products in the Treatment of Primary Osteoporosis. (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003406.pdf.)
9 Guidelines for preclinical and clinical evaluation of agents used in the prevention or treatment of postmenopausal osteoporosis. Rockville, MD: Division of Metabolic and Endocrine Drug Products, Food and Drug Administration, April 1994. (http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/WomensHealthResearch/UCM131206.pdf.)
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The Ethics of Placebo in Studies with Fracture End Points in Osteoporosis
N Engl J Med 2010; 363:1367-1370September 30, 2010
This article presents one viewpoint on the issues surrounding placebo-controlled trials in osteoporosis. The other Sounding Board article in this issue presents an opposing view. In a related interactive feature, the authors of each article give their Point of View about the other article. Participate in forming community opinion by choosing one of the viewpoints and, if you like, providing your reasons.
Recent large, randomized, controlled trials indicate that newer therapies for osteoporosis — denosumab,1 tibolone,2 zoledronic acid,3,4 teriparatide,5 strontium ranelate,6 and lasofoxifene7 — significantly decrease the risk of fracture as compared with placebo. At the time of these trials, standard guidelines recommended that pharmacotherapy be administered in patients with osteoporosis,8 since placebo-controlled trials had demonstrated that available drugs, such as bisphosphonates,9,10 reduced the risk of fracture by approximately 40 to 50% relative to placebo.11,12 There is general agreement that placebo-controlled trials are unethical when a therapy that decreases the risk of serious complications or death is available,13-16 which suggests to us that careful review of the ethics of using placebo controls in trials with fracture end points in patients with osteoporosis is indicated.17-21 We and others14,22,23 have identified a number arguments that could support the use of a placebo in trials. We discuss these with respect to osteoporosis trials with fracture end points.
Many believe that it is ethical to withhold an effective treatment when adverse consequences are minor or rare. However, osteoporotic hip and vertebral fractures have serious consequences, including increased risk of death, surgical procedures, and long-term impairment of physical function.24,25
The risk of fracture in women with untreated osteoporosis is substantial, even when those at highest risk are excluded from studies. In one study, 7.2% and 1.2% of women receiving placebo had new vertebral fractures and hip fractures, respectively, as compared with 2.3% and 0.7%, respectively, in the active-treatment group.1 The common practice of excluding patients with the highest risk of fracture from placebo-controlled trials does not resolve concerns about adverse outcomes in patients receiving placebo, but rather, in our view, implicitly acknowledges that untreated osteoporosis carries a risk of clinically important consequences that available treatments can reduce.
One possible justification for contemporary osteoporosis trials is that almost all patients receive calcium and vitamin D. However, review of the available data indicates that calcium alone and calcium and vitamin D have limited efficacy, at best8; a recent meta-analysis reported a 12% reduction in the risk of fractures with calcium or the combination of calcium and vitamin D as compared with placebo.26 Indeed, the benefits of proven osteoporosis therapies have been shown relative to patients taking these supplements.10,27 Adding placebo or an active drug to a baseline drug regimen that is suboptimal does not resolve the ethical concern.
The ethics of performing placebo-controlled studies in countries or regions in which a proven effective therapy is not available are debated.28,29 In countries or regions in which standard therapies are available, the same argument may be raised for patients unable to afford these standard drugs, since some patients might receive an effective therapy in a placebo-controlled trial. Would a placebo-controlled study that would be considered unethical in patients with access to standard treatment be ethical in those without access? Such a trial could not include any patients who could afford recommended therapy, since a trial must be ethical for all its participants. In addition, ethical guidelines mandate that extreme caution be used in studies in which a patient's vulnerability becomes an incentive for participation.30-32 Thus, in countries in which standard therapy is available, specifically enrolling patients who do not have access to such therapy into a study in which it will in fact be withheld from some would nearly always be unacceptable.
Regulatory authorities require the demonstration of efficacy and safety of a new drug in well-controlled trials,33 with preference given in general to placebo control because this is almost always the most scientifically rigorous and economical design. However, as effective treatments are identified and the consequences of untreated disease defined over time, previously accepted study designs may become unethical, despite their scientific efficiency. For example, once placebo-controlled studies showed that treatment of mild hypertension decreased the risk of cardiovascular events, long-term, placebo-controlled clinical trials of patients with established hypertension were no longer considered ethical.34
Ethical guidelines for research emphasize minimizing risks and protecting the individual patient, rather than obtaining benefits for society at the cost of serious preventable harm to some.15,16,32 Many volunteers participate in studies that have associated risks and that do not provide personal benefit but do provide societal benefit. However, patients are generally not asked to forgo proven effective therapy and to deliberately place themselves at risk of a serious or irreversible event that is the study end point.
Institutional review boards (IRBs) and other committees provide important ethical oversight, but their approval does not necessarily make a study ethical.35 IRB members are seldom as expert in a clinical area as the investigators performing the study; thus IRB members may be swayed by precedent and the researchers' assertions that a particular placebo-controlled trial is ethical. However, some IRBs may be beginning to question the ethics of placebo-controlled studies of fracture in patients with osteoporosis.1,2
Although written informed consent is almost always necessary for a clinical trial to be ethical, it is not sufficient.16 A study must be deemed ethical before enrollment is offered to potential participants. Thus, the ability to obtain consent does not automatically make a trial ethical.16
Could a trial that requested fully informed patients to forgo the proven benefits of long-term treatment for the benefit of society ever be ethical? Although such a study would have some parallels with investigations involving altruistic volunteers, it would raise many difficult questions. If this approach were ever appropriate, it would only be in extremely unusual circumstances that we do not believe are present for osteoporosis studies. Such trials would require extraordinary measures to ensure that patients fully understood the risks to which they would be exposed and to ascertain that patients were not unduly influenced by their physicians or the sponsors of the trial.
Several alternative designs have been considered for placebo-controlled studies of fracture in patients with osteoporosis. These include trials of patients with osteopenia, for whom therapy is not currently indicated; add-on study designs, in which a placebo or new drug is added to the best available therapy; and trials with “informed refusal,”17 in which patients have either refused currently available therapies, cannot tolerate them, or did not benefit from them.4
These alternative designs all have inherent limitations. It may not be valid to extrapolate findings in patients with osteopenia to those with osteoporosis. Add-on trials may have limited clinical relevance. Informed-refusal trials often involve investigators who have an inherent conflict of interest, because the same clinician who advises the patient about currently approved and available therapy may recruit them for a trial that requires refusal of such therapy. Resolving such a conflict could include the use of clinicians not directly involved with the study and without a conflict of interest; such a person would determine the reasons for refusal of standard therapies and obtain informed consent from the patient that demonstrates explicit understanding of the risks of withholding standard therapies. Oversight from third parties about the quality of the informed consent in a sample of study patients would also be needed. Informed-refusal trials may face greater logistic difficulties than other trials in recruiting patients and maintaining adherence, because the participant pool consists of patients who already have been unable or unwilling to take recommended therapies.35
Thus, these alternative-design placebo-controlled trials often will not be feasible. Studies comparing a new drug with an active control generally will be required, even though such trials are more complex and expensive, usually require larger sample sizes, and have more methodologic complexities than placebo-controlled trials.36 However, these challenges should not be considered an ethical justification for administering placebo to some patients, which would result in potentially preventable fractures. Furthermore, trials involving active comparison drugs would also provide comparative effectiveness and safety information that is key to rational therapy.
In summary, because several drugs that materially decrease the risk of fractures in patients with osteoporosis are currently available, we believe that placebo-controlled studies with fracture end points in patients with osteoporosis will nearly always be unethical. Such trials cannot be justified by regulatory preferences for placebo-controlled studies, the approval of local IRBs, or informed consent from the participants. Study sponsors and investigators, regulatory authorities, and medical journals must work to ensure that trials with fracture end points in patients with osteoporosis are ethical.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
C. Michael Stein, M.B., Ch.B.; Wayne A. Ray, Ph.D.
From the Department of Medicine, Divisions of Clinical Pharmacology and Rheumatology (C.M.S.), and the Department of Preventive Medicine, Division of Pharmacoepidemiology (W.A.R.), Vanderbilt University School of Medicine, Nashville.
References
1 Cummings SR, Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756-765
2 Cummings SR, Ettinger B, Delmas PD, et al. The effects of tibolone in older postmenopausal women. N Engl J Med 2008;359:697-708
3 Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-1822
4 Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357:1799-1809
5. Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med 2007;146:326-339
6. Reginster JY, Felsenberg D, Boonen S, et al. Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis: results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum
7. Cummings SR, Ensrud K, Delmas PD, et al. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med 2010;362:686-696
8. Qaseem A, Snow V, Shekelle P, Hopkins R, Forciea MA, Owens DK. Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2008;149:404-415
9. Khosla S. Increasing options for the treatment of osteoporosis. N Engl J Med 2009;361:818-820
10. MacLean C, Newberry S, Maglione M, et al. Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteoporosis. Ann Intern Med 2008;148:197-213
11. Stevenson M, Jones ML, De Nigris E, Brewer N, Davis S, Oakley J. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis. Health Technol Assess 2005;9:1-160
12. Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C. Meta-analyses of therapies for postmenopausal osteoporosis. IX. Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23:570-578
13. Temple R, Ellenberg SS. Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues. Ann Intern Med 2000;133:455-463
14. Stein CM, Pincus T. Placebo-controlled studies in rheumatoid arthritis: ethical issues. Lancet 1999;353:400-403
15. WMA Declaration of Helsinki — ethical principles for medical research involving human subjects. (http://www.wma.net/en/30publications/10policies/b3/index.html.)
16. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000;283:2701-2711
17. Brody BA, Dickey N, Ellenberg SS, et al. Is the use of placebo controls ethically permissible in clinical trials of agents intended to reduce fractures in osteoporosis? J Bone Miner Res 2003;18:1105-1109
18. Delmas PD, Calvo G, Boers M, et al. The use of placebo-controlled and non-inferiority trials for the evaluation of new drugs in the treatment of postmenopausal osteoporosis. Osteoporos Int 2002;13:1-5
19. Silverman SL, Cummings SR, Watts NB. Recommendations for the clinical evaluation of agents for treatment of osteoporosis: consensus of an expert panel representing the American Society for Bone and Mineral Research (ASBMR), the International Society for Clinical Densitometry (ISCD), and the National Osteoporosis Foundation (NOF). J Bone Miner Res 2008;23:159-165
20. Reginster JY, Abadie E, Delmas P, et al. Recommendations for an update of the current (2001) regulatory requirements for registration of drugs to be used in the treatment of osteoporosis in postmenopausal women and in men. Osteoporos Int 2006;17:1-7
21. Food and Drug Administration. Center for Drug Evaluation and Research Arthritis Endocrinologic and Metabolic Drugs Advisory Committee meeting, Tuesday September 25, 2002. (http://www.fda.gov/ohrms/dockets/ac/02/transcripts/3888T1.htm.)
22. Rothman KJ, Michels KB. The continuing unethical use of placebo controls. N Engl J Med 1994;331:394-398
23. Michels KB, Rothman KJ. Update on unethical use of placebos in randomised trials. Bioethics 2003;17:188-204
24. Cummings SR, Melton LJ. Epidemiology and outcomes of osteoporotic fractures. Lancet 2002;359:1761-1767
25. Fink HA, Ensrud KE, Nelson DB, et al. Disability after clinical fracture in postmenopausal women with low bone density: the Fracture Intervention Trial (FIT). Osteoporos Int 2003;14:69-76
26 Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007;370:657-666
27. Shea B, Wells G, Cranney A, et al. Calcium supplementation on bone loss in postmenopausal women. Cochrane Database Syst Rev 2004;1:CD004526-CD004526
28. Shapiro HT, Meslin EM. Ethical issues in the design and conduct of clinical trials in developing countries. N Engl J Med 2001;345:139-142
29. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. N Engl J Med 1997;337:853-856
30. United States Department of Health and Human Services. Code of Federal Regulations: Title 45, Part 46. (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#46.111.)
31. Pace C, Miller FG, Danis M. Enrolling the uninsured in clinical trials: an ethical perspective. Crit Care Med 2003;31:Suppl 3:S121-S125
32. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont report: ethical principles and guidelines for the protection of human subjects of research. (http://ohsr.od.nih.gov/guidelines/belmont.html.)
33 European Medicines Agency Committee for Medicinal Products for Human Use. Guideline on the evaluation of medicinal products in the treatment of primary osteoporosis. (http://www.ema.europa.eu/pdfs/human/ewp/55295enfin.pdf.)
34 Al-Khatib SM, Califf RM, Hasselblad V, Alexander JH, McCrory DC, Sugarman J. Medicine: placebo-controls in short-term clinical trials of hypertension. Science 2001;292:2013-2015
35 Tanne JH. FDA puts restrictions on an institutional review board after secret investigation. BMJ 2009;338:b1618-b1618
36 Boers M. EMEA guidelines for trials in osteoporosis: design implications. Neth J Med 2002;60:310-314
Additional trials that considered it unethical to NOT give Vitamin D
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- Why many vitamin D trials fail to find benefits - Nov 2016 unethical is 1 of the 12 reasons
- Ensure a healthy pregnancy and infant with as little as $20 of Vitamin D Vitamin D has proven so successful that some researchers have decided that it is no longer ethical to not give vitamin D during every pregnancy.
- Vitamin D Random Controlled Trials are becoming impossible
- Is it ethical to not give vitamin D in osteoporosis trials– NEJM Sept 2010
- Proof that Vitamin D Works 93 proofs as of July 2022
- In 16 of the proofs ( 21%) vitamin D was given to all participants in 2017
- Search Google Scholar for UNETHICAL "VITAMIN D" 4,400 items in Google Scholar as of July 2022
Unethical to not give to Children
- COVID children helped by Vitamin D, trial terminated: unethical to not give Vitamin D to all: – RCT July 2022
- Autism rate in siblings reduced 4X by vitamin D: 5,000 IU during pregnancy, 1,000 IU to infants – Feb 2016 vitamin D given to all, unethical otherwise
- Growing pains reduced 57 percent by vitamin D therapy – May 2015
- vitamin D given to all, it was unethical otherwise
- Unethical to restrict Vitamin D to half of the asthmatic children in randomized controlled trial – June 2018
There have actually been
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