Scientific Web Editor Blog

Open Access Turns to the Dark Side

Mon, 06 May 2013 18:44:49 +0000

In a recent article, Gina Kolata, a science reporter for the New York Times (1), writes about a disturbing new development in science, the rising number of predatory publishers and for profit conferences that masquerade as legitimate scientific enterprises. These are journals and conferences that are organized for what appears to be the sole purpose of generating profits for their publishers or conference organizers. Often they originate in third world countries and create titles for their enterprises that mimic or even plagiarize established scientific endeavors. Their goal is to dupe scientists into submitting articles or agreeing to be part of conferences and then charging unwitting applicants large fees to publish or present their work in venues that have little scientific credibility. Their business plan is similar to that of many Internet scam artists. They use email to send unsolicited spam to large numbers of legitimate scientists in the hope that a several will respond.

In the case of predatory journals, once a recipient of these emails submits a manuscript, it frequently receives, at most, a cursory review before it is almost automatically accepted for publication. However, after articles are published, unwitting authors find out that they are being charged extremely high fees for this privilege. All of these pseudo-journals use a web-only open access format since this is relatively inexpensive for their “publisher” to maintain. One source quoted in the New York Times article believes that at least a quarter of all open access journals are predatory. Often these journals solicit legitimate scientists to be part of their bogus editorial boards so that they can use their professional standing to lend credence to their real purpose of maximizing profits. Hence, academics need to be wary of unsolicited requests for their participation in editorial boards that are easy to join and almost impossible to leave.

Similarly, unsolicited requests to be part of conferences with unclear origins and dubious organizers should set off “red flags”. Scientists need to be concerned that such conferences are solely designed to enrich the conference organizers rather than advance the frontiers of science.

Jeffery Beal, a research librarian at the University of Colorado in Denver (2), has established a web site that catalogs many of these predatory publishers. He also lists criteria that authors should be concerned about when considering submitting an article to an on line “open access” journal. These include being certain that the editor and staff are reputable, the publisher has goals of advancing science and not just generating profits from the fees charged to the authors and, most importantly, the journal publishes articles of high scientific content.

Joe Lorenzo,
Farmington, CT USA

How Much Calcium And Vitamin D?

Wed, 27 Mar 2013 14:40:36 +0000

Calcium is vital for bone health and normal physiologic function. Hence, its consumption in the diet is important, as is an adequate level of vitamin D, which aids in calcium absorption. To address the issue of what constitutes adequate dietary calcium and vitamin D intake, the Institute of Medicine (IOM) issued guidelines in 2010 (1) that recommended a daily intake of calcium for most adults of 1000 to 1200 mg per day and vitamin D of 600 to 800 IUs per day. A variety of foods are good sources of dietary calcium. These include dairy products, sardines and dark leafy green vegetables like spinach, kale, turnips, and collard greens. Vitamin D is, strictly speaking, not an essential nutrient since it can be made from sunlight in the skin. However, there remains a significant fraction of the population with inadequate circulating levels of 25 (OH) vitamin D (the major circulating metabolite). Because calcium intake from food in many diets is below the IOM recommendations, many health care providers have advised their patients to take calcium and/or vitamin D supplements to maintain bone health. However, recent data have argued that there are side effects of daily calcium supplement intake with or without vitamin D and have also questioned the utility of their intake for preventing fragility fractures.

Therefore, there exists great concern among health care professionals as to what forms and doses of calcium and/or vitamin D are appropriate. This topic has been the subject of several of my previous blogs but recent published data and a position paper by the United States Preventive Services Task Force (USPSTF) suggests a need for me to write about it again.

The USPSTF is an independent panel of non-Federal experts in prevention and evidence-based medicine. Its recent report on vitamin D and calcium supplements to prevent fractures (2) stated the following: 1) The current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men, 2) The current evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with greater than 400 IU of vitamin D3 and greater than 1,000 mg of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women and 3) The USPSTF recommends against daily supplementation with 400 IU or less of vitamin D3 and 1,000 mg or less of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women.

These recommendations were based on a review of the available literature. The USPSTF was particularly influenced by the results of the Women’s Health Initiative clinical trial (3). This study examined 36,282 postmenopausal women, 50 to 79 years of age. Participants were randomly assigned to receive 1000 mg of calcium as calcium carbonate with 400 IU of vitamin D₃ daily or placebo. Fractures were ascertained for an average follow-up period of 7 years. It found that in healthy postmenopausal women, calcium with vitamin D supplementation resulted in a small (6%, p<0.01) improvement in hip BMD, did not significantly affect fracture incidence, and increased the risk of kidney stones by 17% (CI, 1.02 to 1.34).

There also continues to be a concern that calcium supplements with or without vitamin D can increase cardiovascular events (4). In 2012 Bolland et al (5) published a subgroup analysis of women in the WHI study who did not self-prescribe calcium supplements at baseline and found an increased risk of cardiovascular events associated with the use of calcium (1000 mg) and vitamin D (400 IU). However, Prentice et al (6) also reviewed the WHI clinical trial data for women not taking calcium supplements at baseline and included data from the WHI observational study of 93,676 post-menopausal women in their assessment of the benefits of calcium and vitamin D. These authors concluded, “Long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women”. They also failed to identify a correlation between calcium intake and cardiovascular events. Hence, for the doses of calcium and vitamin D used in the WHI the conclusions of multiple studies are conflicting. However, there is stronger evidence for a significant risk associated with higher doses of calcium supplements than those used in the WHI. A study by Michaelsson et al (7) recently found that doses of calcium greater than 1400 mg/day correlated with higher death rates from all causes and from cardiovascular disease excluding stroke.

So what should health care providers recommend to their patients? Both the ASBMR (8) and National Osteoporosis Foundation (9) have issued responses to the USPSTF. The ASBMR points out that: “The USPSTF’s recommendations differ from the 2010 Institute of Medicine’s (IOM) findings, primarily because the USPSTF recommendations are based only on fracture outcomes, while the IOM included an examination of the underlying biology of the impact of calcium and vitamin”. Both organizations suggest that the best source of calcium is food and supplements should be taken only to compensate for shortfalls in the IOM recommendations. They also suggest that vitamin D supplements may be needed to achieve the recommended intake. Finally, the ASBMR was concerned that the USPSTF’s recommendations do not apply to institutionalized elderly who are at high risk for osteoporosis or to patients with established osteoporosis.

For patients with established osteoporosis it is reasonable to periodically examine serum 25 OH vitamin D levels and to supplement patients in order to maintain levels above 61 nmol/liter (~24 ng/mL) since this value is associated with a significant decrease in fracture incidence (10). However, there are also concerns about over-supplementation with calcium and vitamin D as intake greater than the IOM recommendations may be detrimental (1).

Joe Lorenzo
Farmington, Ct, USA

The Dilemmas of Science

Fri, 15 Feb 2013 19:43:35 +0000

I recently came across the editorial work of Ferric Fang and Arturo Casadevall through a profile in the magazine Science (1). They are well-known microbiologists and editors of publications for the American Society of Microbiology. In addition to their scientific contributions, they have authored a series of editorials and papers about the current state of science and the pressures that confront scientists. Some of their publications have explored the problem of scientific fraud and the stresses that many scientists feel to publish in high impact journals in order to better assure success in achieving grant funding and career advancement. Although not the first to do so, Fang and Casadevall found that there was a direct correlation between the rate that papers were retracted from a journal and the impact factor of that journal (2). In a publication with R. Grant Steen (3) in the Proceedings of the National Academy of Sciences of the United States of America, they reviewed 2,047 retracted biomedical and life-science research articles and found that 67% of retractions were attributable to misconduct, including fraud or suspected fraud (43%), duplicate publication (14%), and plagiarism (10%). While the actual number of papers that are retracted is very low (about 1 in 10,000), the impact of any scientific fraud is far reaching and includes much wasted effort and resources by other scientists in attempts to reproduce the fraudulent finding as well as a loss of confidence by the general public in the integrity of scientists. The latter point is particularly troubling since it is the taxpayers of most countries who provide the funds, which support the majority of research worldwide. Finally, they found that males commit the majority of scientific fraud and that senior scientists have the highest rate of fraud (4).

However, Fang and Casadevall also have written an editorial that outlines their vision of the steps that need to taken to improve the infrastructure of science (5). They point out that the primary issue, particularly in the United States, is inadequate funding. They state:

“Grant review panels are regularly forced to decide between competing highly meritorious projects. While some competition is inarguably good for science, excessive competition is demoralizing, destructive, and counterproductive. Funding agencies cannot continue to reject more than nine-tenths of grant applications without seriously damaging science. In the current climate, good ideas are going unsupported, opportunities are being squandered, and capable scientists are being lost.”

They are also critical of the “increasing emphasis on targeted funded research”. They point out that many novel therapies are the products of results from basic research that was performed without a clinical application for that research. An example they cite is the rapid development of anti-HIV medications, which relied on years of research into retroviruses that was performed when there was scant evidence that these agents caused human diseases.
Other areas that need to be addressed are the failure to adequately promote women and minorities in science and the increasing administrative burden imposed on scientists by regulatory agencies.

However they are most critical of the current peer review process. They state:
“Review panels are able to accurately identify bad science but have a poor record of distinguishing highly innovative work or work that challenges existing dogma. Reviewers can be counted on to identify the top 20 to 30% of grant applications, but identifying the top 10% is impossible without a crystal ball or time machine.”

They list a variety of solutions for these ills. Foremost among them is a demand for a system that provides more stability for the funding of science. They also deem it critical that basic research be recognized as an essential element of science. They cite articles that indicate that there are diminishing returns in the efficiency of a laboratory after it exceeds a critical size and suggest that it may be better to limit the size of any one investigator’s funding to maintain labs at optimum size. Finally, they ask that a careful evaluation of the current regulatory burden on scientists be performed and that the scientific method itself be used to best determine how science should be structured to enable it to generate the greatest benefits for all of us.

Joe Lorenzo
Farmington, CT, USA

The Year in Review

Wed, 02 Jan 2013 15:33:33 +0000

As 2012 fades into memory, it is a good time to reflect on events of the past twelve months that influenced to our field. As is typical, the past year brought both high and low points. The best news is that our Society continues to be strong. Both our Annual Meeting and Journal remain the leaders of their respective categories and our membership is strong. In addition, the last twelve months brought exciting new advances in both clinical and basic research related to diseases of bone and mineral metabolism. However, there are also a number of challenges to the continued advancement of our field. Perhaps the most difficult issue is uncertainty about funding for scientific research. For most scientists, the majority of their financial support comes from national governments. However, in most developed countries the economic slowdown that occurred after the global financial crisis of 2008 has put a significant strain on the treasuries of national government and this, in turn, has affected the research budgets of the government agencies that fund science. While global economies continue to recover slowly, uncertainty about research funding will likely remain with us for at least in the near future. This affects all scientists but is most challenging for junior investigators, who have yet to establish a track record of accomplishments and hence, are more vulnerable to the vagaries of research support.

This year brought advancement in our ability to identify those individuals who are at the greatest risk for developing osteoporosis. We found new risk factors for future fractures, like serum sclerostin levels, and made progress developing high resolution imaging technologies for bone. These make it hopeful that we will soon be able to better decide whom and when to treat patients to prevent osteoporotic fragility fractures. However, the elusive concept of “bone quality” remains to be measured in a way that will allow health care providers to identify individuals with modest decreases in bone density who are most likely to develop fragility fractures.

In basic science we continue to identify new factors and mechanisms that affect bone cell function. Advances in our understanding of the genetic code and its epigenetic modification have greatly advanced our perception of normal bone physiology and the derangements that produce clinical diseases. Perhaps no advance will more affect our field than the rapid increases in our ability to sequence the genome and identify specific polymorphisms in DNA that link to disease states. With the surprising discovery that up to eighty percent of the genome is active and many different forms of non-coding RNA play a significant role in controlling gene expression, it is becoming apparent that defining the sequences that cause specific genetic diseases like osteoporosis or Paget’s disease requires a full interrogation of the entire genome. As we advance in our appreciation of the links between genetics and functions of bone, it is almost certain that areas of the genome, which are remote from those coding proteins, will have significant effects on the development of bone diseases.

Next year holds additional hope for advancement in our field. At least one new therapeutic for osteoporosis appears to be near final review and others are in the late stages of development. Additionally, new areas of research that combine studies of bone with studies of muscle or immune cells promise to provide a more integrated approach to understanding the skeleton and may lead to a better appreciation of bone physiology and the mechanisms of skeletal diseases.

Joe Lorenzo,
Farmington, CT, USA

Male Osteoporosis

Tue, 27 Nov 2012 19:41:41 +0000

Male osteoporosis is a significant clinical problem that is often not diagnosed until patients suffer a fragility fracture. Approximately 20% of the 44 million Americans with osteoporosis (defined as a DXA bone mineral density T-score below 2.5) are men (1). However, men disproportionately account for 30-40% of the osteoporotic fractures (1-2). In addition, mortality rates in men with hip fractures are two to three times greater than in women (3) and this difference increases with age (2). Hence, improvements in the diagnosis and treatment of men at high risk for osteoporosis would significantly improve both their quality of life and overall healthcare costs.

The risk factors for the development osteoporotic fragility fractures in males include: age, race, bone mineral density, alcohol consumption, smoking, corticosteroid use, a history of a prior fragility fracture within the past year, a family history of fragility fractures, a history of a fall within the past year and hypogonadism. Both the Endocrine Society and the National Osteoporosis Foundation recommend that all men over 70 undergo screening for osteoporosis by DXA (4-5). This is because epidemiologic data clearly demonstrates that the overall risk of a fragility fracture in men is significantly increased after this age (6). In addition, DXA screening should be performed on younger men if additional risk factors are present.

As in any patient being evaluated for osteoporosis, a careful history and physical are essential. In addition, serum 25 OH vitamin D levels and screening studies to rule out undiagnosed hyperparathyroidism or hematologic malignancy should be performed.

Approved pharmacologic therapies for male osteoporosis include a number of the available bisphosphonates, as well as denosumab and teriparatide. It is also interesting to speculate about the potential role of a selective estrogen receptor modulator (SERM) in male osteoporosis (7). In both men and women estrogens mediate the majority of the effects of sex steroids on bone mass (7). In males, aromatization of androgens to estrogens is critical since men who lack the enzyme for this conversion have a syndrome of low bone mass that is responsive to estrogen therapy (8). Hence, SERMs, which selectively mimic the effects of estrogen on bone but not on some other tissues, may have utility for the treatment of male osteoporosis. However, currently, no SERM is approved for this condition.

The use of androgens for treating male osteoporosis is more controversial. Profound hypogonadism produces significant symptoms. Therefore, androgen replacement therapy is indicated for this condition. However, testosterone levels in men generally decrease with age and there have been inconsistent effects on bone mass of androgen replacement therapy in an elderly population with mild androgen deficiency (7).

In summary, male osteoporosis is a condition that health care providers should be more aware of since early intervention in appropriate high-risk individuals can significantly decrease fracture rates, improve patients’ quality of life and lower overall health care costs.

Joe Lorenzo
Farmington, CT, USA

Mentorship

Wed, 17 Oct 2012 14:34:48 +0000

Probably no function that a scientist performs is more important than being a mentor for trainees. Science is taught primarily by apprenticeships rather than by classroom learning. Graduate students and post-doctoral fellows who are pursuing a career in basic science need hands-on training in the laboratory to master the techniques of modern science. They achieve this by working on a project under the close supervision of a mentor. Similarly, students who are developing an academic career in clinical research need to be in highly supervised environments where their activities can be observed and directed.

There are many elements to becoming a successful researcher. Probably foremost is the desire by the student to succeed. One needs “a fire in the belly” to do this job, which is a fundamental trait that can’t be taught. Part of a mentor’s job is to counsel trainees to have patience and perseverance when their career might not be progressing as rapidly as they would like. Scientific experiments often don’t work as planned. Clinical researchers continually battle with the problems of recruiting subjects and maintaining subject compliance with a study’s guidelines. Papers don’t always get a favorable review and grants don’t always get funded. Any one of these setbacks can be disheartening to a trainee with little experience in science. It is the job of a mentor to give perspective to these events as they inevitably befall a young scientist. Experiments can be revised, subjects contacted and encouraged to continue in a study and papers and grants can be rewritten and resubmitted.

Probably the most important role of a mentor is to teach students how to think like a scientist. Students need to learn how to frame scientific questions as well-defined and testable hypotheses. They also need to comprehend how to devise experiments or clinical studies in a way that gives relatively unambiguous answers. Both basic science experiments and clinical studies need proper controls that account for all the variables of an experimental plan. Trainees also need to appreciate the importance of appropriate statistical testing. Studies must be structured so that their outcome and conclusions are statistically sound. Finally, students have to appreciate the intricacies of any scientific technique. Experiments have limits regarding the ability their outcome to support a scientific hypothesis. This primarily results from the limits of our technologies and scientists must understand these limits.

Patience is a virtue in science, which is necessary because scientific questions often require many months or years to answer. It is sometimes difficult for trainees to understand that progress in science often moves slowly; sometimes glacially.

For mentors the rewards are very similar to that of parenting. Students progress and go on to independent careers. Trainees become mentors and science advances.

Joe Lorenzo
Farmington, CT, USA

ENCODE, the Genome and Genetic Disease

Wed, 19 Sep 2012 18:33:06 +0000

The mysteries of the human genome are slowly being unraveled. Since shortly after the discoveries of Watson and Crick, it has been known that DNA uses a 4 base code alphabet to encode the information for assembling proteins. However, it was not until the complete sequencing of the human genome (roughly three billion base pairs of DNA) over 10 years ago that we became aware of how little of our genetic code is directly involved in protein coding. Current estimates are that roughly 3 percent of our genetic information is dedicated to coding for between 20,000 and 25,000 genes. So what is the rest of the genome doing? Up until recently, the answer from most scientists would have been nothing and this inter-coding sequence was often called “junk” DNA. However, a consortium of international scientists named ENCODE (Encyclopedia of DNA Elements) has recently released a torrent of papers (6 in Nature, 18 in Genome Research, 4 in Genome Biology and 1 in BioMed Central) that radically alters our understanding of the regions of DNA in our genome that do not directly code for proteins. Full access to this work is available here. ENCODE, is a project funded by the National Human Genome Research Institute of the US National Institutes of Health, involving 440 scientists from 32 laboratories around the world. Its goal is to identify all regions of transcription, transcription factor association, chromatin structure and histone modification in the human genome. Thanks to the results of this effort, we now know that, rather then containing inactive “junk”, up to 80% of the components of the human genome have at least one biochemical function.

This new data demonstrates that the majority of the genome is involved in regulating the activity of the 3 percent of DNA that directly codes for proteins. One surprising fact of the work is that up to 75 percent of the genome is transcribed into RNA in some cell system. It is the function of non-coding RNA sequences that is the least well understood. We are aware that some of these RNAs such as ribosomal, transfer and micro-RNA have roles in regulating levels of coding RNA and in protein translation but what about the other forms? It is an ongoing area of research to understand all the functions of non-coding RNA. The ENODE project also confirmed the importance of understanding the three dimensional structure of chromatin. During interphase, over 10 feet of DNA is packaged in tightly wound coils around histone proteins to form chromatin in the nucleus. We have known for years that transcription factor proteins bind to regions in the promoters of protein coding genes to activate transcription (RNA synthesis of the gene). It has now become clear that DNA in adjacent loops, which may be thousands of base pairs up- or down-stream from the promoter region of a gene may lie contiguous to the promoter in the folded chromatin. These contiguous elements are now known to act as additional targets for transcription protein binding and transcriptional activation. Hence, studies of transcriptional regulation need to involve relatively large stretches of DNA sequence to identify all the regulatory elements of a gene.

In terms of disease that involve a large genetic component, such as osteoporosis, these new studies emphasize the importance of studying the entire human genome to identify polymorphisms in the genetic code that predispose to disease. Studies that correlate results from whole genome sequencing of populations with disease incidence are just beginning. Advances in high-speed sequencing of DNA and computerized bioinformatics now make such studies economically feasible. I suspect that over the next 10 years because of these advances, we will understand much more about the intricacies of genomic DNA and how it relates to diseases like osteoporosis.

Joe Lorenzo,
Farmington, CT, USA

Making the First Fracture the Last Fracture

Wed, 15 Aug 2012 14:57:03 +0000

Osteoporosis is a common disease. One study in the United Kingdom estimated that the lifetime risk of any fracture after age 50 was 53% for women and 21 % for men (1). However, identifying which individuals will develop fractures is an imperfect science. The analysis of who is at risk relies, for the most part, on measurements of bone mineral density, typically by DEXA, and assessment of additional risk factors, including but not limited to: age, family history, medication history and the level of circulating sex steroids or the age when these were lost. However, no event is more definitive in demonstrating the presence of osteoporosis than the development of a fragility fracture, which is roughly defined as a fracture that is unlikely to occur under similar conditions in a healthy young adult. The advantages of intervention in this condition are multiple. Patients who are appropriately diagnosed and treated after a fragility fracture markedly decrease their risk for subsequent fractures (2). This, in turn, dramatically improves the quality of life for the patient and also significantly decreases health care costs.

Hence, one would expect that in an ideal world it would be routine for patients with a suspected fragility fracture to be investigated for the presence of osteoporosis and, if they are found to have this condition, recommended for treatment and follow-up assessment. Unfortunately, we do not live in an ideal world. Currently, it is estimated that less than one third of individuals with a fragility fracture receive appropriate diagnosis and therapy (3). In order to address this clinical dilemma the ASBMR established a Task Force on Secondary Fracture Prevention, which has now reported on what steps should be taken to correct this problem (4). The Task Force focused on reducing the risk of hip fractures by 20% in the next eight years since these “carry the greatest morbidity and mortality and are the most costly”. Furthermore, they state “Initiatives to prevent secondary fractures should be offered to all men and women over age 50 years with any fragility fractures, because all fragility fractures such as wrist fractures are often “sentinel” fractures that may precede a hip fracture in the cycle in which fracture leads to fracture.”

Chief among the committee’s recommendations is the routine adaptation in hospitals and other acute care sites of a Fracture Liaison Service (FLS) to act as a bridge between acute care providers (typically emergency physicians and orthopaedic surgeons) and clinicians who specialize in osteoporosis therapy (usually endocrinologists and rheumatologists). The FLS coordinator is frequently, but not inevitably, a nurse who interacts automatically with the patient shortly after a fracture occurs. The coordinator's role is to provide a care pathway, which ensures that clinicians evaluate patients with recent fragility fractures for the presence of osteoporosis, their future fracture risk, and their need for treatment.

The chief impediment to the broad utilization of FLS programs in most health care settings is the lack of a business model that can provide resources to support such a plan. The Task Force report outlines a number of key elements that illustrate how a FLS service can be financially justified. Chief among these are the cost savings that are inherent to the entire medical delivery system from the prevention of secondary fractures as well as the inherent benefits to the patient of avoiding the morbidity and possible mortality of a hip fracture. The report sites numerous instances around the world where such programs have been initiated and have succeeded in both increasing the incidence of appropriate treatment after fragility fractures and lowering the cost of health care. Based on the excellent arguments in the report, it seems obvious that instituting such programs broadly should be an imperative for all modern health care systems.

Joe Lorenzo

Farmington, CT U.S.A.

Vitamin D Supplements and the Risk of Fractures

Mon, 16 Jul 2012 13:51:42 +0000

Vitamin D is essential for the maintenance of bone health. However, its role in the prevention of osteoporotic fractures has been controversial. Previous published trials have been inconsistent in their results. Now Bischoff-Ferrari et al (1) have performed an extensive meta-analysis of 11 previous double blind, randomized placebo controlled trials of vitamin D supplementation, encompassing 31,022 participants. These involved people 65 years of age or older (predominantly women) in which vitamin D supplementation (with or without calcium) was compared to a control (non-treated) group. Significantly, these authors obtained the primary data from the original studies and estimated the actual amount of vitamin D that each participant consumed. They then divided treated participants into four quartiles depending on the amount of actually consumed vitamin D. The primary end points of the meta-analysis were the risks of hip fracture and nonvertebral fracture. The authors also performed additional tests of their data, including a sensitivity analysis, which excluded additional supplemental doses of vitamin D that were outside those of the study protocol from the calculation of actual intake, and an internal validation analysis, which compared the highest quartile of actual intake of vitamin D with the lowest quartile, regardless of the randomized study-group assignment. For the primary analyses, one analysis for hip fracture and one analysis for nonvertebral fracture was performed in which all quartiles of actual intake of vitamin D were compared to the control group. Because of the potential for false positive results due to multiple testing, a P value of 0.0125 was used to indicate significant differences between the treated and control groups.

An intention-to-treat analysis, which analyzed all participants entering the trial regardless of whether they finished, demonstrated a nonsignificant reduction in the risk of hip fracture with vitamin D supplementation (hazard ratio = 0.90; 95% confidence interval [CI] = 0.80 to 1.01), which did not differ according to assigned treatment dose. However, when the authors performed an actual intake analysis of the quartile treated with the highest dose of vitamin D (792 to 2000 IU/ day, median = 800 IU/day), they found a significant (30%) reduction in the incidence of hip fractures compared to the controls (HR = 0.70, CI = 0.58-0.86). Similarly, the actual intake analysis demonstrated a 14% decrease in nonvertebral fractures (HR = 0.86, CI = 0.76–0.96) in subjects consuming the highest dose of vitamin D compared to the controls. These results were confirmed by both the sensitivity analysis and the internal validation analysis.

The authors also performed a subgroup analysis of 4383 subjects for whom baseline 25 hydroxy-vitamin D measurements were available. This suggested a dose response relationship between the risk of fracture (either at the hip or nonvertebral) and the quartiles of baseline vitamin D. In addition, individuals with vitamin D levels at entry of 61 nmol/liter (~24 ng/mL) or greater had a risk of hip fracture that was reduced by 37% (HR = 0.63; CI = 0.46 to 0.87) and a risk of nonvertebral fracture that was reduced by 31% (HR = 0.69; CI = 0.57 to 0.84). Finally, pooled subgroup analyses of eight trials that used vitamin D combined with calcium indicated that the risk of fracture was reduced only in the group that was treated with the highest actual-intake level of vitamin D. In addition, at the highest actual-intake level of vitamin D, there was the suggestion that calcium supplementation of less than 1000 mg per day was more beneficial in reducing the risk of fracture than calcium supplementation of greater than or equal to 1000 mg per day.

Limitations of this analysis are the lack of follow-up measurements of serum 25 hydroxyvitamin D during treatment to assess the ability of supplements to raise this value or correlate treatment serum 25 hydroxyvitamin D values with fracture risk. In addition, all of the trials that were analyzed lacked a group that treated subjects without calcium but with the highest doses of vitamin D (up to 2000 IU/day). However, the data do demonstrate that supplementation with vitamin D of at least 800 IU per day as recommended by the most recent Institute of Medicine report (2) appear to be beneficial for reducing the risk of osteoporotic fractures. Finally, they argue that values of 25 hydroxyvitamin D of 60 nmol/liter (24 ng/mL) or greater are desirable to prevent fractures.

Joe Lorenzo,
Farmington, CT USA

Calcium Supplements and Cardiovascular Risk

Tue, 05 Jun 2012 14:58:06 +0000

The association between the use of calcium supplements and the development of cardiovascular disease in individuals without renal failure has been a topic of much controversy and the subject of a number of my blogs (1, 2, 3). Originally identified by Bolland et al (4), this association has been seen in a number of additional studies from this group (5, 6). However, others in separate analyses have failed to confirm this effect (7, 8). Last year the Professional Practice Committee of the ASBMR published a position paper on this topic (9) and decided that: “…the weight of evidence is insufficient to conclude that calcium supplements cause adverse cardiovascular events; however, the debate continues.”

Now a study from Li et al (10) has examined data from almost 24,000 individuals in Germany who were part of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. In this study participants between the ages of 35 and 64 years old, who were without known cardiovascular disease, were recruited and followed for an average of 11 years. Detailed records of food intake were obtained at baseline and periodically thereafter, using a food frequency questionnaire. In the analysis of the results individuals were divided into quartiles based on total calcium intake (food + supplements) normalized to total food caloric intake (2200 kcal for men and 1700 kcal for women). These broke down into mean total calcium intakes of 513, 675, 820 and 1130 mg/day, respectively for quartiles 1 through 4. The analysis was also divided into a comparison of individuals who used calcium supplements and those who did not. Cardiovascular events were reported by participants or their next of kin in follow-up surveys and verified from medical records or official death certificates. Compared with non-users, users of calcium supplements were more likely to be women, physically more active and less likely to be overweight/ obese. Users of calcium supplements were also older, had an overall lower educational level and a longer duration of smoking.

In the analysis of participants that was based on total calcium intake it was found that, after adjustment for potential confounders including age and smoking history, a statistically significant inverse association existed between total dietary calcium intake and myocardial infarction (MI) risk for the comparison of the third quartile with the first (HR=0.69; 95% CI 0.50 to 0.94). However, this was not true for comparisons between any other quartiles. These results argue that moderate calcium intake is somewhat protective for cardiovascular risk compared to low calcium intake. However, the study found vastly different results when the group on calcium supplements was compared to those who did not use them. In this analysis, after adjustment for potential confounders, users of calcium supplements had a statistically significantly increased MI risk (HR=1.86; 95% CI 1.17 to 2.96), which persisted after MI cases that occurred in the first 2 years of follow-up were excluded (HR=2.70; 95% CI 1.26 to 5.79). There were no associations of total calcium intake or the use of calcium supplements with the risk of stoke or with cardiovascular mortality.

The results of this study are provocative but far from definitive. Concerns center around the relatively low number of MI events in the calcium supplement groups (7 in the group that just took calcium supplement). There are also concerns about the accuracy of the food frequency questionnaire and the lack of the ability of this study to do any dose response analysis for calcium supplements because of the nature of the data gathered in the questionnaire. However, the results do raise concerns. In view of the failure of any study so far to find a detrimental effect on cardiovascular health of calcium in food, it is probably prudent for medical providers to emphasize this form of dietary calcium over calcium supplements, whenever feasible.

Joe Lorenzo
Farmington, CT, USA