Are the Benefits of Vitamin D Overhyped?

2 Studies Find Little Evidence That Vitamin D Prevents Heart Disease or Cancer

 Another day, and another vitamin has failed to live up to all of its hype. This time it’s vitamin D.

The reality check is coming from two new research reviews published in the Annals of Internal Medicine.

The reviews, which looked at hundreds of previous studies of the “sunshine vitamin,” conclude that there’s little evidence that vitamin D protects against cancer or heart disease.

They also show that vitamin D doesn’t prevent fractures when it’s taken alone. Pairing vitamin D with extra calcium does appear to help prevent broken bones in the elderly, however.

“For many years, the enthusiasm for vitamin D has outpaced the evidence,” says JoAnn Manson, MD, DrPH, who heads the division of preventive medicine at Brigham and Women’s Hospital in Boston.

“The evidence is actually fairly thin,” especially for any benefits beyond bone health, she says.

To help fill the knowledge gap, Manson is mounting a nationwide trial that will test vitamin D and fish oil for the prevention of heart attacks and cancer. She was not involved in the reviews.

Is Vitamin D a Dud?

In recent years, vitamin D has been touted as a nutritional superstar.

Beyond its well-known role as a bone builder, studies have suggested that high levels of D, usually achieved by taking supplements, may do everything from reducing chronic pain to preventing the common cold.

At the same time, other reports have found that as many as half of all adults have less than ideal blood levels of D.

That has sent sales of vitamin D blood tests and supplements soaring.

But experts say science doesn’t yet support the use of the high doses that many people may be taking.

Last year, the Institute of Medicine increased the recommended dietary allowance (RDA) of vitamin D for children and adults ages 1-70 to 600 international units (IU), and adults over 70 to 800 IU. But the agency also said many people already get that much from sun exposure and from foods like fish and fortified dairy products.

But the promise of D is so powerful that many policy makers continue to consider emerging evidence.

The latest is the U.S. Preventive Services Task Force, which is set to update its recommendations on vitamin D for cancer and fracture prevention in January. They commissioned one of these two new evidence reviews.

Vitamin D, Cancer, and Fractures

For that review, researchers at Tufts University reanalyzed data from more than 40 studies on vitamin D.

They set out to answer several key questions:

  • Does vitamin D, taken with or without calcium, affect the risk for cancer or broken bones?
  • Are high or low blood levels of vitamin D linked to a person’s risk for cancer or broken bones?
  • Are there harms linked to taking extra D?
  • Among several studies of vitamin D taken alone or with calcium, researchers say a high degree of statistical uncertainty made it impossible to tell whether taking supplements increased or decreased the risk of cancer.
  • With respect to fractures, data from five other studies showed that vitamin D supplementation alone, in doses ranging from 400 to 1,370 IU daily, did not appear to reduce the risk of breaking a bone.
  • That picture changed when calcium was combined with vitamin D.
  • Across 11 studies of more than 52,000 people who were followed from one to seven years, those taking 300 to 1,000 IU of vitamin D each day, along with 500 to 1,200 milligrams of daily calcium, saw their risk of breaking a bone drop by an average of 12% compared with those taking a placebo.
  • To answer the second question, researchers relied on studies that looked at the relationship between blood levels of vitamin D and the risk for breast, prostate, colorectal, or any kind of cancer.
  • There was some evidence that higher blood levels of vitamin D might protect against colon cancer. But there was no evidence that having a higher vitamin D level could protect a person against breast or prostate cancer.
  • In fact, some studies suggested that men who had higher levels of D had an increased risk for cancer death. The same did not appear to be true for women.
  • Other possible harms included an increased risk for kidney stones and bladder stones seen in one study among women taking vitamin D supplements.
  • In the second review, Irish researchers looked at the connection between vitamin D and heart health.
  • They found biological evidence that vitamin D is linked with heart and blood vessel health. For example, vitamin D regulates hormones that affect blood pressure. It also controls blood calcium levels. Calcium helps keep muscle cells working smoothly.
  • But trials that have put vitamin D supplementation to the test for heart disease prevention haven’t panned out, they say.
  • The studies that look at the effect of vitamin D supplementation on heart disease and stroke risk “have been inconclusive or contradictory,” says Cora McGreevy, MBBCh, a clinical lecturer at the Royal College of Surgeons in Dublin, Ireland, in an email.
  • McGreevy says vitamin D may simply turn out to be a sign of other health problems that put a person at risk for heart attacks and strokes.
  • Until more is known, “vitamin D cannot be recommended as a treatment for [heart disease and stroke],” she says.
  • Bottom line: Even though there are some promising signs for vitamin D, there is not enough scientific evidence yet to show that taking vitamin D supplements will “prevent” heart attacks and strokes, Manson says.

·         Vitamin D and Heart Disease


Dexpramipexole in ALS: Cautious Optimism

Results of a phase II trial of dexpramipexole in patients with ALS not only suggest that the drug is safe and well tolerated but also hint that it may slow disease progression.

The only pharmacological agent proven to slow disease progression in amyotrophic lateral sclerosis (ALS) is riluzole, and its efficacy is quite modest, prolonging survival on average by only 2 to 3 months. Given this somewhat bleak background, the recently reported results of a phase II trial of dexpramipexole, a putative mitochondrial modulator, are of particular interest to patients with ALS and the neurologists who provide their care. This multicenter trial proceeded in two parts. In part 1, 102 patients were randomized to receive placebo or dexpramipexole at 50 mg, 150 mg, or 300 mg per day for 12 weeks. In part 2, after 4 weeks of drug washout, 92 patients were available for re-randomization to receive dexpramipexole at 50 mg or 300 mg per day for 24 weeks.

Overall, the drug was safe and well tolerated; the only notable adverse effect was reversible neutropenia in five patients. A hint of clinical benefit with dexpramipexole in the slowing of disease progression was observed on some outcome measures — e.g., median decline in ALS Functional Rating Scale–Revised (ALSFRS-R) scores was slower with 300 mg of dexpramipexole compared with placebo; and treatment failures, defined as a ≥6-point drop in ALSFRS-R score in part 1, were less frequent with 150 mg and 300 mg of dexpramipexole than with placebo. But no clinical benefit was found on other measures — e.g., slope of ALSFRS-R scores and slope of upright vital capacity.

Comment: Phase III trials in ALS have historically been motivated by evidence of efficacy in preclinical models combined with evidence of safety and tolerability in humans. Therefore, finding some suggestion of a clinical benefit in a phase II trial is both exciting and refreshing. The interest in and enthusiasm for further development of dexpramipexole as a potential therapeutic agent for patients with ALS has been evidenced by rapid recruitment for the ongoing phase III trial, the results of which are eagerly anticipated.

source: Journal Watch Neurology

Potential CF Therapy Kalydeco (VX-770) Available to People with Critical Medical Need

An expanded access program for a potential new CF drug, Kalydeco™ (VX-770), is now available at participating clinical sites throughout the country for people with the G551D mutation who have highly limited lung function and may benefit from treatment.

Vertex Pharmaceuticals, Inc., the maker of Kalydeco (kuh-LYE-deh-koh), created this program for patients while awaiting review of the drug by the U.S. Food and Drug Administration (FDA).

The company is seeking FDA approval for Kalydeco in people ages 6 and older with at least one copy of the G551D mutation.

People with CF who may be eligible for this program and want more information should talk to their CF doctor or call the Vertex Expanded Access Call Center at 1-800-745-4484.

Kalydeco is an oral drug in development that targets the underlying cause of cystic fibrosis. Kalydeco was developed by Vertex with CF Foundation support and research input.

Source:CF foundation/FDA


Denosumab Delays Development of Bone Metastases in Prostate Cancer

Denosumab recipients achieved a 4.2-month improvement in bone metastasis–free survival compared with placebo recipients.

Prostate cancer is a highly bone-tropic neoplasm, as illustrated by the near universal presence of bone metastases in men dying of the disease. Drug development for prevention of bone metastases has been focused largely on prevention or delay of skeletal-related events (SREs), which include pathologic fracture, spinal-cord compression, bone pain, and the need for radiation therapy or surgery in patients with castration-resistant metastatic disease. One agent that was found to be superior in delaying the time to SREs when compared to the bisphosphonate zoledronic acid is denosumab, a human monoclonal antibody that binds and inactivates RANK ligand (RANKL), which mediates the interaction between osteoblasts and osteoclasts.

To determine whether denosumab can delay the development of bone metastases in men with castration-resistant prostate cancer and no metastases, international investigators conducted an industry-sponsored, phase III trial involving 1432 such patients with evidence of prostate-specific antigen progression (PSA values 8.0 within 3 months before randomization or PSA doubling time 10 months or both) and castrate levels of testosterone (<50 ng/mL). Patients were randomized to receive subcutaneous denosumab (120 mg) or placebo every 4 weeks. The primary endpoint was bone metastasis–free survival or death from any cause; secondary endpoints included time to first bone metastasis and overall and progression-free prostate cancer survival.

The median time on study for denosumab and placebo recipients was 20.2 and 19.0 months, respectively. Denosumab recipients achieved a 4.2-month improvement in bone metastasis–free survival compared with placebo recipients as well as longer time to both first and symptomatic bone metastases. Median overall survival was similar between the denosumab and placebo groups (43.9 and 44.8 months), as were rates of the most common adverse events: back pain, constipation, arthralgias, diarrhea, and urinary tract infections. Osteonecrosis of the jaw occurred in 5% of denosumab recipients versus no placebo recipients.

Comment: The results of this clinical trial provide additional insight into the role of RANKL in prostate cancer bone metastases. As noted by an editorialist, the delay in time to metastases documented in this trial is similar to the delay in time to SREs reported in the aforementioned comparison of denosumab against zoledronic acid in men with metastatic castration-resistant prostate cancer without an effect on survival. This observation provides a rationale to suggest the optimal time for the use of this agent is at the time of bone metastases in the castrate setting.

Source: Journal Watch Oncology and Hematology


Cognitive reframing for carers of people with dementia

Dementia is primarily a disease of older people, particularly those over 80 years, and the prevalence is increasing. For example, nearly 8 million people in Europe have dementia and this is predicted to double by 2050. The costs to social and healthcare organizations and the impact on families are expected to escalate in the coming decades, and the identification of effective strategies to help the carers of people with dementia is a priority for governments and the health services.

There is good evidence that psychosocial interventions help caregivers of people with dementia, as well as delaying the need for their relative to enter an institution. These interventions involve multiple mechanisms of action but appear to be more successful when they are tailor-made and offer a choice of interventions. It is important, therefore, to try to identify the key elements within these complex approaches and this Cochrane Review, which was published in November 2011, brings together the evidence on one of these elements: cognitive reframing.

Cognitive reframing is a component of cognitive behavioral therapy (CBT) and seeks to change a person’s core beliefs about something. In dementia care, cognitive reframing interventions focus on the family carer’s maladaptive, self-defeating or distressing feelings about the behavior of their relative and about their own performance in the caring role.

Different theoretical models have been used in the development of cognitive reframing interventions and three models were used in the studies identified for this review: the stress coping model, the stress management model and the CBT model. The differences in the theories underlying these three approaches are minor, with CBT being the most structured model.

In the stress coping model, people faced with a stressor make two appraisals, referred to as the primary and secondary appraisal. The primary appraisal involves an assessment of how stressful or threatening the situation is. The secondary appraisal involves the person’s assessment of his or her ability to cope, including an assessment of personal and physical resources. This secondary appraisal is often equated to Bandura’s concept of self-efficacy. Once someone has appraised the situation, they then employs their coping skills. These can include emotion-focused approaches (for example avoidance, magical thinking), problem-focused strategies (changing behaviors), and utilization of social support systems. According
to the stress coping model, the application of coping skills results in an outcome that prompts new appraisals, sparks new applications of skills, and so on. In this way, coping is conceptualized not as a static event but as a process that unfolds in a cyclic pattern.

In the stress management model, treatment is oriented toward changing specific aspects of the carer situation that have been linked with carer stress, namely increasing their understanding of the patient’s disease, improving their management of problem behaviors,
and helping them to identify and use more informal and formal supports.

Interventions based on CBT typically include cognitive reframing as part of the intervention. In this context, the cognitive reframing element focuses on family carers’ maladaptive, self defeating or distressing feelings (cognitions) about their relatives’ behaviors and their own performance as a carer. It aims to alter these feelings directly, making them better adapted to the situation.

The balance of evidence about whether psychosocial interventions for caregivers of people with dementia could reduce carers’ psychological morbidity and delay their relatives’ institutionalisation is now widely regarded as moderately positive . Multi-component, tailor-made psychosocial interventions are considered to be particularly promising . These interventions involve multiple mechanisms of action. In this review we focused solely on the effectiveness of one element within psychosocial interventions, cognitive reframing. Cognitive reframing is a component of cognitive behavioral therapy (CBT). In dementia care, cognitive reframing interventions focus on family carers’ maladaptive, self-defeating or distressing cognitions about their relatives’ behaviors and about their own performance in the caring role.

Objectives:The objective of this review was to evaluate the effectiveness of cognitive reframing interventions for family carers of people with dementia on their psychological morbidity and stress.

Search Strategy The trials were identified by searching (5 April 2009) the Cochrane Dementia and Cognitive Improvement Group Specialized Register, which contains records from major healthcare databases: The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS, ongoing trial databases and grey literature sources. For more detailed information on what the Group’s specialized register contains and to view the search strategies see the Cochrane Dementia and Cognitive Improvement Group methods used in reviews.

Data collection and analysis Three assessors (MVD, ID, JmC) independently judged whether the intervention being studied was documented in a trial; two assessors assessed trial quality.

The authors of the Cochrane Review sought randomized trials in which carers of people with dementia had been randomly allocated to receive the cognitive reframing intervention or a different approach, conducting comprehensive searches in 2009. Six of the included studies used the CBT model, one used the stress management model and four used the stress coping model. In total, approximately 1500 family carers took part in the 11 randomised trials, the results of most of which were reported in the last decade.

It was not possible to include all of the studies in all of the meta-analyses because different studies reported different outcomes. However, pooling the findings of sub-sets of the studies revealed significant beneficial effects of cognitive reframing interventions on family carers’ psychological morbidity, including anxiety, depression and subjective stress. The meta-analysis of depression used data from 595 carers in 6 trials to produce a standardised mean difference (SMD) of -0.66 (95% confidence interval: -1.27 to -0.05) but with an I2 statistic of 93% indicating considerable statistical heterogeneity. This was due to one trial of 85 patients which had a particularly striking benefit. When it was removed from the meta-analysis the result remained statistically significant (SMD: -0.24; -0.42 to -0.07) and the I2 statistic fell to 0%.

The authors of the Cochrane Review conclude that their findings support the use of the general cognitive reframing model for the carers of people with dementia, suggesting that it may be an effective component of individualised, multi-component interventions for family carers.

Source:The Cochrane Library.


Poststroke Blood Pressure Affects Risk for Recurrent Stroke

Risk was elevated with low and high systolic BP.

Risk for a first ischemic stroke is generally proportional to the level of systolic blood pressure (BP), but optimal poststroke BP for prevention of recurrent stroke is less clear. To examine this issue, researchers conducted a post hoc analysis of data from a previously published secondary prevention study that involved about 20,000 patients (mean age, 66; two thirds men) with recent noncardioembolic ischemic stroke .

The original study addressed the role of various antiplatelet regimens, and BP was managed by investigators at their discretion. Patients were assessed several times during a mean follow-up of 2.5 years, during which the risk for recurrent stroke was about 8%. Compared with patients who had low-normal systolic BP (120–129 mm Hg), risk for recurrent stroke was elevated in patients whose mean systolic BP during the study was very low (<120 mm Hg; 29% relative increase), high (140–149 mm Hg; 23% increase), or very high (≥150 mm Hg; 108% increase); risk with high-normal systolic BP (130–139 mm Hg) was similar to that with low-normal BP. These analyses were adjusted for clinical and demographic factors.

Comment: These post hoc analyses are sufficiently strong to support a recommendation to maintain systolic BP in the normal range (120–139 mm Hg) –– but not lower — in stroke patients. However, rigorous prospective studies to confirm this conclusion are warranted.

source:Journal Watch General Medicine

French women ‘must have faulty breast implants removed’

French authorities are to ask all the 30,000 women who received a potentially defective type of breast implant to have them removed, reports say.

There are concerns that the implants supplied by Poly Implant Prothese (PIP) carry potential health risks, according to the newspaper, Liberation.

PIP was found last year to have used a non-authorised silicone gel that caused abnormally high implant rupture rates.

The French government has formed a special committee to look at the issue.

“We have to remove all these implants,” Dr Laurent Lantieri, a plastic surgeon on the committee, told Liberation. “We’re facing a health crisis, linked to a fraud.”

Government spokeswoman Valerie Pecresse told French television that a plan of action would be unveiled later this week.

“All women who have PIP implants should return to see their surgeons urgently,” she added.

Cancer fears

Investigations by the French Society of Plastic Surgeons last year found that PIP implants had a higher rate of rupture than other implants and that the silicone in them was not meant for medical use.

PIP went into administration last year and the use of its implants was banned.

Police have received 2,000 complaints from women who received the implants and have opened a criminal investigation into the firm, the AFP news agency reports.

Since the defects were discovered, 523 implants have been removed, according to the Le Monde newspaper.

Eight cases of cancer had so far been reported in patients with PIP implants, France’s Director General for Health, Jean-Yves Grall, told Liberation. A ninth patient in Gers died of cancer last year.

Mr Grall added that all costs related to the removal of the implants would be reimbursed, although it is not clear if this will extend to paying for replacement implants.

PIP implants were among the cheapest available, and were also exported outside France. It is thought that as many as 40,000 British women may have them.

The role of the endothelium in the short-term complications of hematopoietic SCT

In this review, we analyse the role of the endothelium in the development of several complications that appear soon after haematopoietic SCT (HSCT). Once it had been demonstrated that sinusoidal damage is the initiating event of the sinusoidal obstruction syndrome, it was considered that other short-term complications with overlapping clinical manifestations, such as capillary leak syndrome, engraftment syndrome, transplant-associated microangiopathy, diffuse alveolar haemorrhage and idiopathic pneumonia syndrome, could have an endothelial origin. During HSCT, endothelial cells (ECs) are activated and damaged by several factors, including conditioning, cytokines released by damaged tissues, endotoxins translocated through damaged mucosa, drugs used in the procedure, the engraftment, and—in the allogeneic setting—immunological reactions. The different clinical syndromes that occur could be determined by the predominant phenotypic change in the ECs and the location of this change (organ dependant or systemic). Several translational studies have provided evidence of this endothelial dysfunction on the basis of analysis of soluble markers, soluble forms of adhesion molecules, the enumeration of circulating ECs and microparticles, and morphologic and functional changes induced in cultured ECs. This increased knowledge has opened up a wide range of potential pharmacologic interventions to prevent or treat endothelial damage and, consequently, to improve the outcome of patients receiving HSCT.

Source:Bone Marrow Transplant

Micronutrient supplementation ‘may increase malaria risk.

A WHO recommendation to supply all iron-deficient children with micronutrient supplements has been called into question by a study that has found this may increase the risk of malaria.

Giving supplements containing iron, folic acid, copper and vitamins to more than 600 Tanzanian children — aged between six months and five years — with iron deficiency increased their likelihood of contracting malaria by 41 per cent, researchers found.

Supported by another study conducted in 2006 — which found that iron and folic acid supplements increased malaria-related hospitalisation and deaths by 12 per cent — the authors have concluded that, although more research is needed, iron could be responsible for the increased risk.

Although the overall incidence of malaria across the whole study was not affected, children given micronutrients contracted the disease for the first time earlier in their lives. Micronutrient supplementation was also linked with a greater number of malaria parasites in the blood of babies less than 18 months with severe malaria — but this effect reduced with age.

The results, published in PLoS Medicine last month (22 November), add to growing concerns that providing micronutrients —  which the WHO recommends for young children and pregnant women — may be doing more harm than good in malaria-endemic areas.

“For many parts of Africa, we caution against supplementation with vitamins and minerals other than zinc as there is considerable evidence that this can increase the risk of malaria,” Hans Verhoef, a researcher at Wageningen University, Netherlands, and the London School of Hygiene and Tropical Medicine, United Kingdom, and an author of the study, told SciDev.Net.

“This is a dilemma, because children and women are often deficient in these micronutrients,” he added.

The study also showed that zinc supplements have no effect on malaria rates, dashing hopes that it could provide an extra tool for fighting malaria.

Although the study calls into question the validity of the WHO’s recommendation, Verhoef agreed that a small amount of iron (less than is contained in the supplements) added to fortified foods may improve the health of women and children.

He added that women in malaria-prone areas should continue to take iron supplements during pregnancy but should also ensure that they receive antimalarials in accordance with guidelines issued by their governments.

But Elizabeth Juma, an epidemiologist for the Kenya Medical Research Institute, said that iron supplements should continue to be provided as they are important for combatting the anaemia that malaria often causes.

By only providing patients with iron supplements after the malarial symptoms have been treated, the reduction of the drugs’ effects could be avoided, she said.



Simple tools speed up quake warnings

Researchers have developed a new technique for quickly assessing the magnitude of large earthquakes, cutting down the time required in the case of the recent quake in Japan, for example, from about 20 minutes to just 2-3 minutes. Those crucial minutes would have helped with tsunami warnings and in making sure that even far-away communities like Tokyo had proper alerts as soon as possible, says Yehuda Bock of the University of California, San Diego, who developed the technique.

The strategy involves tying together real-time data coming from seismic instruments, which detect shaking, as well as Global Positioning System (GPS) instruments, which detect the absolute movements of the ground. Both devices are already installed in places such as Japan and California — the key is to ensure that they are delivering the right sort of data simultaneously, says Bock, who reported on his progress at the American Geophysical Union (AGU) meeting in San Francisco, California, on 8 December. Bock and his colleagues this month received funding to build and test a prototype upgrade device, and hope to have an initial system in place in California within six months.

Seismic instruments are very sensitive, but have a hard time discriminating between large quakes of magnitude 7 or higher in the first seconds or minutes of an earthquake, because the shaking simply goes off the scale. In the case of the March 2011 Tohoku earthquake in Japan, for example, the Japan Meteorological Agency estimated the quake’s magnitude as just 6.8 after 38 seconds, and 8 after a few minutes, says Bock. It was not until weaker seismic readings from much further away were added to the analysis that they could say, 20 minutes after the quake began, that it was a devastating magnitude 9 — 30 times stronger than a magnitude-8 quake.
Accelerometers add another layer of information, but their data take too long to process to be of use. GPS instruments are more useful. The station closest to the epicentre, for example, showed a 1.5-metre drop of the ground in the first 100 seconds of the quake. “That’s huge,” says Bock. This provides a quick and obvious indication of large vertical ground displacement — the thing that causes tsunamis — and can be combined with seismic data to quickly assess quake size. But most GPS networks were designed to provide long-term data about ground movement, not short-term information during earthquakes; they may be designed to take readings once every 30 minutes and deliver data once a day, for example. And they aren’t necessarily installed next to seismometers. Of Japan’s 1,200 GPS stations — all of which are real time — only 180 are close enough to seismic stations to be of use in this sort of system, and so far they haven’t been utilized this way.

“Japan’s earthquake system is one of the best in the world. But their GPS system, which is also the best in the world, is ignored,” says Bock. This is partly because flowing the data together and interpreting them is tricky, and partly because the seismic community hasn’t communicated much with the ‘geodesy’ community that works with GPS signals, says Bock. “There’s a separation between communities that we need to fix,” he says.

Likewise, the western United States has about 1,200 GPS stations, of which 600 transmit data in real time, but only a few dozen are next to seismometers. Adding a full seismometer to each GPS location would cost perhaps US$22,000 per station, says Bock. But he has worked out a cheap way to build and attach an accelerometer that would do the job for just a few thousand dollars. One prototype has been tested on a ‘shake table’, and they are now aiming to build and field test more. “We want to update as many areas as we can,” says Bock.

“It should work really well, where it works,” says Andrew Newman of the Georgia Institute of Technology in Atlanta. Only a few places have suitable GPS and seismic devices in place, he notes. And in some places, like island arcs, there isn’t enough land to install the needed arrays of instruments. Newman advocates the installation of GPS devices that can work underwater, although these would be much more expensive (see his Nature Comment piece, Hidden depths).

Hiroo Kanamori, a long-time earthquake researcher also at the AGU meeting, now retired from the California Institute of Technology in Pasadena, agrees that Japan’s earthquake warning system could be made better. “The technology exists; it just isn’t utilized,” he says.