WUSTL.edu – High-dose vitamin D relieves joint pain and muscle pain for many breast cancer patients taking estrogen-lowering drugs, according to a new study from Washington University School of Medicine in St. Louis.

The medications, known as aromatase inhibitors, are commonly prescribed to shrink breast tumors fueled by the hormone estrogen and help prevent cancer recurrence. They are less toxic than chemotherapy, but for many patients, the drugs may cause severe musculoskeletal discomfort, including pain and stiffness in the hands, wrists, knees, hips, lower back, shoulders and feet.

“About half of patients can experience these symptoms,” says Antonella L. Rastelli, MD, assistant professor of medicine and first author of the study published online in the journal Breast Cancer Research and Treatment. “We don’t know exactly why the pain occurs, but it can be very debilitating – to the point that patients decide to stop taking aromatase inhibitors.”

Because the drugs reduce cancer recurrence, finding a way to help patients stay on them is important for long-term, relapse-free survival, according to Rastelli. Aromatase inhibitors are prescribed to post-menopausal women for at least five years and often longer after a breast cancer diagnosis. There is some evidence that patients who experience the drugs’ side effects are less likely to see their cancer return, providing even more incentive to help these patients continue taking them.

It was Rastelli’s colleague, Marie E. Taylor, MD, assistant professor of radiation oncology, who first noticed that patients on aromatase inhibitors who experienced this pain found some relief from high doses of vitamin D.

So Rastelli’s group recruited 60 patients who reported pain and discomfort associated with anastrozole, one of three FDA-approved aromatase inhibitors. The patients they studied also had low vitamin D levels. Half the group was randomly assigned to receive the recommended daily dose of vitamin D (400 international units) plus a 50,000-unit vitamin D capsule once a week. The other half received the daily dose of 400 units of vitamin D plus a weekly placebo. All subjects received 1,000 milligrams of calcium daily throughout the study.

Patients in the study reported any pain they experienced through three different questionnaires. They were asked to quantify their pain intensity, as well as report how much the pain altered their mood, affected their work and interfered with relationships and daily activities. The results show that patients receiving high-dose vitamin D every week reported significantly less musculoskeletal pain and also were less likely to experience pain that interfered with daily living.

“High-dose vitamin D seems to be really effective in reducing the musculoskeletal pain caused by aromatase inhibitors,” Rastelli says. “Patients who get the vitamin D weekly feel better because their pain is reduced and sometimes goes away completely. This makes the drugs much more tolerable. Millions of women worldwide take aromatase inhibitor therapy, and we may have another ‘tool’ to help them remain on it longer.”

Like anastrozole used in this study, the other two FDA-approved aromatase inhibitors, letrozole and exemestane, also cause musculoskeletal pain. Given the similar side effects, Rastelli says patients on these drugs may also benefit from high-dose vitamin D.

The vitamin used in this study is a plant-derived type called vitamin D2. Rastelli says it achieves the best results when given weekly because the body metabolizes it within seven to 10 days. Rastelli and her colleagues did not use high-dose vitamin D3 (cholecalciferol), which remains in the body longer. Vitamin D3 is the form made by the skin when exposed to sunlight.

“This was a very carefully conducted study, and the placebo control makes the findings quite compelling,” says Matthew J. Ellis, MD, PhD, the study’s senior author and director of the Breast Cancer Program at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis. “We should follow up these findings further to determine the most efficacious and safe approach to vitamin D supplementation in our breast cancer patients.”

Since vitamin D helps the body absorb calcium, too much of it can cause high levels of calcium in the urine, which may increase the risk of kidney stones. Such possible side effects emphasize the importance of tracking patients’ urine calcium levels while taking high-dose vitamin D.

“It’s important to monitor the patients, but overall it appears to be very safe,” Rastelli says. “Because vitamin D2 is eliminated from the body so quickly, it’s very hard to overdose.”

In addition to relieving pain, the group wanted to examine whether vitamin D could protect against the bone loss often seen in patients taking aromatase inhibitors. The researchers measured each patient’s bone density at the beginning of the study and again after six months.

Perhaps because of its role in calcium absorption, high-dose vitamin D did appear to help maintain bone density at the neck of the femur, the top of the thighbone near the hip joint. Although the result did not reach statistical significance, Rastelli calls the result promising and worth further studies.

“It’s great that we have something as simple as vitamin D to help patients alleviate some of this pain,” Rastelli says. “It’s not toxic — it doesn’t cause major side effects. And if it is actually protecting against bone loss, that’s even better.”

Reference: Rastelli AL, et al. Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial. Breast Cancer Research and Treatment. Online June 2011.

Endo-society.org – The Endocrine Society recently released “Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline.” The clinical practice guideline (CPG) is published in the July 2011 issue of the Journal of Clinical Endocrinology & Metabolism (JCEM), a publication of The Endocrine Society.

The major source of vitamin D for children and adults is exposure to natural sunlight as very few foods naturally contain or are fortified with vitamin D. Vitamin D deficiency is common throughout the world and results in abnormalities of calcium, phosphorus and bone metabolism which can lead to muscle weakness, osteomalacia, osteopenia and osteoporosis. In children, vitamin D deficiency can result in skeletal deformities known as rickets.

“Vitamin D deficiency is very common in all age groups and it is important that physicians and health care providers have the best evidence-based recommendations for evaluating, treating and preventing vitamin D deficiency in patients at highest risk,” said Michael F. Holick, PhD, MD, of the Boston University School of Medicine and chair of the task force that authored the CPG. “The Society’s new Clinical Practice Guideline was developed by experts in the field who carefully reviewed the current literature and features the latest and most comprehensive recommendations available on the prevention and treatment of vitamin D deficiency.”

Recommendations from the CPG include:

• Screening for vitamin D deficiency in individuals at risk for deficiency;

• Measurement of vitamin D level by a reliable assay as the initial diagnostic test in patients at risk for deficiency; and

• Treatment with either vitaminD2 or vitamin D3 for deficient patients.

The CPG also features recommendations for dietary intake of vitamin D in patients at risk for vitamin D deficiency. These recommendations include:

• Infants and children ages 0-1 year require at least 400 IU/day (IU=25 ng) of vitamin D and children 1 year and older require at least 600 IU/day to maximize bone health. To raise the blood level of vitamin D consistently above 30 ng/ml may require at least 1,000 IU/day of vitamin D;
• Adults aged 19-50 years require at least 600 IU/day of vitamin D to maximize bone health and muscle function and at least 1,500-2,000 IU/day of vitamin D may be needed to maintain blood level of vitamin D above 30 ng/ml;
• Adults aged 50-70 years and adults older than 70 years require at least 600 IU/day and 800 IU/day respectively of vitamin D. At least 1,500-2,000 IU/day of vitamin D may be needed to maintain blood level of vitamin D above 30 ng/ml; and
• Pregnant and lactating women require at least 600 IU/day of vitamin D and at least 1,500 IU/day of vitamin D may be needed to maintain blood level of vitamin D above 30 ng/ml.

“At the present time, there is not sufficient evidence to recommend screening individuals who are not at risk for deficiency or to prescribe vitamin D to attain the non-calcemic benefit for cardiovascular protection,” said Dr Holick.

Ohio.edu – Yo-yo dieters may be healthier and live longer than those who stay obese, according to a new Ohio University animal study.

Mice that switched between a high-fat and low-fat diet every four weeks during their approximate two-year lifespan lived about 25 percent longer and had better blood glucose levels than obese animals that ate a high-fat diet. The yo-yo dieters also lived about as long as a control group of mice steadily fed a low-fat diet.

Some experts argue that constantly shedding and regaining pounds can be harmful to health. The new research, presented recently at the annual meeting of the Endocrine Society in Boston, suggests, however, that yo-yo dieting may be preferable to remaining obese and not dieting at all.

“If the conventional wisdom is true, it would discourage a lot of overweight people from losing weight,” said study lead author Edward List, a scientist at Ohio University’s Edison Biotechnology Institute. “The new research shows that the simple act of gaining and losing weight does not seem detrimental to lifespan.”

About 34 percent of American adults are considered to be obese; an additional 34 percent are classified as overweight, according to the Centers for Disease Control and Prevention. Although millions of Americans diet each year, research has shown that few people maintain long-term weight loss.

In the first study on yo-yo dieting of its kind, List and colleagues followed 30 mice on one of three dietary regimens over the course of a little over two years, the typical lifespan of this particular strain of laboratory mouse. The animals on the high-fat diet ate more, weighed more and had higher levels of body fat and higher fasting blood glucose levels. They also become glucose intolerant, or pre-diabetic, said List, whose research is supported by the National Institutes of Health, AMVETS and Ohio University.

The health profile of the mice on the yo-yo diet declined during their high-fat food phases, but their weight and blood glucose levels returned to normal levels during their low-fat diet stages. Lifespan – the “gold standard” for lifelong health status – was 2.04 years for the yo-yo dieting mice, compared to 1.5 years for the obese mice. The control group lived, on average, for 2.09 years.

Although replicating the research in humans is ideal, List said, it would be challenging to pursue a long-term controlled diet study. Various factors, including illness, can impact weight cycling. Mice can serve as a good model for obesity research, he noted, as they allow researchers to follow the effects of diet choices on lifespan over a relatively short time period.

“The study adds to our understanding of the benefit of losing weight,” he said. “I would hope that this encourages people to not give up.”

List plans to expand the study to a larger population of mice. He’ll also further examine preliminary findings that suggest that the yo-yo dieting animals experienced a reduction in cytokine levels. High levels of cytokine are linked to increased inflammation, which is associated with diseases such as diabetes, heart disease and cancer.

Editorial note: Parallels may exist between certain kinds of “yo-yo” dieting and “intermittent fasting,” the latter of which has also been studied before in mice (see this abstract of a 2003 study). Intermittent fasting in that study had many of the health benefits of calorie restriction – a finding that suggests that the fasting experience (which may parallel food or calorie restriction when dieting) may be triggering beneficial changes in the activity of genes related to metabolism. Also, some nutrition researchers think that some of the benefits of a Mediterranean diet could be attributed to the episodic religious fasting patterns of peoples in Mediterranean countries. A major problem here is the difference between a controlled laboratory study and the real-life behavior of many yo-yo dieters. Yo-yo dieting can be associated with patterns of binges on junk food followed by extreme diets that may not be healthy in their nutritional profile. Repeated rational efforts at weight management – even if frustrating to the dieter – may nonetheless carry some of the benefits that the above animal study has found – Dr Z.

Sportsmed.org – Vitamin D deficiency has been known to cause an assortment of health problems, and a recent study suggests that lack of vitamin D might also increase the chance of muscle injuries in athletes, specifically NFL football players. The study was presented at the American Orthopaedic Society for Sports Medicine’s (AOSSM) Annual Meeting in San Diego.

“Eighty percent of the football team we studied had vitamin D insufficiency. African American players and players who suffered muscle injuries had significantly lower levels,” said Michael Shindle, MD, lead researcher and member of Summit Medical Group.

Researchers identified 89 football players from a single NFL team and provided laboratory testing of vitamin D levels in the spring 2010 as part of routine pre-season evaluations. The mean age of the players was 25. The team provided data to determine the number of players who had lost time due to muscle injuries. Vitamin D levels were then classified based on player race and time lost due to muscle injury.

Twenty-seven players had deficient levels (<20 ng/ML) and an additional 45 had levels consistent with insufficiency (20-31.9 ng/mL). Seventeen players had values within normal limits (>32 ng/mL). The mean vitamin D level in white players was 30.3 ng/mL while the mean level for black players was 20.4 ng/mL. Sixteen players suffered a muscle injury with a mean vitamin D level of 19.9.

“Screening and treatment of vitamin D insufficiency in professional athletes may be a simple way to help prevent injuries,” said Dr. Scott Rodeo, MD, Co-Chief of the Sports Medicine and Shoulder Service at the Hospital for Special Surgery. “Further research also needs to be conducted in order to determine if increasing vitamin D leads to improved maximum muscle function,” said Dr. Joseph Lane, MD, Director of the Metabolic Bone Disease Service at the Hospital for Special Surgery.”

HSS.edu – Vitamin D levels should be maintained above the limits recently recommended by the Institute of Medicine (IOM) in order to fully optimize a drug therapy for osteoporosis and low bone mineral density (BMD), according to a new study by researchers from Hospital for Special Surgery in New York. The findings were presented at the Endocrine Society’s Annual Meeting in Boston, June 2011.

The study demonstrated that maintaining a circulating vitamin D level above 33 ng/ml is associated with a seven-fold greater likelihood of having a more favorable outcome with bisphosphonate therapy. Last November, the IOM issued recommendations that 25-hydroxyvitamin D levels of 20-30 ng/ml were adequate for normal, healthy people.

“You are seven times more likely to respond to bisphosphonates if your 25-Hydroxy vitamin D level is 33 ng/ml and above. If you want to see a particular outcome from this treatment, then maybe 20 to 30 is not appropriate,” said Richard Bockman, M.D., Ph.D., chief of the Endocrine Service at Hospital for Special Surgery, who directed the study. “When you see a seven times greater effect, that is pretty impressive.”

More than 20 million people take bisphosphonates to preserve and improve skeletal health, and reduce the risk of fractures that can be caused by low BMD and osteoporosis. These drugs, however, do not work well in some patients. Because vitamin D is important to bone health, the researchers investigated whether they could identify levels of vitamin D that are associated with improved outcomes in patients taking bisphosphonates.

They conducted a retrospective chart review of patients seen in an osteoporosis practice of Hospital for Special Surgery. They identified subjects who were female, postmenopausal, had been taking one of four FDA-approved bisphosphonate drugs for at least 18 months, and had undergone at least two BMD scans separated by 18 to 60 months. The four drugs are alendronate, residronate, ibandronate and zolendronate. Patients were not included if they were nonadherent to bisphosphonate therapy, were chronic steroid users, or had metabolic bone disease or chronic kidney disease.

The researchers collected data on age, body mass index, type of bisphosphonate taken, treatment duration, concurrent calcium supplementation, fracture prior to and during bisphosphonate therapy, BMD and T-score at four sites – lumbar spine, femoral neck, trochanter, and total hip – from the two most recent bone scans. “The way the data are expressed for a bone density is how many standard deviations are you away from the normal,” explained Dr. Bockman. “One standard deviation from the normal is a T score of one. Two standard deviations is a T score of two. Below the normal, it is a minus two and above the normal is a plus two. If your bone density is more than 2.5 standard deviations below the normal, that defines a low bone mass that is considered to be osteoporosis.” The researchers also collected data on circulating levels of vitamin D, obtained with and between the two most recent bone scans.

Patients were deemed nonresponders if they had more than a 3 percent decrease in BMD between the initial and follow-up bone scans, a low-trauma fracture or a T-score less than -3.0 despite at least 24 months of bisphosphonate therapy.

The study included 160 patients, of whom 89 were responders, and 71 were nonresponders, with 42 having decreased BMD, 17 sustaining a fracture, and 12 having a persistent low T-score. The investigators found that only 16.8 percent of responders whereas 54.9 percent of nonresponders had vitamin D levels less than 33 ng/ml. Patients with an average circulating vitamin D level of 33 ng/ml and above had a seven-fold greater likelihood of having a favorable response to bisphosphonates. “We selected 33 as the cutoff and subsequently showed that it was the right choice, with more being better,” Dr. Bockman said. Nonresponse rates were higher in patients who had low levels of vitamin D: < 20 ng/ml (83.3 percent), 20-30 ng/ml (77.8 percent), 30-40 ng/ml (42.3 percent), and >40 ng/ml (24.6 percent).

“If you look at the medical literature, researchers talk perhaps about a 20 percent increase in response rate, occasionally a doubling, but when you see a sevenfold improvement in outcome, you have to be impressed that it is probably important,” said Dr. Bockman, who is also professor of Medicine in the Endocrine Division of Weill Cornell Medical College.

Before this study, researchers had not formally studied the relationship between vitamin D levels and the effectiveness of bisphosphonates. “There has been a lot of controversy over the correct vitamin D level for people to have,” Dr. Bockman said. “Vitamin D status should be optimized to improve outcomes in patients taking bisphosphonates.”

Dr. Bockman pointed out that three associations – the American Geriatric Society, Endocrine Society, and the American College of Rheumatology – are coming out with or have guidelines that recommend vitamin D levels higher than the IOM recommended levels for healthy people.

In a large study of men in Japan, the presence of fatty liver disease by ultrasonography showed an inverse (reduced risk) association with the frequency of moderate alcohol consumption; however, there was some suggestion of an increase in fatty liver disease with higher volume of alcohol consumed per day. Moderate drinkers had lower levels of obesity than did non-drinkers, and both obesity and metabolic abnormalities were positively associated with fatty liver disease.

These findings support the results of a number of other recent studies showing that moderate drinking does not increase the risk of this common type of liver disease; instead, it is associated with a lower risk of its occurrence. We agree with the implications of these studies as stated by the authors: “These results suggest that lifestyle modifications aimed at fighting central obesity and metabolic abnormalities should be the most important recommendations for the management of fatty liver. In addition, it seems unlikely that the risk of fatty liver can be reduced by the discontinuation and/or reduction of alcohol consumption alone.”

A detailed critique of this paper is available free online here:

Frequent moderate drinking of alcohol linked to lower risk of fatty liver disease

Reference: Hiramine Y, et al. Alcohol drinking patterns and the risk of fatty liver in Japanese men. J Gastroenterol 2011 46:519. DOI 10.1007/s00535-010-0336-z.