Health Benefits of Vitamin D - Osteoporosis and Fracture Risk

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Vitamin D and Calcium Supplementation to Prevent Fractures in Adults

U.S. Preventive Services Task Force Recommendation Statement:

The U.S. Preventive Services Task Force (USPSTF) makes recommendations about the effectiveness of specific clinical preventive services for patients without related signs or symptoms.

It bases its recommendations on the evidence of both the benefits and harms of the service and an assessment of the balance. The USPSTF does not consider the costs of providing a service in this assessment.

The USPSTF recognizes that clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.

Summary of Recommendations and Evidence

The USPSTF concludes that 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 (I statement).

The USPSTF concludes that 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 (I statement).

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 (D recommendation).

The USPSTF has previously concluded in a separate recommendation that vitamin D supplementation is effective in preventing falls in community-dwelling adults aged 65 years or older who are at increased risk for falls (B recommendation).

Fractures, particularly hip fractures, are associated with chronic pain and disability, loss of independence, decreased quality of life, and increased mortality (1). One half of all postmenopausal women will have an osteoporosis-related fracture during their lifetime.

Appropriate intake of vitamin D and calcium are essential to overall health. The Institute of Medicine has published recommended dietary allowances.However, the benefits and harms of daily supplementation with greater than 400 IU of vitamin D3 and greater than 1,000 mg of calcium to prevent fractures are not clearly understood.

Benefits of Preventive Medication

In premenopausal women and in men, there is inadequate evidence to determine the effect of combined vitamin D3 and calcium supplementation on the incidence of fractures. In postmenopausal women, there is adequate evidence that daily supplementation with 400 IU of vitamin D3 combined with 1,000 mg of calcium has no effect on the incidence of fractures. However, there is inadequate evidence regarding the effect of higher doses of combined vitamin D and calcium supplementation on fracture incidence in noninstitutionalized postmenopausal women.

Harms of Preventive Medication

Adequate evidence indicates that supplementation with 400 IU or less of vitamin D3 and 1,000 mg or less of calcium increases the incidence of renal stones. The USPSTF assessed the magnitude of this harm as small.

USPSTF Assessment

Noninstitutionalized, community-dwelling postmenopausal women. The USPSTF concludes that evidence is lacking about the benefit 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, and the balance of benefits and harms cannot be determined.

The USPSTF concludes with moderate certainty that daily supplementation with 400 IU or less of vitamin D3 and 1,000 mg or less of calcium has no net benefit for the primary prevention of fractures.

Men and premenopausal women. The USPSTF concludes that evidence is lacking about the benefit of vitamin D supplementation with or without calcium for the primary prevention of fractures, and the balance of benefits and harms cannot be determined.

Vitamin D deficiency reduces bone quality

Everyone knows that as we grow older our bones become more fragile. Now a team of U.S. and German scientists led by researchers with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) Berkeley has shown that this bone-aging process can be significantly accelerated through deficiency of vitamin D – the sunshine vitamin.

Vitamin D deficiency is a widespread medical condition that has been linked to the health and fracture risk of human bone on the basis of low calcium intake and reduced bone density. However, working at Berkeley Lab’s Advanced Light ALS), a DOE national user facility, the international team demonstrated that vitamin D deficiency also reduces bone quality.

“The assumption has been that the main problem with vitamin D deficiency is reduced mineralization for the creation of new bone mass, but we’ve shown that low levels of vitamin D also induces premature aging of existing bone,” says Robert Ritchie, who led the U.S. portion of this collaboration. Ritchie holds joint appointments with Berkeley Lab’s Materials Sciences Division and the University of California (UC) Berkeley’s Materials Science and Engineering Department.

“Unraveling the complexity of human bone structure may provide some insight into more effective ways to prevent or treat fractures in patients with vitamin D deficiency,” says Björn Busse, of the Department of Osteology and Biomechanics at the University Medical Center in Hamburg, Germany, who led the German portion of the team.

Ritchie and Busse have reported their findings in the journal Science Translational Medicine. The paper is titled “Vitamin D Deficiency Induces Early Signs of Aging in Human Bone, Increasing the Risk of Fracture.” Co-authors also include Hrishikesh Bale, Elizabeth Zimmermann, Brian Panganiban, Holly Barth, Alessandra Carriero, Eik Vettorazzi, Josef Zustin, Michael Hahn, Joel Ager, Klaus Püschel and Michael Amling.

Vitamin-D is essential for the body to absorb calcium. The body normally synthesizes vitamin D in the skin following exposure to sunlight – hence the “sunshine” moniker. However, when vitamin D serum concentrations become deficient, the body will remove calcium from bone to maintain normal calcium blood levels. This removal of calcium from existing bone hampers the mineralization process required for the formation of new bone mass. In children, vitamin D deficiency can lead to rickets. In adults, vitamin D deficiency causes osteomalacia, a softening of the bones associated with defective mineralization that results in bone pain, muscle weakness, and increased risk of bone deformation and fracture. While treatments with vitamin D and calcium supplements are effective, success has been achieved with only modest increases in bone mineral density, suggesting other factors also play a role in reducing fracture risks.

“We hypothesized that restoring the normal level of vitamin D not only corrects the imbalance of mineralized and non-mineralized bone quantities, but also initiates simultaneous multiscale alterations in bone structure that affects both the intrinsic and extrinsic fracture mechanisms,” Ritchie says.

To test this hypothesis, Busse and his German team collected samples of iliac crest bone cores from 30 participants, half of whom were deficient in vitamin D and showed early signs of osteomalacia. For this study, a normal vitamin D level was defined as a serum concentration of 20 micrograms per liter or higher. For the vitamin D deficiency group the mean serum concentration was 10 micrograms per liter.

The bone samples were sent to Ritchie and his team for analysis at the ALS using Fourier Transform Infrared (FTIR) spectroscopy and X-ray computed microtomography. The FTIR spectroscopy capabilities of ALS beamlines 1.4.3 and 5.4.1 provide molecular-level chemical information, and ALS Beamline 8.3.2 provides non-destructive 3D imaging at a resolution of approximately one micron.

“We were interested in spatially resolved data that would help us to follow the formation of cracks under mechanical loading,” Ritchie says. “The ALS beamlines enabled us to measure the structure/composition and mechanical properties of the bone samples at different size-scales, ranging from nanometers to micrometers. We measured the resistance to crack growth and by following crack growth in real-time were able to observe how cracks and structure interact. This enabled us to relate mechanical properties to specific structural changes.”

Ritchie and his team found that while vitamin D-deficient subjects had less overall mineralization due to a reduction of mineralized bone, underneath the new non-mineralized surfaces, the existing bone was actually more heavily mineralized, and displayed the structural characteristics – mature collagen molecules and mineral crystals – of older and more brittle bone.

“These islands of mineralized bone were surrounded by a collagenous boundary that prevented them from being properly remodeled,” Busse says. “Cut off from a supply of osteoclasts, the cells that normally remodel the bone, these isolated sections of mineralized bone begin to age, even as overall bone mineralization decreases from a lack of calcium.”

Says Ritchie, “In situ fracture mechanics measurements and CT-scanning of the crack path indicated that vitamin D deficiency increases both the initiation and propagation of cracks by 22- to 31-percent.”

From their study, Busse, Ritchie and their co-authors say that vitamin-D levels should be checked and kept on well-balanced levels to maintain the structural integrity of bones and avoid mineralization defects and aging issues that can lead to a risk of fractures.

Vitamin D Supplementation Effective In Fracture Risk Reduction In Older Adults

Based on the results of a pooled analysis of 11 unrelated randomized clinical trials investigating vitamin D supplementation and fracture risk in more than 31,000 older adults, Bess Dawson-Hughes, MD, director of the Bone Metabolism Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging (USDA HNRCA) at Tufts University, says higher doses of Vitamin D may be the most beneficial in reducing bone fractures in this age group.

As part of the study, published in The New England Journal of Medicine, Dawson-Hughes and colleagues divided the subjects into quartiles ranging from 0 to 2,000 International Units (IUs) of daily vitamin D intake. The top quartile sustained 30% fewer hip fractures and 14% fewer fractures of other bones compared to the control groups.

"Taking between 800 IUs and 2,000 IUs of vitamin D per day significantly reduced the risk of most fractures, including hip, wrist and forearm in both men and women age 65 and older," said Dawson-Hughes, the study's senior author. "Importantly, we saw there was no benefit to taking Vitamin D supplements in doses below 800 IUs per day for fracture prevention."

Dawson-Hughes and colleagues analyzed each participant's vitamin D supplementation within and independent of the study protocol, controlling for age, vitamin D blood levels at baseline, additional calcium supplementation and whether the person lived independently or under medical care.

"Evaluation of individual-level data is the gold-standard of meta-analysis," said lead author Heike Bischoff-Ferrari, MD, D.Ph., director of the Centre on Aging and Mobility at the University of Zurich and Waid City Hospital and a visiting scientist in the Bone Metabolism Laboratory at the USDA HNRCA. "Our results make a compelling contribution to the existing data on Vitamin D and fracture risk in men and women age 65 and older, whose vulnerability to bone density loss and osteoporosis leave them prone to fractures resulting from thinning bones."

The current Dietary Reference Intake (DRI) for vitamin D in older adults set by the Institute of Medicine (IOM) is a minimum of 600 IUs per day for adults between 51 and 70 years-old and 800 IUs in adults over 70.

"Vitamin D supplementation is an efficient intervention for a costly injury that affects thousands of older adults each year," said Dawson-Hughes, who is also a professor at Tufts University School of Medicine. "The average recovery is long and painful and deeply impacts quality of life. After a fracture, older patients may only regain partial mobility, resulting in a loss of independence that is personally demoralizing and that can place added stress on family members and caregivers"

Financially, Vitamin D supplements cost pennies a day, Dawson-Hughes said, whereas the American Academy of Orthopaedic Surgeons estimated the cost of treating a hip fracture was $26,912 in 2007.

Dawson-Hughes adds that older adults, unless they are exposed to bright, year-round sunlight, require supplementation to meet their vitamin D needs. Typically, adults consume 150 IUs per day from food sources such as tuna or salmon or fortified milk. On average, multivitamins contain 400 IUs of vitamin D and there are individual vitamin D supplements with 400, 800 or 1,000 IUs. While vitamin D toxicity is rare, the IOM suggests capping intake at 4,000 IUs per day.

Dawson-Hughes said the results of the current study would be strengthened by large interventional trials investigating the impact of vitamin D supplementation on fracture risk. She and the authors also call for further investigation of the impact of combining calcium supplementation with high doses of vitamin D, as their data was inconclusive.

Vitamin D insufficiency sustained over 5 years contributes to increased 10-year fracture risk in elderly women

A study presented at the World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases shows that long-term low levels of vitamin D intake are associated with higher 10-year fracture risk in elderly women.

Vitamin D insufficiency in seniors has been shown to contribute to increased risk of osteoporotic fractures. Previous studies have used single vitamin D measurements to investigate effects on bone. However, in elderly women, relatively little is known about the effects of long-term vitamin D insufficiency on bone health.

The study by Swedish researchers used sequential assessment of serum vitamin D to determine if sustained hypovitaminosis D in elderly women leads to increased 10-year fracture incidence.

Study participants at baseline were 1044 Swedish women, all aged 75, with 715 attending at the 5-year follow up. Serum 25-hydroxyvitamin D (25OHD) levels (nmol/l) were classified as low (<50 and="" high="" intermediate="">75). Women with values in the same 25OHD category at both samplings were considered to have consistently low, intermediate or high levels. Fracture data was followed for 10 years through X-rays at the radiology department.

The results showed that the incidence of hip fractures within 10 years was significantly lower in those women who were vitamin D sufficient (≥50 nmol/l) at baseline and maintained this level at 5 years. The proportion of women sustaining FRAX fractures was 26.2% and 30% in the group which had consistently high or intermediate 25OHD levels compared to 45.6 % in the group with consistently low levels. The incidence of shoulder, radius and vertebral fractures was not associated with 25OHD status in the study. The majority of fractures occurred between 5 and 10 years after baseline (hip 77%; FRAX 64%) however the time to first fracture (hip and FRAX) did not significantly differ between the three categories of 25OHD using either a single or serial measurement.

Professor Kristina Akesson, Clinical and Molecular Osteoporosis Research Unit at Lund University, Chair of the IOF Capture the Fracture Campaign, stated, "This study concludes that in the population sample of elderly women, vitamin D insufficiency sustained over 5-years was associated with increased 10-year risk of osteoporotic fracture."

She added, "This is part of a body of research which increasingly suggests that falls and fracture risk in the elderly could be lower by having higher vitamin D levels. The International Osteoporosis Foundation (IOF) global recommendations for vitamin D advise daily intakes of 800 to 1000 IU/day in seniors for fracture and falls prevention, and if the on-going research shows that vitamin D levels are increased it may be a relatively simple and low-cost public health measure that could have significant positive effects on the incidence of osteoporotic fractures with aging."

High levels of vitamin D needed for bone density drugs to work

To fully optimize a drug therapy for osteoporosis and low bone mineral density (BMD), patients should maintain vitamin D levels above the limits recently recommended by the Institute of Medicine (IOM), according to a new study by researchers from Hospital for Special Surgery in New York. The study was presented at the Endocrine Society's Annual Meeting in Boston, June 4-7, 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-Hydroxy vitamin 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%), 20-30 ng/ml (77.8%), 30-40 ng/ml (42.3%), and >40 ng/ml (24.6%).

"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.

Vitamin D intake may be associated with lower stress fracture risk in girls

Vitamin D may be associated with a lower risk of developing stress fractures in preadolescent and adolescent girls, especially among those very active in high-impact activities, according to a report published Online First by Archives of Pediatrics & Adolescent Medicine, one of the JAMA/Archives journals.

Stress fractures, a relatively common sports-related injury, occur when stresses on a bone exceed its capacity to withstand and heal from those forces. But while consumption of calcium and calcium-rich dairy produ cts is routinely encouraged for optimal bone health, researchers note in their study background that the evidence for this recommendation has been challenged.

Kendrin R. Sonneville, Sc.D., R.D., of Children's Hospital Boston, and colleagues conducted a study to identify whether calcium, vitamin D and/or the intake of dairy were prospectively associated with stress fracture risk among girls. The study included 6,712 preadolescent and adolescent girls (age 9 to 15 at baseline) in the Growing Up Today Study.

During seven years of follow-up, 3.9 percent of the girls developed a stress fracture. Dairy and calcium intakes were unrelated to risk of developing a stress fracture. However, vitamin D intake was associated with a lower risk of developing a stress fracture, particularly among those girls who participate in at least one hour a day of high-impact activity.

"In contrast, there was no evidence that calcium and dairy intakes were protective against developing a stress fracture or that soda intake was predictive of an increased risk of stress fracture or confounded the association between dairy, calcium or vitamin D intakes and fracture risk," the authors comment.

The authors also note that in a stratified analysis that high calcium intake was associated with a greater risk of developing a stress fracture, although they suggest that "unexpected finding" warrants more study.

The authors conclude their findings support the Institute of Medicine's recent increase in the recommended dietary allowance for vitamin D for adolescents from 400 IU/d to 600 IU/d.

"Further studies are needed to ascertain whether vitamin D intake from supplements confers a similarly protective effect as vitamin D consumed through dietary intake," they comment.

Timing of calcium and vitamin D supplementation may affect how bone adapts to exercise

Taking calcium and vitamin D before exercise may influence how bones adapt to exercise, according to a new study. The results were presented in 2013 at The Endocrine Society's 95th Annual Meeting in San Francisco.

"The timing of calcium supplementation, and not just the amount of supplementation, may be an important factor in how the skeleton adapts to exercise training," said study lead author Vanessa D. Sherk, PhD, postdoctoral research fellow at the University of Colorado Anschutz Medical Campus. "Further research, however, is needed to determine whether the timing of calcium supplementation affects the skeletal adaptations to exercise training."

Previous research has shown that a year of intense training is associated with substantial decreases in bone mineral density among competitive road cyclists. Experts believe that this kind of exercise-induced bone loss could be related to the loss of calcium during exercise. As blood calcium levels drop, the parathyroid gland produces excess parathyroid hormone, which can mobilize calcium from the skeleton.

In this study, investigators found that an exercise-induced decrease in blood calcium occurred whether calcium supplements were taken before or after exercising. Pre-exercise supplementation, however, resulted in less of a decrease. Although not statistically significant, parathyroid hormone levels increased slightly less among cyclists who took calcium before exercising.

"These findings are relevant to individuals who engage in vigorous exercise and may lose a substantial amount of calcium through sweating," Sherk said. "Taking calcium before exercise may help keep blood levels more stable during exercise, compared to taking the supplement afterwards, but we do not yet know the long-term effects of this on bone density."

The timing of calcium supplementation did not cause a difference in blood levels of a compound that is a biological indicator of bone loss. Both the before- and after-exercise groups exhibited 50-percent increases in the level of this compound, called CTX, for collagen type-1 C-telopeptide.

Study participants included 52 men aged 18 to 45 years. Investigators randomly assigned participants to take 1,000 milligrams of calcium and 1,000 international units of vitamin D either 30 minutes before or one hour after exercise. The exercise comprised a simulated 35-kilometer time trial, and participants wore skin patches to absorb sweat.

Investigators measured blood levels of calcium and parathyroid hormone before and immediately after exercise. They also measured CTX before and 30 minutes after exercise. They used pre- and post-body weight, adjusted for fluid intake, combined with the calcium measured in the sweat from the skin patches, to estimate the amount of calcium lost through the skin during exercise.