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Clinical Guidelines |

Vitamin D and Calcium Supplementation to Prevent Fractures in Adults: U.S. Preventive Services Task Force Recommendation Statement FREE

Virginia A. Moyer, MD, MPH, on behalf of the U.S. Preventive Services Task Force*
[+] Article and Author Information

* For a list of members of the USPSTF, see the Appendix.

This article was published at www.annals.org on 26 February 2013.


From the U.S. Preventive Services Task Force, Rockville, Maryland.

Disclaimer: Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Financial Support: The USPSTF is an independent, voluntary body. The U.S. Congress mandates that the Agency for Healthcare Research and Quality support the operations of the USPSTF.

Potential Conflicts of Interest: None disclosed. Disclosure forms from USPSTF members can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-0215.

Requests for Single Reprints: Reprints are available from the USPSTF Web site (www.uspreventiveservicestaskforce.org).


Ann Intern Med. 2013;158(9):691-696. doi:10.7326/0003-4819-158-9-201305070-00603
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Chinese translation

Description: New U.S. Preventive Services Task Force (USPSTF) recommendation statement on vitamin D and calcium supplementation to prevent fractures in adults.

Methods: The USPSTF commissioned 2 systematic evidence reviews and a meta-analysis on vitamin D supplementation with or without calcium to assess the effects of supplementation on bone health outcomes in community-dwelling adults, the association of vitamin D and calcium levels with bone health outcomes, and the adverse effects of supplementation.

Population: These recommendations apply to noninstitutionalized or community-dwelling asymptomatic adults without a history of fractures. This recommendation does not apply to the treatment of persons with osteoporosis or vitamin D deficiency.

Recommendation: 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 1000 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 1000 mg or less of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women. (D recommendation)


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.

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 1000 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 1000 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)

See the Clinical Considerations section for suggestions for practice regarding the I statements.

See the Figure for a summary of the recommendation and suggestions for clinical practice.

Grahic Jump Location
Figure.

Vitamin D and calcium supplementation to prevent fractures in adults: clinical summary of U.S. Preventive Services Task Force recommendation.

Grahic Jump Location

Appendix Table 1 describes the USPSTF grades, and Appendix Table 2 describes the USPSTF classification of levels of certainty about net benefit.

Table Jump PlaceholderAppendix Table 1. What the USPSTF Grades Mean and Suggestions for Practice 
Table Jump PlaceholderAppendix Table 2. USPSTF Levels of Certainty Regarding Net Benefit 
Importance

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 (Table). However, the benefits and harms of daily supplementation with greater than 400 IU of vitamin D3 and greater than 1000 mg of calcium to prevent fractures are not clearly understood.

Table Jump PlaceholderTable. Institute of Medicine 2011 Recommended Dietary Allowances for Vitamin D and Calcium 
Benefits of Preventive Medication

In premenopausal women and in men, there is inadequate evidence to determine the effect of combined vitamin D 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 1000 mg of calcium has no effect on the incidence of fractures. However, there is inadequate evidence about 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 1000 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 1000 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 1000 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.

Patient Population Under Consideration

This recommendation applies to noninstitutionalized or community-dwelling asymptomatic adults without a history of fractures. “Community-dwelling” is defined as not living in an assisted living facility, nursing home, or other institutional care setting. This recommendation does not apply to persons with osteoporosis or vitamin D deficiency.

Considerations for Practice Regarding the I Statements
Potential Preventable Burden

The health burden of fractures is substantial in the older adult population.

Potential Harms

In the Women's Health Initiative (WHI), a statistically increased incidence of renal stones occurred in women taking supplemental vitamin D and calcium. One woman was diagnosed with a urinary tract stone for every 273 women who received supplementation over a 7-year follow-up.

Costs

Vitamin D and calcium supplements are inexpensive and readily available without a prescription.

Current Practice

Vitamin D and calcium supplementation are often recommended for women, especially postmenopausal women, to prevent fractures. Surveys estimate that 56% of women aged 60 years or older take supplemental vitamin D and 60% take a supplement containing calcium. The exact dosage is not well-known (2).

Other Approaches to Prevention

The USPSTF recommends screening for osteoporosis in women aged 65 years or older and in younger women whose fracture risk is equal to or greater than that of a 65-year-old white woman who has no additional risk factors. This recommendation statement is available on the USPSTF Web site (www.uspreventiveservicestaskforce.org).

The USPSTF recommends vitamin D supplementation (the median dose of vitamin D in available studies was 800 IU) to prevent falls in community-dwelling adults aged 65 years or older who are at increased risk for falls because of a history of recent falls or vitamin D deficiency (B recommendation). This recommendation statement is available on the USPSTF Web site (www.uspreventiveservicestaskforce.org).

Research Needs and Gaps

Research is needed to determine whether daily supplementation with greater than 400 IU of vitamin D3 and greater than 1000 mg of calcium reduces fracture incidence in postmenopausal women or older men. The comparative effectiveness of different preparations of vitamin D (for example, D2 vs. D3) or different calcium formulations should be evaluated. Prospective studies should assess the potential benefits of vitamin D and calcium supplementation in early adulthood on fracture incidence later in life. Studies are needed to evaluate the effects of vitamin D supplementation on diverse populations. Because white women have the highest risk for osteoporotic fractures, most fracture prevention studies are done in this population and it is difficult to extrapolate results to nonwhite populations.

Burden of Disease

Each year, approximately 1.5 million osteoporotic fractures occur in the United States. Nearly half of all women older than 50 years will have an osteoporosis-related fracture during their lifetime. Fractures are associated with chronic pain, disability, and decreased quality of life. Hip fractures significantly increase illness and death. During the first 3 months after a hip fracture, a person's mortality risk is 2.8 to 4 times that of a person of similar age living in the community without a fracture. Nearly 20% of patients with hip fracture are subsequently institutionalized in long-term care facilities (3).

Scope of Review

The USPSTF used 2 systematic evidence reviews and an updated meta-analysis on vitamin D supplementation with or without calcium (46) to assess the effects of supplementation on bone health outcomes in community-dwelling adults, the association of vitamin D and calcium levels with bone health outcomes, and the adverse effects of supplementation. The USPSTF did not consider questions relating to adequate daily intake of calcium and vitamin D, nor did it examine the effect of calcium supplementation alone. The systematic reviews did not examine other health outcomes, such as pregnancy complications, prevention of falls, cardiovascular disease, or overall mortality.

The assessment of vitamin D supplementation with or without calcium to prevent cancer was removed from this recommendation statement and will be incorporated into a separate, upcoming recommendation statement.

Effectiveness of Preventive Medication

Sixteen randomized, controlled trials with considerable heterogeneity in populations, settings, and interventions examined the effect of vitamin D supplementation with or without calcium on fracture incidence in adults (6). Postmenopausal women represented the largest group of participants in the trials; no trials included women of childbearing age or men younger than 50 years. Almost all trial participants were white. Six trials reported a history of fractures in 10.6% to 26% of participants. Two trials included only adults with a history of fractures, and 5 trials included only elderly institutionalized adults.

Vitamin D doses ranged from 300 to 1370 IU daily, although most trials used at least 800 IU daily. Five trials compared vitamin D with placebo or no treatment, 8 trials compared vitamin D and calcium with placebo or no treatment, 4 trials compared vitamin D and calcium with calcium alone, and 1 trial compared vitamin D and calcium with vitamin D alone; 1 trial had several comparisons. Most of the trials used vitamin D3 as the intervention, but 3 used vitamin D2. Calcium supplementation also varied. Most trials used calcium carbonate, whereas others used citrate-, lactate-, or phosphate-based preparations. Methods for fracture ascertainment included self-report, radiograph confirmation, administrative data, physician verification, or some combination.

The USPSTF considered 6 randomized trials evaluating the use of vitamin D and calcium supplementation within the scope of this recommendation. These trials were conducted in community-dwelling adults, and fewer than 26% had a history of fractures. No statistically significant reduction in fractures was observed in these studies (pooled relative risk, 0.89 [95% CI, 0.76 to 1.04]). The largest trial of fracture outcomes included in the meta-analysis was the WHI trial (7), which enrolled 36 282 healthy postmenopausal women aged 50 to 79 years. Approximately 83% of enrolled women were white, 9% were black, 4% were Hispanic, and 4% were of other races. The intervention group received 400 IU of vitamin D3 and 1000 mg of calcium daily; the control group received placebo. This study reported no statistically significant reduction in hip fracture (hazard ratio, 0.88 [CI, 0.72 to 1.08]) or total fractures (hazard ratio, 0.96 [CI, 0.91 to 1.02]). However, the USPSTF could not generalize the results of the WHI trial beyond the specific dose, preparation, and population studied. Nearly 30% of study participants were already taking 500 mg or more of calcium daily before the start of the trial.

Trials of vitamin D supplementation alone showed no statistical difference (pooled relative risk, 1.03 [CI, 0.84 to 1.26]). Of the 12 trials reporting baseline levels of vitamin D, 5 reported mean vitamin D levels less than 30 nmol/L, a level considered to be vitamin D–deficient. However, neither baseline vitamin D status nor supplement dose correlated with supplement efficacy.

An individual patient data meta-analysis (8) published after the USPSTF's review included 31 022 persons aged 65 years or older from 11 trials, many of which were included in the USPSTF review. The meta-analysis concluded that fractures may be reduced for persons taking higher doses of vitamin D (≥800 IU daily). The effect was seen in both institutionalized and community-dwelling adults. The subgroup thresholds were not predefined by the original trial authors, and the reduction was not considered statistically significant when adjusted for several subgroup analyses. Therefore, any positive findings should be viewed with caution.

Potential Harms of Preventive Medication

Reporting of adverse outcomes in clinical trials and observational studies of vitamin D and calcium supplementation is limited. The WHI trial (9) reported an increased risk for nephrolithiasis (hazard ratio, 1.17 [CI, 1.02 to 1.34]). The absolute risk was 2.5% in the intervention group and 2.1% in the placebo group, with a number needed to harm of 273. It is uncertain if this adverse effect occurs in vitamin D–deficient populations. A meta-analysis of calcium supplementation (10) suggests an association between calcium use and increased risk for cardiovascular disease, but the link has not been consistently demonstrated. The effect was primarily seen in persons taking calcium alone and not in combination with vitamin D. None of the studies reviewed by the USPSTF reported this adverse effect.

Estimate of Magnitude of Net Benefit

Except for postmenopausal women, there is inadequate evidence to estimate the benefits of vitamin D or calcium supplementation to prevent fractures in noninstitutionalized adults. Due to the lack of effect on fracture incidence and the increased incidence of nephrolithiasis in the intervention group of the WHI trial, the USPSTF concludes with moderate certainty that daily supplementation with 400 IU of vitamin D3 and 1000 mg of calcium has no net benefit for the primary prevention of fractures in noninstitutionalized, postmenopausal women. Although women enrolled in WHI were predominately white, the lower risk for fractures in nonwhite women makes it very unlikely that a benefit would exist in this population.

Response to Public Comments

A draft version of this recommendation statement was posted for public comment on the USPSTF Web site from 12 June to 10 July 2012. The USPSTF received more than 40 comments. In response, information was added to the Rationale section to reinforce the basic dietary requirements for vitamin D and calcium. Several recently published studies on the benefits and harms of vitamin D and calcium supplementation were reviewed, and their results were highlighted in the Discussion section. The dose of calcium used in the WHI trial was clarified throughout the statement.

How Does Evidence Fit With Biological Understanding?

Calcium is one of the main building blocks of bone growth. Vitamin D helps bones absorb calcium. Normal healthy bones turn over calcium constantly, replacing calcium loss with new calcium received from dietary intake. There are 2 main sources of vitamin D in the human body. Ergocalciferol, or vitamin D2, is consumed in the diet, mainly in the form of fatty fish. Fortified foods, such as milk, yogurt, and orange juice, provide other dietary sources of vitamin D. Cholecalciferol, or vitamin D3, is synthesized in the skin by ultraviolet B rays from the sun. Vitamin D3 is converted to its active form by means of enzymatic processes in the liver and kidney. Most cells contain specific receptors for the active form of vitamin D. Stimulation of skeletal muscle receptors promotes protein synthesis, and vitamin D has a beneficial effect on muscle strength and balance. Vitamin D controls calcium absorption in the small intestines, interacts with parathyroid hormone to help maintain calcium homeostasis between the blood and bones, and is essential for bone growth and maintaining bone density. Insufficient amounts of vitamin D obtained through the diet or sun exposure can lead to inadequate levels of the hormone calcitriol (the active form of vitamin D), which in turn can lead to impaired dietary calcium absorption. Subsequently, the body uses calcium from skeletal stores, which can weaken existing bones.

The Institute of Medicine (Table) (11) and the World Health Organization (12) have recommended standards for adequate daily intake of calcium and vitamin D as a part of overall health. Neither organization has made recommendations specific to fracture prevention. The Institute of Medicine notes the challenge of determining dietary reference intakes given the complex interrelationship between calcium and vitamin D, the inconsistency of studies examining bone health outcomes, and the need to limit sun exposure to minimize skin cancer risk.

Appendix: U.S. Preventive Services Task Force

Members of the U.S. Preventive Services Task Force at the time this recommendation was finalized † are Virginia A. Moyer, MD, MPH, Chair (Baylor College of Medicine, Houston, Texas); Michael L. LeFevre, MD, MSPH, Co-Vice Chair (University of Missouri School of Medicine, Columbia, Missouri); Albert L. Siu, MD, MSPH, Co-Vice Chair (Mount Sinai School of Medicine, New York, and James J. Peters Veterans Affairs Medical Center, Bronx, New York); Linda Ciofu Baumann, PhD, RN (University of Wisconsin, Madison, Wisconsin); Kirsten Bibbins-Domingo, PhD, MD (University of California, San Francisco, San Francisco, California); Susan J. Curry, PhD (University of Iowa College of Public Health, Iowa City, Iowa); Mark Ebell, MD, MS (University of Georgia, Athens, Georgia); Glenn Flores, MD (University of Texas Southwestern, Dallas, Texas); Adelita Gonzales Cantu, RN, PhD (University of Texas Health Science Center, San Antonio, Texas); David C. Grossman, MD, MPH (Group Health Cooperative, Seattle, Washington); Jessica Herzstein, MD, MPH (Air Products, Allentown, Pennsylvania); Wanda K. Nicholson, MD, MPH, MBA (University of North Carolina School of Medicine, Chapel Hill, North Carolina); and Douglas K. Owens, MD, MS (Veteran Affairs Palo Alto Health Care System, Palo Alto, California, and Stanford University, Stanford, California). Former USPSTF members who contributed to the development of this recommendation are Diana Petitti, MD, MPH; Timothy J. Wilt, MD, MPH; and Bernadette Melnyk, PhD, RN.

† For a list of current Task Force members, go to www.uspreventiveservicestaskforce.org/members.htm.

Nelson HD, Haney EM, Dana T, Bougatsos C, Chou R. Screening for osteoporosis: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2010; 153:99-111.
PubMed
 
Gahche J, Bailey R, Burt V, Hughes J, Yetley E, Dwyer J, et al. Dietary supplement use among U.S. adults has increased since NHANES III (1988-1994). NCHS Data Brief. 2011; 1-8.
PubMed
 
Office of the Surgeon General.  Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Office of the Surgeon General; 2004. Accessed at www.ncbi.nlm.nih.gov/books/NBK45513/ on 31 May 2012.
 
Cranney A, Horsley T, O'Donnell S, Weiler H, Puil L, Ooi D, et al.  Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment No. 158. Rockville, MD: Agency for Healthcare Research and Quality; 2007. Accessed at www.ncbi.nlm.nih.gov/books/NBK38410/ on 31 May 2012.
 
Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, et al.  Vitamin D and Calcium: A Systematic Review of Health Outcomes. Evidence Report/Technology Assessment No. 183. Rockville, MD: Agency for Healthcare Research and Quality; 2009. Accessed at www.ncbi.nlm.nih.gov/books/NBK32603/ on 31 May 2012.
 
Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011; 155:827-38.
PubMed
CrossRef
 
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006; 354:669-83.
PubMed
CrossRef
 
Bischoff-Ferrari HA, Willett WC, Orav EJ, Oray EJ, Lips P, Meunier PJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012; 367:40-9.
PubMed
CrossRef
 
Wallace RB, Wactawski-Wende J, O'Sullivan MJ, Larson JC, Cochrane B, Gass M, et al. Urinary tract stone occurrence in the Women's Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements. Am J Clin Nutr. 2011; 94:270-7.
PubMed
CrossRef
 
Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010; 341:c3691.
PubMed
CrossRef
 
Ross CA, Taylor CL, Yaktine AL, Del Valle HB, eds; Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Institute of Medicine.  Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press; 2011. Accessed at www.nap.edu/catalog.php?record_id=13050 on 31 May 2012.
 
World Health Organization and Food and Agriculture Organization of the United Nations.  Vitamin and Mineral Requirements in Human Nutrition. 2nd ed. Geneva, Switzerland: World Health Organization; 2004. Accessed at www.who.int/nutrition/publications/micronutrients/9241546123/en/index.html on 31 May 2012.
 

Figures

Grahic Jump Location
Figure.

Vitamin D and calcium supplementation to prevent fractures in adults: clinical summary of U.S. Preventive Services Task Force recommendation.

Grahic Jump Location

Tables

Table Jump PlaceholderTable. Institute of Medicine 2011 Recommended Dietary Allowances for Vitamin D and Calcium 
Table Jump PlaceholderAppendix Table 2. USPSTF Levels of Certainty Regarding Net Benefit 
Table Jump PlaceholderAppendix Table 1. What the USPSTF Grades Mean and Suggestions for Practice 

References

Nelson HD, Haney EM, Dana T, Bougatsos C, Chou R. Screening for osteoporosis: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2010; 153:99-111.
PubMed
 
Gahche J, Bailey R, Burt V, Hughes J, Yetley E, Dwyer J, et al. Dietary supplement use among U.S. adults has increased since NHANES III (1988-1994). NCHS Data Brief. 2011; 1-8.
PubMed
 
Office of the Surgeon General.  Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Office of the Surgeon General; 2004. Accessed at www.ncbi.nlm.nih.gov/books/NBK45513/ on 31 May 2012.
 
Cranney A, Horsley T, O'Donnell S, Weiler H, Puil L, Ooi D, et al.  Effectiveness and Safety of Vitamin D in Relation to Bone Health. Evidence Report/Technology Assessment No. 158. Rockville, MD: Agency for Healthcare Research and Quality; 2007. Accessed at www.ncbi.nlm.nih.gov/books/NBK38410/ on 31 May 2012.
 
Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, et al.  Vitamin D and Calcium: A Systematic Review of Health Outcomes. Evidence Report/Technology Assessment No. 183. Rockville, MD: Agency for Healthcare Research and Quality; 2009. Accessed at www.ncbi.nlm.nih.gov/books/NBK32603/ on 31 May 2012.
 
Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011; 155:827-38.
PubMed
CrossRef
 
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Women's Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006; 354:669-83.
PubMed
CrossRef
 
Bischoff-Ferrari HA, Willett WC, Orav EJ, Oray EJ, Lips P, Meunier PJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012; 367:40-9.
PubMed
CrossRef
 
Wallace RB, Wactawski-Wende J, O'Sullivan MJ, Larson JC, Cochrane B, Gass M, et al. Urinary tract stone occurrence in the Women's Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements. Am J Clin Nutr. 2011; 94:270-7.
PubMed
CrossRef
 
Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010; 341:c3691.
PubMed
CrossRef
 
Ross CA, Taylor CL, Yaktine AL, Del Valle HB, eds; Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Institute of Medicine.  Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press; 2011. Accessed at www.nap.edu/catalog.php?record_id=13050 on 31 May 2012.
 
World Health Organization and Food and Agriculture Organization of the United Nations.  Vitamin and Mineral Requirements in Human Nutrition. 2nd ed. Geneva, Switzerland: World Health Organization; 2004. Accessed at www.who.int/nutrition/publications/micronutrients/9241546123/en/index.html on 31 May 2012.
 

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Comments

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In Response
Posted on March 7, 2013
Christpher Nordin, MD, FRACP
Royal Adelaide Hospital
Conflict of Interest: None Declared

This Clinical Guideline will be widely used as an argument against the use of calcium and vitamin D for fracture prevention in postmenopausal women but the summaries that have appeared in the lay press do not appreciate the ambiguity or weakness of the original paper. The US Preventive Services Task Force recommends against daily supplementation with 400 IU or less vitamin D and 1000 mg or less calcium in non-institutionalised postmenopausal women. The common sense implication must be that they would recommend larger doses of both but they do not say so explicitly. The elementary fact is that their recommendation is based on a totally inadequate review of the relevant literature (only 12 references) which excludes the 2 largest meta-analyses of the subject. The first identified 17 randomized trials in 52 625 subjects (mostly women) in which vitamin D and calcium significantly reduced bone loss and fracture incidence particularly with calcium doses of 1200 mg or more and with vitamin D doses of 800 IU or more [1]. The second paper is an analysis of 7 major randomized trials of vitamin D with calcium or vitamin D alone on 68 517 subjects of mean age 69.9 years (14.7% men) which showed no significant effect on fracture of vitamin D alone but showed a very significant effect of vitamin D with calcium [2]. I find it astonishing that an organization with the prestige of the US Preventive Services Task Force can authorise a paper which is so poorly documented, flies in the face of most of the relevant literature and may affect prescribing habits worldwide.

References:

1. Tang BMP, Eslick GD, Nowson G, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007;370:657-66.

2. The DIPART Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 2010;340:b5463.

Comment
Posted on May 16, 2013
Marcus M. Reidenberg, MD, FACP
Weill Cornell Medical College
Conflict of Interest: None Declared

Both the IOM report noted in the editorial and the Women's Health Initiative study, noted in the paper as the largest of the trials, reported that many people in the US are already taking supplements (1). So the conclusions refer to people already having intakes of vitamin D and calcium at or close to the RDA of each, often because they are taking supplements. Furthermore, the WHI analysis used the statistical significance value for the intent to treat analysis. I do recognize the issue of selective drop out during a trial so the groups at the end may not be as comparable to each other as they were at the beginning. In the WHI, only 59% of the treated subjects were taking the prescribed dose. As a pharmacologist, I know that if I want to learn of a drug's effects, I have to give the drug and not just intend to give the drug to see any effects of the drug. One must be very cautious in assuming that lack of statistically significant evidence, especially  with  intent to treat analysis with many drop outs, is evidence of lack.

  1. Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Report Brief accessed Nov 30, 2010, available from http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx
An Achilles' heel for fracture prevention?
Posted on June 4, 2013
Toshihiro Sugiyama, MD, PhD
Yamaguchi University School of Medicine
Conflict of Interest: None Declared

The U.S. Preventive Services Task Force concludes that the current evidence about calcium and vitamin D supplementation to prevent fractures in adults is essentially insufficient (1). This statement may be partly due to the limited anti-fracture efficacy of calcium and vitamin D supplementation resulting from skeletal adaptation to mechanical loading, although vitamin D promotes calcium absorption in the gut and supports bone mineralization that is essential for skeletal stiffness.

Bone responds to local mechanical environment at each skeletal site, as evident by marked bone gain in the dominant arm of professional tennis players or rapid bone loss in the weight-bearing sites of astronauts during space flight; it has been considered that the skeleton adapts to mechanical stimulation through control of bone strength by resulting elastic deformation (strain) of bone. This mechanical strain-related feedback control system is a refinement of Wolff’s law and known as the mechanostat. Recent experimental data in the adult skeleton (2-4) suggest that the mechanical strain-related control of trabecular and cortical bone acts continuously throughout the physiological range and thus even slightly increased or decreased bone strain induces site-specific bone gain or loss, respectively, to maintain the strain level. The concept is compatible with clinical reports in adults that high-impact, but not low-impact, exercise results in bone gain (5), because additional mechanical loading (by exercise) will not stimulate bone when the stimulus does not exceed that already derived from existing mechanical loading (by habitual physical activity) as discussed previously (2).

 

Although neglected, the primary regulator of bone strength is local mechanical environment. Irrespective of suppressing bone resorption and/or promoting bone formation, or increasing bone quantity and/or improving bone quality, an increase in bone strength by nutrients or drugs would result in a decrease in bone strain from mechanical stimuli. The mechanostat based on the latest evidence (2-4) suggests that the decreased bone strain causes the negative feedback of mechanical strain-related control system. Thus, it can be hypothesized that the effect of osteoporosis therapy is limited by the natural homeostatic system in the skeleton. This hypothesis is consistent with rapid resolution of the effects of most osteoporosis drugs except bisphosphonates that bind to bone mineral, and could partly explain the limited effects of calcium plus vitamin D supplementation and even current osteoporosis drugs on fracture prevention, especially at weight-bearing sites that principally contain cortical bone such as the hip. Further research is needed to clarify the present situation.

 

References

1. Moyer VA; U.S. Preventive Services Task Force. Vitamin D and calcium supplementation to prevent fractures in adults: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013;158:691-6.

2. Sugiyama T, Meakin LB, Browne WJ, Galea GL, Price JS, Lanyon LE. Bones’ adaptive response to mechanical loading is essentially linear between the low strains associated with disuse and the high strains associated with the lamellar/woven bone transition. J Bone Miner Res. 2012;27:1784-93.

3. Ellman R, Spatz J, Cloutier A, Palme R, Christiansen BA, Bouxsein ML. Partial reductions in mechanical loading yield proportial changes in bone density, bone architecture, and muscle mass. J Bone Miner Res. 2013;28:875-85.

4. Schulte FA, Ruffoni D, Lambers FM, Christen D, Webster DJ, Kuhn G, Muller R. Local mechanical stimuli regulate bone formation and resorption in mice at the tissue level. PLoS ONE. 2013;8:e62172.

5. Vainionpaa A, Korpelainen R, Vihriala E, Rinta-Paavola A, Leppaluoto J, Jamsa T. Intensity of exercise is associated with bone density change in premenopausal women. Osteoporos Int. 2006;17:455-63.

 

USPSTF Response to Letters on Its Recommendation on the Use of Vitamin D and Calcium Supplementation to Prevent Fractures
Posted on November 5, 2013
Virginia A. Moyer, MD, MPH on behalf of the U.S. Preventive Task Services Force
USPTSF
Conflict of Interest: None Declared
TO THE EDITOR: The U.S. Preventive Services Task Force (USPSTF) appreciates the time Drs. Sugiyama, Reidenberg, and Nordin took to comment on the Task Force’s recommendation on vitamin D and calcium supplementation to prevent fractures. The USPSTF anticipated the challenges and honest scientific disagreements on the use of vitamin D and calcium supplementation to prevent fractures.

Dr. Sugiyama’s suggestion that mechanical effects play a significant role in bone strength and quality, and therefore in risk for fractures, regardless or in spite of supplement use, is an important observation. The Task Force agrees with his suggestion that more research is needed.

Dr. Reidenberg highlights the challenges of drawing conclusions from the Women’s Health Initiative and other randomized, controlled trials of vitamin D and calcium. As he mentions, the standard technique for studying the effectiveness of an intervention is intention-to-treat analysis, to avoid bias due to asymmetric drop out from the trial. The Task Force concurs that there is a difference between statistical and clinical significance and it is important to understand the meaning of the results. The challenges of determining the effectiveness of nutritional supplements is a broader issue that the field will need to address.

Dr. Nordin references two meta-analyses not cited in the USPSTF’s recommendation statement. The USPSTF relied on two systematic reviews and an updated meta-analysis to guide development of its recommendation; these are cited in the recommendation statement. In addition, the Task Force considered several other reviews and meta-analyses, including DIPART (vitamin D Individual Patient Analysis of Randomized Trials) and a more recent patient-level meta-analysis by Bischoff-Ferrari, which are also cited in the recommendation. The Task Force’s systematic review included many of the same studies as DIPART and Tang but excluded others that did not meet inclusion criteria. The six trials of vitamin D and calcium that were considered by the Task Force in its final recommendation statement were of fair to good study quality and conducted in community-dwelling adults for the primary prevention of fractures. The large number of studies on vitamin D and calcium supplements would lead one to believe that there should be resolution of the question of whether these supplements are effective in preventing fractures. However, the body of evidence in this area is exceedingly heterogeneous; therefore, the Task Force used particular caution when drawing conclusions about the population encompassed within its scope, which is asymptomatic, community-dwelling adults. The negative results of the Women’s Health Initiative (without adjusting for outside supplement use, as noted by Reidenberg) make it clear that lower doses of vitamin D and calcium have no effect. Whether there is an effect at higher doses remains uncertain from the Task Force’s perspective. We agree with Dr. Nordin’s point that it can be difficult for the public to understand the nuance of the recommendation, but we are confident that the recommendation is based on a well-done and comprehensive review of the evidence.

Virginia A. Moyer, M.D., M.P.H.
Chair, U.S. Preventive Services Task Force

Michael L. LeFevre, M.D., M.S.P.H.
Vice Chair, U.S. Preventive Services Task Force

Albert L. Siu, M.D., M.S.P.H.
Vice Chair, U.S. Preventive Services Task Force


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Vitamin D and Calcium Supplementation to Prevent Fractures in Adults: U.S. Preventive Services Task Force Recommendation Statement

The full report is titled “Vitamin D and Calcium Supplementation to Prevent Fractures in Adults: U.S. Preventive Services Task Force Recommendation Statement.” It is in the 7 May 2013 issue of Annals of Internal Medicine (volume 158, pages 691-696). The authors are V.A. Moyer, for the U.S. Preventive Services Task Force.

This article was published at www.annals.org on 26 February 2013.

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