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How much vitamin D should you recommend to your nonpregnant patients?
No question: Vitamin D plays a vital role in bone health. In recent years, the possibility that it plays a role in other aspects of health has prompted considerable speculation, fueled by both widespread media coverage and dissemination of conflicting information about the potential nonskeletal benefits of high-dose vitamin D supplementation. Controversy has emerged about:
- the appropriate criteria for defining vitamin D deficiency
- the extent to which vitamin D influences nonskeletal health conditions
- the optimal level of vitamin D supplementation.
In 2010, the Institute of Medicine (IOM) released a report that provided recommendations for vitamin D intake, which were also summarized in a recent article for clinicians.1,2 The IOM report provided much-needed clinical guidance, but it has also fueled additional questions.
This article describes the IOM recommendations, explains what we know now about the effect of vitamin D on various health outcomes, and offers concrete recommendations on vitamin D measurement, intake, and supplementation.
How the Institute of Medicine formulated its recommendations
The Institute of Medicine (IOM) committee conducted a comprehensive review of the literature to date on the relationship between vitamin D (and calcium) intake and several health outcomes. In terms of skeletal health, the IOM committee concluded that a 25OHD level of at least 20 ng/mL is sufficient to meet the needs of at least 97.5% of the population. The vitamin D intake thought to be necessary to achieve this 25OHD level for at least 97.5% of the population was provided for different age groups (TABLE 2).
The Recommended Dietary Allowance (RDA) of vitamin D is 600 IU daily for all adults up to age 70 years, and 800 IU daily for adults older than 70 years. These values were based on an assumption of minimal sun exposure, due to wide variability in vitamin D synthesis from ultraviolet light, as well as the risk of skin cancer. The IOM concluded that there is no compelling evidence that a 25OHD level above 20 ng/mL or a vitamin D intake greater than 600 IU (800Â IU for adults over 70) affords greater skeletal or nonskeletal benefits.
The IOM recommendations were based on the integration of bone health outcomes. The evidence supporting causal relationships between vitamin D insufficiency and nonskeletal outcomes such as cancer, cardiovascular disease, diabetes, impaired physical performance, autoimmune disorders, and other chronic diseases was found to be inconsistent and inconclusive.
The IOM report also noted the emergence of a “U”-shaped curve in regard to vitamin D and several health outcomes, which has fueled concern about attainment of a 25OHD level above 50 ng/mL. The IOM committee designated 4,000 IU daily as the tolerable upper intake but emphasized that research into long-term outcomes and safety at intakes above the RDA is limited. Therefore, this upper limit should not be interpreted as a target intake level.
How is vitamin D metabolized?
Vitamin D is produced endogenously in the skin in the form of vitamin D3 (cholecalciferol). It also can be ingested exogenously in the form of vitamin D3 or vitamin D2 (ergocalciferol). Cutaneous synthesis of vitamin D is stimulated by solar ultraviolet radiation.
Vitamin D2 and D3 are hydroxylated in the liver to form 25-hydroxyvitamin D (25OHD). Measurement of the serum 25OHD level is thought to be the most reliable indicator of vitamin D exposure.3 25OHD is hydroxylated again, primarily in the kidneys, to the most active form of vitamin D (1,25-dihydroxyvitamin D).
The adverse skeletal effects of severe vitamin D deficiency are well established; those effects include calcium malabsorption, secondary hyperparathyroidism, bone loss, and increased risk of fracture. In this setting, secondary hyperparathyroidism results from both decreased gastrointestinal calcium absorption and decreased suppression of parathyroid hormone (PTH) production by the parathyroid glands from vitamin D metabolites. Secondary hyperparathyroidism leads to increased bone resorption and bone loss. Rickets, osteomalacia, hypocalcemia, hypophosphatemia, muscle weakness, and bone pain are less common effects that can occur with severe vitamin D deficiency.
It is worth noting that women of color are at increased risk of vitamin D deficiency as a result of greater skin pigmentation.3 Obesity is also a risk factor for vitamin D deficiency.3 Additional risk factors for vitamin D insufficiency are listed in TABLE 1.
TABLE 1
Risk factors for vitamin D insufficiency
| Obesity |
| Dark skin pigmentation |
Decreased sun exposure
|
| Low dietary intake of vitamin D |
| Malabsorption of ingested vitamin D |
Increased hepatic degradation of 25-hydroxyvitamin D
|
| Decreased hepatic hydroxylation of vitamin D (occurs only with severe hepatic disease) |
| Impaired renal hydroxylation of vitamin D (renal insufficiency) |
| Osteoporosis or osteopenia |
How should vitamin D insufficiency be defined?
Biochemical criteria for defining vitamin D insufficiency vary. That makes it difficult to estimate the prevalence of vitamin D insufficiency.
Severe vitamin D deficiency is commonly defined as a serum 25OHD level below 10 ng/mL.3 Vitamin D insufficiency has been variably defined as a serum 25OHD level below 20 to 32 ng/mL,3,4 and the lower limit of normal in most clinical laboratories is now typically 30 to 32 ng/mL. Many patients become concerned when their serum 25OHD level is flagged as “low” on a laboratory report, and it’s likely that you are called on from time to time to interpret and make recommendations about the appropriate response to this “abnormal” finding.
The broad definition of vitamin D insufficiency stems, in part, from the assessment of a wide range of outcomes. Measures that have been used include fracture risk, calcium absorptive capacity, and the serum concentration of PTH. In regard to calcium absorption, most studies suggest that maximal dietary calcium absorption occurs when the 25OHD level reaches 20 ng/mL, although some studies suggest a higher threshold.1,3
The optimal level of 25OHD for PTH suppression remains unclear. Several studies have suggested that the PTH level increases when the 25OHD concentration falls below 30 ng/mL,4,5 although this threshold has varied substantially across studies.6
How prevalent is vitamin D insufficiency?
Estimates of the prevalence of vitamin D insufficiency vary by the criteria used to define the condition. A recent report using data from the National Health and Nutrition Examination Survey (NHANES) estimated that approximately 30% of US adults 20 years of age or older have a 25OHD level below 20Â ng/mL, and more than 70% of this age group has a 25OHD level below 32 ng/mL.7
The IOM committee noted that several reports have most likely overestimated the prevalence of vitamin D insufficiency through the use of 25OHD cut points higher than 20Â ng/mL.
The data on vitamin D insufficiency and skeletal health
Many studies have examined the relationship between vitamin D supplementation or the 25OHD level and fracture risk, and conflicting results have emerged. Many trials have examined the combination of calcium and vitamin D supplementation, the effects of which are tightly interwoven, confounding interpretation.
Interpretation of large observational studies is further confounded by the inability to attribute association to causation. In the Women’s Health Initiative (WHI) study of calcium with vitamin D, treatment of healthy postmenopausal women with 1,000 mg of calcium and 400 IU of vitamin D daily led to improved bone density at the hip but no statistically significant reduction in hip fracture.8 However, a reduced risk of hip fracture was demonstrated in secondary analyses among women who adhered to treatment and among women 60 years or older. Meta-analyses of clinical trials have reported that treatment with varying doses of vitamin D (more than 400 IU daily) reduces the risk of vertebral,9 nonvertebral,10 and hip fractures.10
Several studies have examined the relationship between the 25OHD level and fracture risk, with inconsistent findings:
- A nested case-control study from the WHI found that the risk of hip fracture was significantly increased among postmenopausal women who had a 25OHD level of 19 ng/mL or lower.11
- A 2009 report from the Agency for Healthcare Research and Quality (AHRQ) concluded that the association between the 25OHD level and the risk of fracture was inconsistent.12
After a comprehensive review of the available research, the IOM committee concluded that a serum 25OHD level of 20 ng/mL would meet the needs for bone health for at least 97.5% of the US and Canadian populations.
TABLE 2
Calcium and vitamin D dietary reference intakes for adults, by life stage
| Life stage (gender) | Calcium | Vitamin D | |||
|---|---|---|---|---|---|
| RDA (mg/d) | Tolerable upper intake level (mg/d)* | RDA (IU/d) | Serum 25OHD level (ng/mL) (corresponding to the RDA)† | Tolerable upper intake level (IU/d)* | |
| 19–50 yr (male and female) | 1,000 | 2,500 | 600 | 20 | 4,000 |
| 51–70 yr (male) | 1,000 | 2,000 | 600 | 20 | 4,000 |
| 51–70 yr (female) | 1,200 | 2,000 | 600 | 20 | 4,000 |
| 71+ yr (male and female) | 1,200 | 2,000 | 800 | 20 | 4,000 |
| Adapted from: Ross AC, Manson JE, Abrams SA, et al. J Clin Endocrinol Metab. 2011;96(1):53–58. RDA = Recommended Dietary Allowance, 25OHD=25-hydroxyvitamin D * The tolerable upper intake level is the threshold above which is a risk of adverse events. The upper intake level is not intended to be a target intake. There is no consistent evidence of greater benefit at intake levels above the RDA. The serum 25OHD level corresponding to the upper intake level is 50 ng/mL. † Measures of the serum 25OHD level corresponding to the RDA and covering the requirements of at least 97.5% of the population. | |||||
The data on vitamin D insufficiency and nonskeletal outcomes
Many observational studies have reported relationships between vitamin D insufficiency and myriad nonskeletal health outcomes, particularly cardiovascular disease, cancer, diabetes, and autoimmune disorders.3 However, well-designed randomized clinical trials that examine nonskeletal outcomes as primary pre-specified outcomes are lacking.13 Such studies will be essential to elucidate the relationship between vitamin D insufficiency and nonskeletal chronic diseases. The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing large-scale, randomized clinical trial designed to evaluate the role of supplementation with 2,000 IU of vitamin D3 daily in the primary prevention of cancer and cardiovascular disease.14
- Vitamin D plays a vital role in bone health
- The Institute of Medicine released a 2010 report that provided public health recommendations for vitamin D intake based on bone health outcomes
- Many observational studies have reported a relationship between vitamin D insufficiency and adverse nonskeletal health outcomes, including cardiovascular disease, cancer, diabetes, and autoimmune disorders, but evidence from randomized clinical trials on the potential nonskeletal benefits of vitamin D is sparse
- Excessive vitamin D intake should be avoided because of the potential for harm and the lack of evidence from well-designed clinical trials that vitamin D intake beyond the recommended amount affords greater skeletal or nonskeletal health benefits
- Among women who have an increased risk of vitamin D insufficiency or bone loss, 25OHD concentration should be measured and vitamin D supplementation should be provided as necessary to achieve the target 25OHD level
What we recommend for treatment
The IOM report provided the medical community with evidence-based recommendations for vitamin D intake at the population level, based on a public health perspective.1,2 However, the public health guideline model must be distinguished from the medical model, in which shared clinical decision-making between physician and patient occurs on an individual level and is informed by individual clinical risk factors. The public health recommendations detailed in the IOM report are not intended to replace or interfere with clinical judgment or preclude individualized clinical decision-making.
The debate over optimal levels of vitamin D supplementation for individual patients who have osteoporosis or other health conditions continues.15 Here, we provide general guidelines for treatment, based on the evidence available to date.
Clear benefits of vitamin D in bone health notwithstanding, advise your patients to avoid excessive intake because it can cause harm. See “More is not necessarily better”.
Recommendations for healthy adult nonpregnant women
Vitamin D intake: We recommend a daily vitamin D intake of 600 IU for healthy nonpregnant women up to age 70 years (and 800 Â IU daily for women older than 70 years) who are at average risk of vitamin D insufficiency and bone loss, consistent with the IOM recommendations. The IOM guidelines assume minimal to no sun exposure.
Measurement of 25OHD: It is not necessary to routinely measure the 25OHD level in these women. However, it is prudent to measure 25OHD in women who have risk factors for vitamin D insufficiency (TABLE 1) or a clinical condition associated with severe vitamin D deficiency. In these cases, if the 25OHD level is found to be below 20 ng/mL, vitamin D therapy should be initiated, with the goal of boosting the 25OHD level above the threshold of 20 ng/mL.
Treatment of vitamin D insufficiency: Options include daily vitamin D supplementation and higher-dose weekly preparations.
Many clinicians treat severe vitamin D insufficiency with 50,000 IU of vitamin D2 once weekly for 8 weeks, followed by a maintenance dose (described below) of vitamin D to preserve the target 25OHD level.5 An alternative is daily vitamin D supplementation, with the dosage based on the degree of insufficiency.
A general rule of thumb, for persons who have normal vitamin D absorption, is that every 1,000 IU of vitamin D3 ingested daily increases the 25OHD level by approximately 6 to 10 ng/mL.4,16 However, the incremental increase in the 25OHD concentration varies among individuals, depending on the baseline 25OHD level, with a greater incremental increase occurring at lower baseline 25OHD levels.
Monitoring of the 25OHD level after adjustment of the dosage is necessary to ensure that the target level is achieved.
Maintaining an adequate vitamin D level: Once vitamin D insufficiency has been corrected, a maintenance dosage of vitamin D should be selected—commonly 800 to 1,000 Â IU daily. A higher maintenance dosage may be required for persons who have genetic or ongoing environmental factors that predispose them to vitamin D insufficiency.
Vitamin D3 is reportedly more potent than D2 in increasing the 25OHD level,17 although this finding has not been universal.18 Monthly or twice-monthly administration of 50,000 IU of vitamin D2 is another option for maintenance of vitamin D sufficiency,5,16 although daily doses are more commonly used and are readily available in over-the-counter preparations.
Regardless of the regimen selected, the 25OHD level should be measured again approximately 3 months after a change in dosage to ensure that the target level has been achieved, with further dosage adjustments as indicated.
Recommendations for adult women at increased risk of skeletal disease
Measurement of 25OHD: The 25OHD level should be measured among women at increased risk of vitamin D insufficiency, bone loss, or fracture and among women who have established skeletal disease.
Vitamin D intake: We recommend that women at increased risk of osteoporosis and women older than 70 years receive at least 800 IU daily and, potentially, more if necessary to achieve the target 25OHD level.
Although the evidence to date does not support routine achievement of a 25OHD level substantially above 20 ng/mL in most women, many clinicians recommend that women in this higher-risk group maintain a 25OHD level above 30 ng/mL because of the possibly greater (although unproven) skeletal and nonskeletal benefits. As more data become available regarding the benefits and safety of vitamin D doses higher than those recommended by the IOM, these recommendations may be revised.
In 2010, the National Osteoporosis Foundation (NOF) recommended a vitamin D intake of 800 to 1,000 IU daily for all adults 50 years and older. Among persons at risk of deficiency, the NOF also recommended measurement of the serum 25OHD level, with vitamin D supplementation, as necessary, to achieve a 25OHD level of 30 ng/mL or higher.19 Also in 2010, the International Osteoporosis Foundation (IOF) recommended a target 25OHD level above 30 ng/mL for all older adults. The IOF also estimated that the average dosage required to achieve this level in older adults is 800 to 1,000 IU daily, noting that upward adjustment may be required in some people.4 It is unclear whether these guidelines will be revised in the future, based on the IOM report.
We recommend against achieving a 25OHD level above 50 ng/mL, based on evidence suggesting potential adverse health effects above this level.
Excessive vitamin D intake should be avoided because of the potential for harm and the lack of evidence from well-designed clinical trials that vitamin D intake beyond the currently recommended amount affords greater skeletal or nonskeletal health benefits. Although moderate vitamin D supplementation has proven skeletal benefits, a “U-shaped” curve for some outcomes has emerged, suggesting that excessive vitamin D supplementation may pose health risks. Notably, a recent clinical trial reported a higher risk of fracture (and falls) among elderly women treated annually with high-dose (500,000 IU) oral vitamin D3 versus placebo.20
A suggestion of adverse effects associated with 25OHD levels above 50 ng/mL has also emerged, from observational studies, for several nonskeletal health outcomes, including pancreatic cancer,21 cardiovascular disease,1 and all-cause mortality.22
Limited evidence is available regarding the safety and overall risk-benefit profile of long-term maintenance of 25OHD levels above the recommended dietary allowance (RDA) range. Therefore, you should remind your patients that, despite the importance of both prevention and treatment of vitamin D insufficiency, more is not necessarily better.
We want to hear from you! Tell us what you think.
1. Institute of Medicine. 2011 Dietary Reference Intakes for Calcium and Vitamin D. Washington DC: National Academies Press; 2011.
2. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53-58.
3. Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J Med. 2011;364(3):248-254.
4. Dawson-Hughes B, Mithal A, Bonjour JP, et al. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010;21(7):1151-1154.
5. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.
6. Sai AJ, Walters RW, Fang X, Gallagher JC. Relationship between vitamin D parathyroid hormone, and bone health. J Clin Endocrinol Metab. 2011;96(3):E436-446.
7. Yetley EA. Assessing the vitamin D status of the US population. Am J Clin Nutr. 2008;88(2):558S-564S.
8. Jackson RD, LaCroix AZ, Gass M, et al. Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669-683.
9. Papadimitropoulos E, Wells G, Shea B, et al. Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev. 2002;23(4):560-569.
10. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169(6):551-561.
11. Cauley JA, Lacroix AZ, Wu L, et al. Serum 25-hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med. 2008;149(4):242-250.
12. Chung M, Balk EM, Brendel M, et al. Vitamin D and calcium: a systematic review of health outcomes. Evid Rep Technol Assess (Full Rep). 2009;(183):1-420.
13. Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer—ready for prime time? N Engl J Med. 2011;364(15):1385-1387.
14. Manson JE. Vitamin D and the heart: why we need large-scale clinical trials. Cleve Clin J Med. 2010;77(12):903-910.
15. The Forum at Harvard School of Public Health. Boosting Vitamin D: Not enough or too much? The Andelot Series on Current Science Controversies. http://www.hsph.harvard.edu/forum/boosting-vitamin-d-not-enough-or-too-much.cfm. Published March 29 2011. Accessed April 22, 2011.
16. Binkley N, Gemar D, Engelke J, et al. Evaluation of ergocalciferol or cholecalciferol dosing, 1,600 IU daily or 50,000 IU monthly in older adults. J Clin Endocrinol Metab. 2011;96(4):981-988.
17. Heaney RP, Recker RR, Grote J, Horst RL, Armas LA. Vitamin D(3) is more potent than vitamin D(2) in humans. J Clin Endocrinol Metab. 2011;96(3):E447-452.
18. Holick MF, Biancuzzo RM, Chen TC, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab. 2008;93(3):677-681.
19. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington DC: National Osteoporosis Foundation; 2010. http://www.nof.org/professionals/clinical-guidelines. Accessed June 7, 2011.
20. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303(18):1815-1822.
21. Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, et al. Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):81-93.
22. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168(15):1629-1637.
 | Hear Dr. Szmuilowicz discuss treatment recommendations |
Emily D. Szmuilowicz, MD, MS
Dr. Szmuilowicz is Clinical Instructor in the Division of Endocrinology, Metabolism, and Molecular Medicine at Northwestern University, Chicago, Ill.
JoAnn E. Manson, MD, DrPH
Dr. Manson is Chief of the Division of Preventive Medicine at Brigham and Women’s Hospital and Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, Boston, Mass.
Dr. Szmuilowicz reports no financial relationships relevant to this article. Dr. Manson reports that she was a member of the Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. She and her colleagues at Brigham and Women’s Hospital, Harvard Medical School, are recipients of funding from the National Institutes of Health to conduct the VITamin D and OmegA-3 TriaL (VITAL), a large-scale randomized trial of vitamin D and omega-3s in the prevention of cancer and cardiovascular disease.
| Hear Dr. Szmuilowicz discuss treatment recommendations |
Emily D. Szmuilowicz, MD, MS
Dr. Szmuilowicz is Clinical Instructor in the Division of Endocrinology, Metabolism, and Molecular Medicine at Northwestern University, Chicago, Ill.
JoAnn E. Manson, MD, DrPH
Dr. Manson is Chief of the Division of Preventive Medicine at Brigham and Women’s Hospital and Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, Boston, Mass.
Dr. Szmuilowicz reports no financial relationships relevant to this article. Dr. Manson reports that she was a member of the Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. She and her colleagues at Brigham and Women’s Hospital, Harvard Medical School, are recipients of funding from the National Institutes of Health to conduct the VITamin D and OmegA-3 TriaL (VITAL), a large-scale randomized trial of vitamin D and omega-3s in the prevention of cancer and cardiovascular disease.
| Hear Dr. Szmuilowicz discuss treatment recommendations |
Emily D. Szmuilowicz, MD, MS
Dr. Szmuilowicz is Clinical Instructor in the Division of Endocrinology, Metabolism, and Molecular Medicine at Northwestern University, Chicago, Ill.
JoAnn E. Manson, MD, DrPH
Dr. Manson is Chief of the Division of Preventive Medicine at Brigham and Women’s Hospital and Professor of Medicine and the Michael and Lee Bell Professor of Women’s Health at Harvard Medical School, Boston, Mass.
Dr. Szmuilowicz reports no financial relationships relevant to this article. Dr. Manson reports that she was a member of the Institute of Medicine Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. She and her colleagues at Brigham and Women’s Hospital, Harvard Medical School, are recipients of funding from the National Institutes of Health to conduct the VITamin D and OmegA-3 TriaL (VITAL), a large-scale randomized trial of vitamin D and omega-3s in the prevention of cancer and cardiovascular disease.
No question: Vitamin D plays a vital role in bone health. In recent years, the possibility that it plays a role in other aspects of health has prompted considerable speculation, fueled by both widespread media coverage and dissemination of conflicting information about the potential nonskeletal benefits of high-dose vitamin D supplementation. Controversy has emerged about:
- the appropriate criteria for defining vitamin D deficiency
- the extent to which vitamin D influences nonskeletal health conditions
- the optimal level of vitamin D supplementation.
In 2010, the Institute of Medicine (IOM) released a report that provided recommendations for vitamin D intake, which were also summarized in a recent article for clinicians.1,2 The IOM report provided much-needed clinical guidance, but it has also fueled additional questions.
This article describes the IOM recommendations, explains what we know now about the effect of vitamin D on various health outcomes, and offers concrete recommendations on vitamin D measurement, intake, and supplementation.
How the Institute of Medicine formulated its recommendations
The Institute of Medicine (IOM) committee conducted a comprehensive review of the literature to date on the relationship between vitamin D (and calcium) intake and several health outcomes. In terms of skeletal health, the IOM committee concluded that a 25OHD level of at least 20 ng/mL is sufficient to meet the needs of at least 97.5% of the population. The vitamin D intake thought to be necessary to achieve this 25OHD level for at least 97.5% of the population was provided for different age groups (TABLE 2).
The Recommended Dietary Allowance (RDA) of vitamin D is 600 IU daily for all adults up to age 70 years, and 800 IU daily for adults older than 70 years. These values were based on an assumption of minimal sun exposure, due to wide variability in vitamin D synthesis from ultraviolet light, as well as the risk of skin cancer. The IOM concluded that there is no compelling evidence that a 25OHD level above 20 ng/mL or a vitamin D intake greater than 600 IU (800Â IU for adults over 70) affords greater skeletal or nonskeletal benefits.
The IOM recommendations were based on the integration of bone health outcomes. The evidence supporting causal relationships between vitamin D insufficiency and nonskeletal outcomes such as cancer, cardiovascular disease, diabetes, impaired physical performance, autoimmune disorders, and other chronic diseases was found to be inconsistent and inconclusive.
The IOM report also noted the emergence of a “U”-shaped curve in regard to vitamin D and several health outcomes, which has fueled concern about attainment of a 25OHD level above 50 ng/mL. The IOM committee designated 4,000 IU daily as the tolerable upper intake but emphasized that research into long-term outcomes and safety at intakes above the RDA is limited. Therefore, this upper limit should not be interpreted as a target intake level.
How is vitamin D metabolized?
Vitamin D is produced endogenously in the skin in the form of vitamin D3 (cholecalciferol). It also can be ingested exogenously in the form of vitamin D3 or vitamin D2 (ergocalciferol). Cutaneous synthesis of vitamin D is stimulated by solar ultraviolet radiation.
Vitamin D2 and D3 are hydroxylated in the liver to form 25-hydroxyvitamin D (25OHD). Measurement of the serum 25OHD level is thought to be the most reliable indicator of vitamin D exposure.3 25OHD is hydroxylated again, primarily in the kidneys, to the most active form of vitamin D (1,25-dihydroxyvitamin D).
The adverse skeletal effects of severe vitamin D deficiency are well established; those effects include calcium malabsorption, secondary hyperparathyroidism, bone loss, and increased risk of fracture. In this setting, secondary hyperparathyroidism results from both decreased gastrointestinal calcium absorption and decreased suppression of parathyroid hormone (PTH) production by the parathyroid glands from vitamin D metabolites. Secondary hyperparathyroidism leads to increased bone resorption and bone loss. Rickets, osteomalacia, hypocalcemia, hypophosphatemia, muscle weakness, and bone pain are less common effects that can occur with severe vitamin D deficiency.
It is worth noting that women of color are at increased risk of vitamin D deficiency as a result of greater skin pigmentation.3 Obesity is also a risk factor for vitamin D deficiency.3 Additional risk factors for vitamin D insufficiency are listed in TABLE 1.
TABLE 1
Risk factors for vitamin D insufficiency
| Obesity |
| Dark skin pigmentation |
Decreased sun exposure
|
| Low dietary intake of vitamin D |
| Malabsorption of ingested vitamin D |
Increased hepatic degradation of 25-hydroxyvitamin D
|
| Decreased hepatic hydroxylation of vitamin D (occurs only with severe hepatic disease) |
| Impaired renal hydroxylation of vitamin D (renal insufficiency) |
| Osteoporosis or osteopenia |
How should vitamin D insufficiency be defined?
Biochemical criteria for defining vitamin D insufficiency vary. That makes it difficult to estimate the prevalence of vitamin D insufficiency.
Severe vitamin D deficiency is commonly defined as a serum 25OHD level below 10 ng/mL.3 Vitamin D insufficiency has been variably defined as a serum 25OHD level below 20 to 32 ng/mL,3,4 and the lower limit of normal in most clinical laboratories is now typically 30 to 32 ng/mL. Many patients become concerned when their serum 25OHD level is flagged as “low” on a laboratory report, and it’s likely that you are called on from time to time to interpret and make recommendations about the appropriate response to this “abnormal” finding.
The broad definition of vitamin D insufficiency stems, in part, from the assessment of a wide range of outcomes. Measures that have been used include fracture risk, calcium absorptive capacity, and the serum concentration of PTH. In regard to calcium absorption, most studies suggest that maximal dietary calcium absorption occurs when the 25OHD level reaches 20 ng/mL, although some studies suggest a higher threshold.1,3
The optimal level of 25OHD for PTH suppression remains unclear. Several studies have suggested that the PTH level increases when the 25OHD concentration falls below 30 ng/mL,4,5 although this threshold has varied substantially across studies.6
How prevalent is vitamin D insufficiency?
Estimates of the prevalence of vitamin D insufficiency vary by the criteria used to define the condition. A recent report using data from the National Health and Nutrition Examination Survey (NHANES) estimated that approximately 30% of US adults 20 years of age or older have a 25OHD level below 20Â ng/mL, and more than 70% of this age group has a 25OHD level below 32 ng/mL.7
The IOM committee noted that several reports have most likely overestimated the prevalence of vitamin D insufficiency through the use of 25OHD cut points higher than 20Â ng/mL.
The data on vitamin D insufficiency and skeletal health
Many studies have examined the relationship between vitamin D supplementation or the 25OHD level and fracture risk, and conflicting results have emerged. Many trials have examined the combination of calcium and vitamin D supplementation, the effects of which are tightly interwoven, confounding interpretation.
Interpretation of large observational studies is further confounded by the inability to attribute association to causation. In the Women’s Health Initiative (WHI) study of calcium with vitamin D, treatment of healthy postmenopausal women with 1,000 mg of calcium and 400 IU of vitamin D daily led to improved bone density at the hip but no statistically significant reduction in hip fracture.8 However, a reduced risk of hip fracture was demonstrated in secondary analyses among women who adhered to treatment and among women 60 years or older. Meta-analyses of clinical trials have reported that treatment with varying doses of vitamin D (more than 400 IU daily) reduces the risk of vertebral,9 nonvertebral,10 and hip fractures.10
Several studies have examined the relationship between the 25OHD level and fracture risk, with inconsistent findings:
- A nested case-control study from the WHI found that the risk of hip fracture was significantly increased among postmenopausal women who had a 25OHD level of 19 ng/mL or lower.11
- A 2009 report from the Agency for Healthcare Research and Quality (AHRQ) concluded that the association between the 25OHD level and the risk of fracture was inconsistent.12
After a comprehensive review of the available research, the IOM committee concluded that a serum 25OHD level of 20 ng/mL would meet the needs for bone health for at least 97.5% of the US and Canadian populations.
TABLE 2
Calcium and vitamin D dietary reference intakes for adults, by life stage
| Life stage (gender) | Calcium | Vitamin D | |||
|---|---|---|---|---|---|
| RDA (mg/d) | Tolerable upper intake level (mg/d)* | RDA (IU/d) | Serum 25OHD level (ng/mL) (corresponding to the RDA)† | Tolerable upper intake level (IU/d)* | |
| 19–50 yr (male and female) | 1,000 | 2,500 | 600 | 20 | 4,000 |
| 51–70 yr (male) | 1,000 | 2,000 | 600 | 20 | 4,000 |
| 51–70 yr (female) | 1,200 | 2,000 | 600 | 20 | 4,000 |
| 71+ yr (male and female) | 1,200 | 2,000 | 800 | 20 | 4,000 |
| Adapted from: Ross AC, Manson JE, Abrams SA, et al. J Clin Endocrinol Metab. 2011;96(1):53–58. RDA = Recommended Dietary Allowance, 25OHD=25-hydroxyvitamin D * The tolerable upper intake level is the threshold above which is a risk of adverse events. The upper intake level is not intended to be a target intake. There is no consistent evidence of greater benefit at intake levels above the RDA. The serum 25OHD level corresponding to the upper intake level is 50 ng/mL. † Measures of the serum 25OHD level corresponding to the RDA and covering the requirements of at least 97.5% of the population. | |||||
The data on vitamin D insufficiency and nonskeletal outcomes
Many observational studies have reported relationships between vitamin D insufficiency and myriad nonskeletal health outcomes, particularly cardiovascular disease, cancer, diabetes, and autoimmune disorders.3 However, well-designed randomized clinical trials that examine nonskeletal outcomes as primary pre-specified outcomes are lacking.13 Such studies will be essential to elucidate the relationship between vitamin D insufficiency and nonskeletal chronic diseases. The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing large-scale, randomized clinical trial designed to evaluate the role of supplementation with 2,000 IU of vitamin D3 daily in the primary prevention of cancer and cardiovascular disease.14
- Vitamin D plays a vital role in bone health
- The Institute of Medicine released a 2010 report that provided public health recommendations for vitamin D intake based on bone health outcomes
- Many observational studies have reported a relationship between vitamin D insufficiency and adverse nonskeletal health outcomes, including cardiovascular disease, cancer, diabetes, and autoimmune disorders, but evidence from randomized clinical trials on the potential nonskeletal benefits of vitamin D is sparse
- Excessive vitamin D intake should be avoided because of the potential for harm and the lack of evidence from well-designed clinical trials that vitamin D intake beyond the recommended amount affords greater skeletal or nonskeletal health benefits
- Among women who have an increased risk of vitamin D insufficiency or bone loss, 25OHD concentration should be measured and vitamin D supplementation should be provided as necessary to achieve the target 25OHD level
What we recommend for treatment
The IOM report provided the medical community with evidence-based recommendations for vitamin D intake at the population level, based on a public health perspective.1,2 However, the public health guideline model must be distinguished from the medical model, in which shared clinical decision-making between physician and patient occurs on an individual level and is informed by individual clinical risk factors. The public health recommendations detailed in the IOM report are not intended to replace or interfere with clinical judgment or preclude individualized clinical decision-making.
The debate over optimal levels of vitamin D supplementation for individual patients who have osteoporosis or other health conditions continues.15 Here, we provide general guidelines for treatment, based on the evidence available to date.
Clear benefits of vitamin D in bone health notwithstanding, advise your patients to avoid excessive intake because it can cause harm. See “More is not necessarily better”.
Recommendations for healthy adult nonpregnant women
Vitamin D intake: We recommend a daily vitamin D intake of 600 IU for healthy nonpregnant women up to age 70 years (and 800 Â IU daily for women older than 70 years) who are at average risk of vitamin D insufficiency and bone loss, consistent with the IOM recommendations. The IOM guidelines assume minimal to no sun exposure.
Measurement of 25OHD: It is not necessary to routinely measure the 25OHD level in these women. However, it is prudent to measure 25OHD in women who have risk factors for vitamin D insufficiency (TABLE 1) or a clinical condition associated with severe vitamin D deficiency. In these cases, if the 25OHD level is found to be below 20 ng/mL, vitamin D therapy should be initiated, with the goal of boosting the 25OHD level above the threshold of 20 ng/mL.
Treatment of vitamin D insufficiency: Options include daily vitamin D supplementation and higher-dose weekly preparations.
Many clinicians treat severe vitamin D insufficiency with 50,000 IU of vitamin D2 once weekly for 8 weeks, followed by a maintenance dose (described below) of vitamin D to preserve the target 25OHD level.5 An alternative is daily vitamin D supplementation, with the dosage based on the degree of insufficiency.
A general rule of thumb, for persons who have normal vitamin D absorption, is that every 1,000 IU of vitamin D3 ingested daily increases the 25OHD level by approximately 6 to 10 ng/mL.4,16 However, the incremental increase in the 25OHD concentration varies among individuals, depending on the baseline 25OHD level, with a greater incremental increase occurring at lower baseline 25OHD levels.
Monitoring of the 25OHD level after adjustment of the dosage is necessary to ensure that the target level is achieved.
Maintaining an adequate vitamin D level: Once vitamin D insufficiency has been corrected, a maintenance dosage of vitamin D should be selected—commonly 800 to 1,000 Â IU daily. A higher maintenance dosage may be required for persons who have genetic or ongoing environmental factors that predispose them to vitamin D insufficiency.
Vitamin D3 is reportedly more potent than D2 in increasing the 25OHD level,17 although this finding has not been universal.18 Monthly or twice-monthly administration of 50,000 IU of vitamin D2 is another option for maintenance of vitamin D sufficiency,5,16 although daily doses are more commonly used and are readily available in over-the-counter preparations.
Regardless of the regimen selected, the 25OHD level should be measured again approximately 3 months after a change in dosage to ensure that the target level has been achieved, with further dosage adjustments as indicated.
Recommendations for adult women at increased risk of skeletal disease
Measurement of 25OHD: The 25OHD level should be measured among women at increased risk of vitamin D insufficiency, bone loss, or fracture and among women who have established skeletal disease.
Vitamin D intake: We recommend that women at increased risk of osteoporosis and women older than 70 years receive at least 800 IU daily and, potentially, more if necessary to achieve the target 25OHD level.
Although the evidence to date does not support routine achievement of a 25OHD level substantially above 20 ng/mL in most women, many clinicians recommend that women in this higher-risk group maintain a 25OHD level above 30 ng/mL because of the possibly greater (although unproven) skeletal and nonskeletal benefits. As more data become available regarding the benefits and safety of vitamin D doses higher than those recommended by the IOM, these recommendations may be revised.
In 2010, the National Osteoporosis Foundation (NOF) recommended a vitamin D intake of 800 to 1,000 IU daily for all adults 50 years and older. Among persons at risk of deficiency, the NOF also recommended measurement of the serum 25OHD level, with vitamin D supplementation, as necessary, to achieve a 25OHD level of 30 ng/mL or higher.19 Also in 2010, the International Osteoporosis Foundation (IOF) recommended a target 25OHD level above 30 ng/mL for all older adults. The IOF also estimated that the average dosage required to achieve this level in older adults is 800 to 1,000 IU daily, noting that upward adjustment may be required in some people.4 It is unclear whether these guidelines will be revised in the future, based on the IOM report.
We recommend against achieving a 25OHD level above 50 ng/mL, based on evidence suggesting potential adverse health effects above this level.
Excessive vitamin D intake should be avoided because of the potential for harm and the lack of evidence from well-designed clinical trials that vitamin D intake beyond the currently recommended amount affords greater skeletal or nonskeletal health benefits. Although moderate vitamin D supplementation has proven skeletal benefits, a “U-shaped” curve for some outcomes has emerged, suggesting that excessive vitamin D supplementation may pose health risks. Notably, a recent clinical trial reported a higher risk of fracture (and falls) among elderly women treated annually with high-dose (500,000 IU) oral vitamin D3 versus placebo.20
A suggestion of adverse effects associated with 25OHD levels above 50 ng/mL has also emerged, from observational studies, for several nonskeletal health outcomes, including pancreatic cancer,21 cardiovascular disease,1 and all-cause mortality.22
Limited evidence is available regarding the safety and overall risk-benefit profile of long-term maintenance of 25OHD levels above the recommended dietary allowance (RDA) range. Therefore, you should remind your patients that, despite the importance of both prevention and treatment of vitamin D insufficiency, more is not necessarily better.
We want to hear from you! Tell us what you think.
No question: Vitamin D plays a vital role in bone health. In recent years, the possibility that it plays a role in other aspects of health has prompted considerable speculation, fueled by both widespread media coverage and dissemination of conflicting information about the potential nonskeletal benefits of high-dose vitamin D supplementation. Controversy has emerged about:
- the appropriate criteria for defining vitamin D deficiency
- the extent to which vitamin D influences nonskeletal health conditions
- the optimal level of vitamin D supplementation.
In 2010, the Institute of Medicine (IOM) released a report that provided recommendations for vitamin D intake, which were also summarized in a recent article for clinicians.1,2 The IOM report provided much-needed clinical guidance, but it has also fueled additional questions.
This article describes the IOM recommendations, explains what we know now about the effect of vitamin D on various health outcomes, and offers concrete recommendations on vitamin D measurement, intake, and supplementation.
How the Institute of Medicine formulated its recommendations
The Institute of Medicine (IOM) committee conducted a comprehensive review of the literature to date on the relationship between vitamin D (and calcium) intake and several health outcomes. In terms of skeletal health, the IOM committee concluded that a 25OHD level of at least 20 ng/mL is sufficient to meet the needs of at least 97.5% of the population. The vitamin D intake thought to be necessary to achieve this 25OHD level for at least 97.5% of the population was provided for different age groups (TABLE 2).
The Recommended Dietary Allowance (RDA) of vitamin D is 600 IU daily for all adults up to age 70 years, and 800 IU daily for adults older than 70 years. These values were based on an assumption of minimal sun exposure, due to wide variability in vitamin D synthesis from ultraviolet light, as well as the risk of skin cancer. The IOM concluded that there is no compelling evidence that a 25OHD level above 20 ng/mL or a vitamin D intake greater than 600 IU (800Â IU for adults over 70) affords greater skeletal or nonskeletal benefits.
The IOM recommendations were based on the integration of bone health outcomes. The evidence supporting causal relationships between vitamin D insufficiency and nonskeletal outcomes such as cancer, cardiovascular disease, diabetes, impaired physical performance, autoimmune disorders, and other chronic diseases was found to be inconsistent and inconclusive.
The IOM report also noted the emergence of a “U”-shaped curve in regard to vitamin D and several health outcomes, which has fueled concern about attainment of a 25OHD level above 50 ng/mL. The IOM committee designated 4,000 IU daily as the tolerable upper intake but emphasized that research into long-term outcomes and safety at intakes above the RDA is limited. Therefore, this upper limit should not be interpreted as a target intake level.
How is vitamin D metabolized?
Vitamin D is produced endogenously in the skin in the form of vitamin D3 (cholecalciferol). It also can be ingested exogenously in the form of vitamin D3 or vitamin D2 (ergocalciferol). Cutaneous synthesis of vitamin D is stimulated by solar ultraviolet radiation.
Vitamin D2 and D3 are hydroxylated in the liver to form 25-hydroxyvitamin D (25OHD). Measurement of the serum 25OHD level is thought to be the most reliable indicator of vitamin D exposure.3 25OHD is hydroxylated again, primarily in the kidneys, to the most active form of vitamin D (1,25-dihydroxyvitamin D).
The adverse skeletal effects of severe vitamin D deficiency are well established; those effects include calcium malabsorption, secondary hyperparathyroidism, bone loss, and increased risk of fracture. In this setting, secondary hyperparathyroidism results from both decreased gastrointestinal calcium absorption and decreased suppression of parathyroid hormone (PTH) production by the parathyroid glands from vitamin D metabolites. Secondary hyperparathyroidism leads to increased bone resorption and bone loss. Rickets, osteomalacia, hypocalcemia, hypophosphatemia, muscle weakness, and bone pain are less common effects that can occur with severe vitamin D deficiency.
It is worth noting that women of color are at increased risk of vitamin D deficiency as a result of greater skin pigmentation.3 Obesity is also a risk factor for vitamin D deficiency.3 Additional risk factors for vitamin D insufficiency are listed in TABLE 1.
TABLE 1
Risk factors for vitamin D insufficiency
| Obesity |
| Dark skin pigmentation |
Decreased sun exposure
|
| Low dietary intake of vitamin D |
| Malabsorption of ingested vitamin D |
Increased hepatic degradation of 25-hydroxyvitamin D
|
| Decreased hepatic hydroxylation of vitamin D (occurs only with severe hepatic disease) |
| Impaired renal hydroxylation of vitamin D (renal insufficiency) |
| Osteoporosis or osteopenia |
How should vitamin D insufficiency be defined?
Biochemical criteria for defining vitamin D insufficiency vary. That makes it difficult to estimate the prevalence of vitamin D insufficiency.
Severe vitamin D deficiency is commonly defined as a serum 25OHD level below 10 ng/mL.3 Vitamin D insufficiency has been variably defined as a serum 25OHD level below 20 to 32 ng/mL,3,4 and the lower limit of normal in most clinical laboratories is now typically 30 to 32 ng/mL. Many patients become concerned when their serum 25OHD level is flagged as “low” on a laboratory report, and it’s likely that you are called on from time to time to interpret and make recommendations about the appropriate response to this “abnormal” finding.
The broad definition of vitamin D insufficiency stems, in part, from the assessment of a wide range of outcomes. Measures that have been used include fracture risk, calcium absorptive capacity, and the serum concentration of PTH. In regard to calcium absorption, most studies suggest that maximal dietary calcium absorption occurs when the 25OHD level reaches 20 ng/mL, although some studies suggest a higher threshold.1,3
The optimal level of 25OHD for PTH suppression remains unclear. Several studies have suggested that the PTH level increases when the 25OHD concentration falls below 30 ng/mL,4,5 although this threshold has varied substantially across studies.6
How prevalent is vitamin D insufficiency?
Estimates of the prevalence of vitamin D insufficiency vary by the criteria used to define the condition. A recent report using data from the National Health and Nutrition Examination Survey (NHANES) estimated that approximately 30% of US adults 20 years of age or older have a 25OHD level below 20Â ng/mL, and more than 70% of this age group has a 25OHD level below 32 ng/mL.7
The IOM committee noted that several reports have most likely overestimated the prevalence of vitamin D insufficiency through the use of 25OHD cut points higher than 20Â ng/mL.
The data on vitamin D insufficiency and skeletal health
Many studies have examined the relationship between vitamin D supplementation or the 25OHD level and fracture risk, and conflicting results have emerged. Many trials have examined the combination of calcium and vitamin D supplementation, the effects of which are tightly interwoven, confounding interpretation.
Interpretation of large observational studies is further confounded by the inability to attribute association to causation. In the Women’s Health Initiative (WHI) study of calcium with vitamin D, treatment of healthy postmenopausal women with 1,000 mg of calcium and 400 IU of vitamin D daily led to improved bone density at the hip but no statistically significant reduction in hip fracture.8 However, a reduced risk of hip fracture was demonstrated in secondary analyses among women who adhered to treatment and among women 60 years or older. Meta-analyses of clinical trials have reported that treatment with varying doses of vitamin D (more than 400 IU daily) reduces the risk of vertebral,9 nonvertebral,10 and hip fractures.10
Several studies have examined the relationship between the 25OHD level and fracture risk, with inconsistent findings:
- A nested case-control study from the WHI found that the risk of hip fracture was significantly increased among postmenopausal women who had a 25OHD level of 19 ng/mL or lower.11
- A 2009 report from the Agency for Healthcare Research and Quality (AHRQ) concluded that the association between the 25OHD level and the risk of fracture was inconsistent.12
After a comprehensive review of the available research, the IOM committee concluded that a serum 25OHD level of 20 ng/mL would meet the needs for bone health for at least 97.5% of the US and Canadian populations.
TABLE 2
Calcium and vitamin D dietary reference intakes for adults, by life stage
| Life stage (gender) | Calcium | Vitamin D | |||
|---|---|---|---|---|---|
| RDA (mg/d) | Tolerable upper intake level (mg/d)* | RDA (IU/d) | Serum 25OHD level (ng/mL) (corresponding to the RDA)† | Tolerable upper intake level (IU/d)* | |
| 19–50 yr (male and female) | 1,000 | 2,500 | 600 | 20 | 4,000 |
| 51–70 yr (male) | 1,000 | 2,000 | 600 | 20 | 4,000 |
| 51–70 yr (female) | 1,200 | 2,000 | 600 | 20 | 4,000 |
| 71+ yr (male and female) | 1,200 | 2,000 | 800 | 20 | 4,000 |
| Adapted from: Ross AC, Manson JE, Abrams SA, et al. J Clin Endocrinol Metab. 2011;96(1):53–58. RDA = Recommended Dietary Allowance, 25OHD=25-hydroxyvitamin D * The tolerable upper intake level is the threshold above which is a risk of adverse events. The upper intake level is not intended to be a target intake. There is no consistent evidence of greater benefit at intake levels above the RDA. The serum 25OHD level corresponding to the upper intake level is 50 ng/mL. † Measures of the serum 25OHD level corresponding to the RDA and covering the requirements of at least 97.5% of the population. | |||||
The data on vitamin D insufficiency and nonskeletal outcomes
Many observational studies have reported relationships between vitamin D insufficiency and myriad nonskeletal health outcomes, particularly cardiovascular disease, cancer, diabetes, and autoimmune disorders.3 However, well-designed randomized clinical trials that examine nonskeletal outcomes as primary pre-specified outcomes are lacking.13 Such studies will be essential to elucidate the relationship between vitamin D insufficiency and nonskeletal chronic diseases. The VITamin D and OmegA-3 TriaL (VITAL) is an ongoing large-scale, randomized clinical trial designed to evaluate the role of supplementation with 2,000 IU of vitamin D3 daily in the primary prevention of cancer and cardiovascular disease.14
- Vitamin D plays a vital role in bone health
- The Institute of Medicine released a 2010 report that provided public health recommendations for vitamin D intake based on bone health outcomes
- Many observational studies have reported a relationship between vitamin D insufficiency and adverse nonskeletal health outcomes, including cardiovascular disease, cancer, diabetes, and autoimmune disorders, but evidence from randomized clinical trials on the potential nonskeletal benefits of vitamin D is sparse
- Excessive vitamin D intake should be avoided because of the potential for harm and the lack of evidence from well-designed clinical trials that vitamin D intake beyond the recommended amount affords greater skeletal or nonskeletal health benefits
- Among women who have an increased risk of vitamin D insufficiency or bone loss, 25OHD concentration should be measured and vitamin D supplementation should be provided as necessary to achieve the target 25OHD level
What we recommend for treatment
The IOM report provided the medical community with evidence-based recommendations for vitamin D intake at the population level, based on a public health perspective.1,2 However, the public health guideline model must be distinguished from the medical model, in which shared clinical decision-making between physician and patient occurs on an individual level and is informed by individual clinical risk factors. The public health recommendations detailed in the IOM report are not intended to replace or interfere with clinical judgment or preclude individualized clinical decision-making.
The debate over optimal levels of vitamin D supplementation for individual patients who have osteoporosis or other health conditions continues.15 Here, we provide general guidelines for treatment, based on the evidence available to date.
Clear benefits of vitamin D in bone health notwithstanding, advise your patients to avoid excessive intake because it can cause harm. See “More is not necessarily better”.
Recommendations for healthy adult nonpregnant women
Vitamin D intake: We recommend a daily vitamin D intake of 600 IU for healthy nonpregnant women up to age 70 years (and 800 Â IU daily for women older than 70 years) who are at average risk of vitamin D insufficiency and bone loss, consistent with the IOM recommendations. The IOM guidelines assume minimal to no sun exposure.
Measurement of 25OHD: It is not necessary to routinely measure the 25OHD level in these women. However, it is prudent to measure 25OHD in women who have risk factors for vitamin D insufficiency (TABLE 1) or a clinical condition associated with severe vitamin D deficiency. In these cases, if the 25OHD level is found to be below 20 ng/mL, vitamin D therapy should be initiated, with the goal of boosting the 25OHD level above the threshold of 20 ng/mL.
Treatment of vitamin D insufficiency: Options include daily vitamin D supplementation and higher-dose weekly preparations.
Many clinicians treat severe vitamin D insufficiency with 50,000 IU of vitamin D2 once weekly for 8 weeks, followed by a maintenance dose (described below) of vitamin D to preserve the target 25OHD level.5 An alternative is daily vitamin D supplementation, with the dosage based on the degree of insufficiency.
A general rule of thumb, for persons who have normal vitamin D absorption, is that every 1,000 IU of vitamin D3 ingested daily increases the 25OHD level by approximately 6 to 10 ng/mL.4,16 However, the incremental increase in the 25OHD concentration varies among individuals, depending on the baseline 25OHD level, with a greater incremental increase occurring at lower baseline 25OHD levels.
Monitoring of the 25OHD level after adjustment of the dosage is necessary to ensure that the target level is achieved.
Maintaining an adequate vitamin D level: Once vitamin D insufficiency has been corrected, a maintenance dosage of vitamin D should be selected—commonly 800 to 1,000 Â IU daily. A higher maintenance dosage may be required for persons who have genetic or ongoing environmental factors that predispose them to vitamin D insufficiency.
Vitamin D3 is reportedly more potent than D2 in increasing the 25OHD level,17 although this finding has not been universal.18 Monthly or twice-monthly administration of 50,000 IU of vitamin D2 is another option for maintenance of vitamin D sufficiency,5,16 although daily doses are more commonly used and are readily available in over-the-counter preparations.
Regardless of the regimen selected, the 25OHD level should be measured again approximately 3 months after a change in dosage to ensure that the target level has been achieved, with further dosage adjustments as indicated.
Recommendations for adult women at increased risk of skeletal disease
Measurement of 25OHD: The 25OHD level should be measured among women at increased risk of vitamin D insufficiency, bone loss, or fracture and among women who have established skeletal disease.
Vitamin D intake: We recommend that women at increased risk of osteoporosis and women older than 70 years receive at least 800 IU daily and, potentially, more if necessary to achieve the target 25OHD level.
Although the evidence to date does not support routine achievement of a 25OHD level substantially above 20 ng/mL in most women, many clinicians recommend that women in this higher-risk group maintain a 25OHD level above 30 ng/mL because of the possibly greater (although unproven) skeletal and nonskeletal benefits. As more data become available regarding the benefits and safety of vitamin D doses higher than those recommended by the IOM, these recommendations may be revised.
In 2010, the National Osteoporosis Foundation (NOF) recommended a vitamin D intake of 800 to 1,000 IU daily for all adults 50 years and older. Among persons at risk of deficiency, the NOF also recommended measurement of the serum 25OHD level, with vitamin D supplementation, as necessary, to achieve a 25OHD level of 30 ng/mL or higher.19 Also in 2010, the International Osteoporosis Foundation (IOF) recommended a target 25OHD level above 30 ng/mL for all older adults. The IOF also estimated that the average dosage required to achieve this level in older adults is 800 to 1,000 IU daily, noting that upward adjustment may be required in some people.4 It is unclear whether these guidelines will be revised in the future, based on the IOM report.
We recommend against achieving a 25OHD level above 50 ng/mL, based on evidence suggesting potential adverse health effects above this level.
Excessive vitamin D intake should be avoided because of the potential for harm and the lack of evidence from well-designed clinical trials that vitamin D intake beyond the currently recommended amount affords greater skeletal or nonskeletal health benefits. Although moderate vitamin D supplementation has proven skeletal benefits, a “U-shaped” curve for some outcomes has emerged, suggesting that excessive vitamin D supplementation may pose health risks. Notably, a recent clinical trial reported a higher risk of fracture (and falls) among elderly women treated annually with high-dose (500,000 IU) oral vitamin D3 versus placebo.20
A suggestion of adverse effects associated with 25OHD levels above 50 ng/mL has also emerged, from observational studies, for several nonskeletal health outcomes, including pancreatic cancer,21 cardiovascular disease,1 and all-cause mortality.22
Limited evidence is available regarding the safety and overall risk-benefit profile of long-term maintenance of 25OHD levels above the recommended dietary allowance (RDA) range. Therefore, you should remind your patients that, despite the importance of both prevention and treatment of vitamin D insufficiency, more is not necessarily better.
We want to hear from you! Tell us what you think.
1. Institute of Medicine. 2011 Dietary Reference Intakes for Calcium and Vitamin D. Washington DC: National Academies Press; 2011.
2. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53-58.
3. Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J Med. 2011;364(3):248-254.
4. Dawson-Hughes B, Mithal A, Bonjour JP, et al. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010;21(7):1151-1154.
5. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.
6. Sai AJ, Walters RW, Fang X, Gallagher JC. Relationship between vitamin D parathyroid hormone, and bone health. J Clin Endocrinol Metab. 2011;96(3):E436-446.
7. Yetley EA. Assessing the vitamin D status of the US population. Am J Clin Nutr. 2008;88(2):558S-564S.
8. Jackson RD, LaCroix AZ, Gass M, et al. Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669-683.
9. Papadimitropoulos E, Wells G, Shea B, et al. Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev. 2002;23(4):560-569.
10. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169(6):551-561.
11. Cauley JA, Lacroix AZ, Wu L, et al. Serum 25-hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med. 2008;149(4):242-250.
12. Chung M, Balk EM, Brendel M, et al. Vitamin D and calcium: a systematic review of health outcomes. Evid Rep Technol Assess (Full Rep). 2009;(183):1-420.
13. Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer—ready for prime time? N Engl J Med. 2011;364(15):1385-1387.
14. Manson JE. Vitamin D and the heart: why we need large-scale clinical trials. Cleve Clin J Med. 2010;77(12):903-910.
15. The Forum at Harvard School of Public Health. Boosting Vitamin D: Not enough or too much? The Andelot Series on Current Science Controversies. http://www.hsph.harvard.edu/forum/boosting-vitamin-d-not-enough-or-too-much.cfm. Published March 29 2011. Accessed April 22, 2011.
16. Binkley N, Gemar D, Engelke J, et al. Evaluation of ergocalciferol or cholecalciferol dosing, 1,600 IU daily or 50,000 IU monthly in older adults. J Clin Endocrinol Metab. 2011;96(4):981-988.
17. Heaney RP, Recker RR, Grote J, Horst RL, Armas LA. Vitamin D(3) is more potent than vitamin D(2) in humans. J Clin Endocrinol Metab. 2011;96(3):E447-452.
18. Holick MF, Biancuzzo RM, Chen TC, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab. 2008;93(3):677-681.
19. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington DC: National Osteoporosis Foundation; 2010. http://www.nof.org/professionals/clinical-guidelines. Accessed June 7, 2011.
20. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303(18):1815-1822.
21. Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, et al. Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):81-93.
22. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168(15):1629-1637.
1. Institute of Medicine. 2011 Dietary Reference Intakes for Calcium and Vitamin D. Washington DC: National Academies Press; 2011.
2. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53-58.
3. Rosen CJ. Clinical practice. Vitamin D insufficiency. N Engl J Med. 2011;364(3):248-254.
4. Dawson-Hughes B, Mithal A, Bonjour JP, et al. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010;21(7):1151-1154.
5. Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.
6. Sai AJ, Walters RW, Fang X, Gallagher JC. Relationship between vitamin D parathyroid hormone, and bone health. J Clin Endocrinol Metab. 2011;96(3):E436-446.
7. Yetley EA. Assessing the vitamin D status of the US population. Am J Clin Nutr. 2008;88(2):558S-564S.
8. Jackson RD, LaCroix AZ, Gass M, et al. Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669-683.
9. Papadimitropoulos E, Wells G, Shea B, et al. Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev. 2002;23(4):560-569.
10. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169(6):551-561.
11. Cauley JA, Lacroix AZ, Wu L, et al. Serum 25-hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med. 2008;149(4):242-250.
12. Chung M, Balk EM, Brendel M, et al. Vitamin D and calcium: a systematic review of health outcomes. Evid Rep Technol Assess (Full Rep). 2009;(183):1-420.
13. Manson JE, Mayne ST, Clinton SK. Vitamin D and prevention of cancer—ready for prime time? N Engl J Med. 2011;364(15):1385-1387.
14. Manson JE. Vitamin D and the heart: why we need large-scale clinical trials. Cleve Clin J Med. 2010;77(12):903-910.
15. The Forum at Harvard School of Public Health. Boosting Vitamin D: Not enough or too much? The Andelot Series on Current Science Controversies. http://www.hsph.harvard.edu/forum/boosting-vitamin-d-not-enough-or-too-much.cfm. Published March 29 2011. Accessed April 22, 2011.
16. Binkley N, Gemar D, Engelke J, et al. Evaluation of ergocalciferol or cholecalciferol dosing, 1,600 IU daily or 50,000 IU monthly in older adults. J Clin Endocrinol Metab. 2011;96(4):981-988.
17. Heaney RP, Recker RR, Grote J, Horst RL, Armas LA. Vitamin D(3) is more potent than vitamin D(2) in humans. J Clin Endocrinol Metab. 2011;96(3):E447-452.
18. Holick MF, Biancuzzo RM, Chen TC, et al. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D. J Clin Endocrinol Metab. 2008;93(3):677-681.
19. National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington DC: National Osteoporosis Foundation; 2010. http://www.nof.org/professionals/clinical-guidelines. Accessed June 7, 2011.
20. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303(18):1815-1822.
21. Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, et al. Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010;172(1):81-93.
22. Melamed ML, Michos ED, Post W, Astor B. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168(15):1629-1637.
The Women’s Health Initiative: Implications for clinicians
More than 2 years have passed since we published the results of the Women’s Health Initiative (WHI), which caused a storm of information—and misinformation—about the effect of long-term dietary intervention on disease outcomes in postmenopausal women. Now that the dust has long settled, what have we learned from this landmark study?
The WHI results led to numerous additional analyses of all aspects of the study.1–7 What are the implications of all the analyses to clinical practice?
In this article, we summarize key aspects of the clinical trial, including study design, interventions, main results, and future plans. We also discuss potential clinical applications and practical considerations for public health efforts.
WHO WAS ELIGIBLE, WHO WAS NOT
A total of 48,835 postmenopausal women were randomly assigned to either no dietary intervention (n = 29,294) or a dietary intervention (n = 19,541) (see below).7 Participants were followed at 40 clinical centers between 1993 and 2005.4 Their mean age was 62.3 years; 18.6% were members of minorities.
Women were eligible if they were post-menopausal and had a daily dietary fat intake of at least 32% of total calories, based on assessment via a food-frequency questionnaire. They were excluded from the study if they had any of the following: a history of breast cancer, colorectal cancer, or other cancer except skin cancer during the past 10 years; type 1 diabetes; a medical condition in which the predicted survival was less than 3 years; and a potential barrier to adherence to the study regimen, including alcoholism or a lifestyle that involved often eating meals away from home.
THE WHI DIET: LESS FAT, BUT MORE FRUITS, VEGETABLES, GRAINS
The WHI dietary intervention was designed to prevent breast cancer, based on the evidence available when the study was planned. The targets included a total fat intake of less than 20% of energy (in kilocalories), increasing the intake of fruits and vegetables to at least five servings per day, and increasing the intake of grains to at least six servings per day.
Although reduction in saturated fat intake per se was not part of the WHI protocol, we assumed from previous pilot studies8 that the reduction of total fat intake would simultaneously produce a reduction in saturated fat intake to 7% of total calories.
A simpler dietary intervention
Unlike the 2006 American Heart Association guidelines and the US Department of Agriculture’s Dietary Guidelines for Americans 2005, the WHI dietary intervention had no specifications for dietary fiber, specific fatty acids (trans-fatty acids, omega-3 fatty acids, conjugated linoleic acid), complex carbohydrates, whole grains, vegetable protein, or other factors that have emerged as potential risk factors for cardiovascular and other chronic diseases since the study began. The WHI intervention also included no specific recommendation for total calorie intake, nor were patients in the intervention group encouraged to lose weight, as this could have confounded the results of the dietary intervention.
Education and encouragement
Those in the intervention group were each assigned a fat-gram goal, calculated on the basis of height. They were taught how to monitor their intake of total fat, fruits, vegetables, and grains. They attended intensive behavioral modification sessions to encourage them to keep to the dietary program: 18 group sessions in the first year and quarterly maintenance sessions thereafter, touching on a wide variety of nutrition- and behavior-related topics.7,9 Specially trained and certified nutritionists supervised the dietary intervention and the behavioral modification sessions according to the WHI study protocol.
Control-group participants received a copy of the US Department of Agriculture’s Dietary Guidelines for Americans10 and other health-related materials. They had no contact with the study nutritionists.
Other arms of the study
The WHI trial design included several arms,4,11–13 and many participants joined more than one arm: 20,592 postmenopausal women (42.2% of the total enrollment) chose dietary modification only, 8,050 (16.5%) chose diet plus hormone replacement therapy, 25,210 (51.6%) chose diet plus calcium and vitamin D supplementation, and 5,017 (10.3%) enrolled in all three.
Length of follow-up
Participants were followed from enrollment until they died, were lost to follow-up, or requested no further contact, or until the trial’s planned completion date, regardless of adherence to the dietary intervention, according to intention-to-treat analysis. All participants were contacted by clinic staff at 6-month intervals to provide updates on their health outcomes.
Factors assessed
Height, weight, waist circumference, and blood pressure were measured at annual visits using standardized procedures. Fasting blood samples were collected at baseline and at year 1 from all participants and from a subsample of 2,816 women (5.8% of the study population) at years 3 and 6. This subsample was randomly chosen with oversampling of minority women, for whom the odds for selection were six times higher than for white women.
Physical activity was assessed at baseline and at years 1, 3, 6, and 9. Walking and participation in sports and hours of activity per week were calculated for each participant. Physical activity was expressed as metabolic equivalent tasks per week for the analyses.
A food-frequency questionnaire6 to assess average dietary intake in the past 3 months was given at baseline and at year 1 for all participants. A third of all participants completed the questionnaire each year in a rotating sample. Completion rates were 100% at baseline and 81% thereafter. Follow-up data were collected from years 5 through 7. Also, 4-day food records were provided by all women before randomization.
HOW OUTCOMES WERE ASSESSED
The primary assessments of clinical outcome1–3 were mammographic screening, a self-reported medical history documented by a review of medical records, and electrocardiograms digitally obtained every 3 years. Mammograms and electrocardiograms were centrally adjudicated. The diagnosis of acute myocardial infarction was based on an algorithm that included cardiac pain, enzyme levels, and electrocardiographic readings.
OVERALL RESULTS
At 8.1 years, the incidence of breast cancer was 9% lower in the intervention group than in the comparison group (95% confidence interval [CI] = 0.83–1.01; P = .07, P = .09 weighted for length of follow-up).3 Subgroup analysis further showed that women who reported higher intakes of total dietary fat at baseline reduced their risk of breast cancer by 22% (95% CI = 0.64–0.96). Whether extended follow-up will show a significant association has yet to be determined.
Colon cancer rates did not differ between groups, but the number of polyps and adenomas reported was significantly lower in the dietary intervention group.1 The rate of colon cancer will also be included in the extended follow-up study of the WHI.
Risk factors for coronary heart disease in both groups—including levels of serum total cholesterol and serum low-density lipoprotein cholesterol, body weight, body mass index, diastolic blood pressure, and factor VIIc—improved slightly, but at year 3 of the trial, differences in overall rates of coronary heart disease and stroke in the two groups were not statistically significant.2 In addition, the low-fat diet intervention was associated with a reduction in blood estradiol concentrations between baseline and year 1.3 At the end of the study, however, differences in rates of breast cancer, colorectal cancer, and heart disease between the two groups were not statistically significant.
RESULTS OF DIETARY MODIFICATIONS
Fat as a percentage of total calories
At the beginning of the WHI, all participants reported consuming an average of 35% of their caloric intake from fat (Table 1). At 1 year from baseline, the fat intake decreased to 24.3% in the intervention group (short of the study goal of 20%); this level had risen again to 26.7% by year 3 and to 28.8% at the end of the study. Stratified by quartile, women who achieved the greatest reductions in saturated and trans-fatty acids or the largest increases in their intake of fruits and vegetables appeared to have a moderate reduction in the risk of coronary heart disease.2 Women in the comparison group also decreased their fat intake initially, but to a lesser degree, and gradually increased it again thereafter. The mean net difference in self-reported total fat intake between the intervention group and the comparison group at 6 years was 8.2% (P < .001) (study goal, 13%).1–3
Intake of fruits, vegetables, and grains
At baseline, fruit and vegetable intake averaged 3.6 servings per day (Table 1). In the intervention group, this increased to 5.1 servings per day at year 1, and to 5.2 servings at year 3, but at the end of the study it had decreased to 4.9 servings.
Women in the intervention group were eating 4.7 servings of grains per day at baseline. This increased to 5.1 servings at year 1 and then decreased to 4.6 servings at year 3 and to 4.3 servings at the end of the study. It seems that as the women grew older their determination to increase servings of these foods diminished.
Proponents of some currently popular diets blame weight gain on a higher intake of carbohydrates, but the women following the WHI low-fat diet did not gain weight.2
Total fat vs saturated fat
Intake of total fat and saturated fat decreased in the intervention group during the study, but the difference between fat intake in the intervention group and that in the comparison group did not reach the degree expected.
At year 1, total fat as a percentage of total caloric intake was 10.8 percentage points below that of the comparison group, whereas the study expected difference was 13.0. At the end of the trial, the difference was only 8.2 percentage points, whereas the expected difference was 11.0.
Intake of all fatty acids (saturated and unsaturated) decreased at year 1, but then went back up slightly by the end of the trial but did not exceed baseline levels, and saturated fatty acids remained well below baseline levels: 9.5% vs 12.5% of caloric intake at baseline.4
INTERPRETING THE RESULTS
It might be tempting to dismiss the results of the WHI dietary intervention trial as not significant and therefore not meaningful. This would be unfortunate. The trial had some remarkable accomplishments and offers important lessons for future investigations.
The initial reductions in total fat intake were impressive, and women who had the highest total fat intake at baseline achieved the greatest reduction of total fat (to less than 22% of total calories).3 Nonetheless, the dietary intervention goal of less than 20% of calories from fat was not achieved despite intensive dietary counseling and a highly motivated study population. Thus, this dietary fat target may not be reasonable in the general population.
Also, despite the absence of targeted intervention on specific fatty acids, the observed blood cholesterol levels were as expected based on the well-known formula of Mensink and Katan,14 which incorporates information on changes in saturated fat, polyunsaturated fat, and dietary cholesterol intake. The predicted reduction in low-density lipoprotein cholesterol was 2.7 mg/dL; the observed reduction was 2.3 mg/dL.2 This illustrates that with greater modifications in specific known dietary risk factors for cardiovascular disease, such as saturated fatty acids, cholesterol, and unsaturated fatty acids, blood cholesterol levels respond in a predictable fashion. This was presumably not observed in WHI precisely because no goals and objectives were provided to participants for intake of saturated or polyunsaturated fatty acids.
Recent findings from the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart)15 further highlight differences in the total cholesterol response to diets of varying macronutrient (carbohydrate, protein, fat) content compared with the WHI dietary intervention.15 Participants in OmniHeart had reductions in levels of low-density lipoprotein cholesterol that were predictable from the changes reported in intake of saturated fatty acids. Presumably, the results of the WHI intervention would have been similar if the study had included this level of detail.
QUESTIONS REMAIN
Questions from the WHI that need consideration for future clinical applications include whether the study population may have already been “too old” to achieve a benefit from dietary modification, and whether the best timing for dietary intervention might be earlier adulthood with sustained changes in saturated fat, cholesterol, and unsaturated fat intake throughout life. Future subgroup analyses based on age at baseline will need to address these questions. Likewise, a longer follow-up period may be needed for a definitive evaluation of the impact of a regular low-fat diet on different health outcomes.
As reported by Patterson et al,16 the major contributors to total dietary fat intake at baseline were “added fats” such as sauces, gravies, butter, and margarines (25.1% of fat intake), followed by meats (20.9% of fat intake), and desserts (12.8% of fat intake). These findings highlight target areas for future interventions in women of this age group.
Another issue is how to standardize the dietary intervention from one clinical center to another—ie, to minimize differences in how each clinical center manages the study patients. Such differences were noted in WHI and other studies.17 Despite standardized training in delivering the dietary intervention, nutritionists encountered regional and cultural differences that required tailoring the dietary intervention to their patients’ needs. Staff turnover, an unavoidable phenomenon in long-term studies, has previously been reported to negatively influence dietary adherence.18
LIMITATIONS
A major limitation of diet modification research in general is the self-reporting of dietary intake, primarily by a food-frequency questionnaire. Although the use of a questionnaire is the most practical way to obtain dietary data for large studies, systematic biases may exist that obscure true nutrient-outcome relationships.19 Biomarker studies of energy balance suggest that people who are overweight or obese may under-report energy intake to a greater degree than people who are not overweight.20 Also, we still do not know how to get people to follow a healthy diet, although theories and models abound, such as social learning and cognitive-behavioral theory, and a lack of data limits our understanding of factors related to dietary adherence.21,22
FUTURE DIRECTIONS IN WHI
The WHI Extension Study is under way and has been funded through the year 2010. Outcomes ascertainment is the primary focus with no ongoing intervention, although the intervention group participants continue to receive a WHI newsletter that simply reiterates the importance of the study and encourages ongoing participation. As of 2006, an estimated 84% of the cohort, including both observational study and clinical trial participants, are involved. Efforts continue to recruit the remaining 16%, but many of these participants now consider themselves too old or too feeble to respond reliably.
In regard to breast cancer, the results published in 2006 are promising, albeit not statistically significant, and definitive statements cannot yet be made. However, postmenopausal women who are eating the diets highest in fat may have the greatest benefit from reductions in total fat.
Other considerations regarding the lack of statistically significant differences between groups may include the possibility that women in the intervention group may have been at lower risk for breast cancer at baseline. Likewise, although the results of the WHI dietary intervention do not include a statistically significant impact on colorectal cancer outcomes, the significant reduction in polyps and adenomas may later translate into a reduction in invasive cancer risk.
Finally, although no significant reduction was seen in the rate of death due to cardiovascular causes, greater reductions in saturated and trans-fatty acid intake were associated with greater reductions in blood cholesterol and cardiovascular risk.
Numerous subgroup analyses and ongoing assessments of the long-term impact of the diet modification are planned. Further associations are expected to emerge. The current and future results will continue to provide new insights that may lead to new clinical and public health recommendations in the future.
The WHI has raised additional issues that warrant further investigation:
- Will earlier dietary intervention, eg, during premenopausal years or even childhood, alter these results?
- Does the low-fat, high-carbohydrate diet used in WHI facilitate weight maintenance or even weight loss, as proposed by Howard et al23?
- Do quantitative changes in physical activity and weight control attenuate morbidity and mortality rates beyond changes in diet alone?
- Do vitamin and mineral supplements or hormone therapy alter disease outcomes or quality of life?
- Which behavioral approaches are best suited to the recruitment of patients for dietary intervention trials?
- Beresford SA, Johnson KC, Ritenbaugh C, et al. Low-fat dietary pattern and risk of colorectal cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295:643–654.
- Howard BV, Van Horn L, Hsia J, et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295:655–666.
- Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive breast cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295:629–642.
- The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998; 19:61–109.
- Ritenbaugh C, Patterson RE, Chlebowski RT, et al. The Women’s Health Initiative Dietary Modification trial: overview and baseline characteristics of participants. Ann Epidemiol 2003; 13 9 suppl:S87–97.
- Patterson RE, Kristal AR, Tinker LF, Carter RA, Bolton MP, Agurs-Collins T. Measurement characteristics of the Women’s Health Initiative food frequency questionnaire. Ann Epidemiol 1999; 9:178–187.
- Tinker LF, Burrows ER, Henry H, Patterson RE, Rupp JW, Van Horn LV. The Women’s Health Initiative: overview of the nutrition components. In:Krummel DA, Kris-Etherton PM, editors. Nutrition in Women’s Health. Gaithersburg, MD: Aspen, 1996:510–542.
- Henderson MM, Kushi LH, Thompson DJ, et al. Feasibility of a randomized trial of a low-fat diet for the prevention of breast cancer: dietary compliance in the Women’s Health Trial Vanguard Study. Prev Med 1990; 19:115–133.
- Bowen D, Ehret C, Pedersen M, et al. Results of an adjunct dietary intervention program in the Women’s Health Initiative. J Am Diet Assoc 2002; 102:1631–1637.
- US Department of Agriculture. Dietary Guidelines for Americans. 6. Washington, DC: US Dept of Health and Human Services, 2005.
- Jackson RD, LaCroix AZ, Cauley JA, McGowan J. The Women’s Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol 2003; 13 9 Suppl:S98–106.
- Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321–333.
- Stefanick ML, Cochrane BB, Hsia J, Barad DH, Liu JH, Johnson SR. The Women’s Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol 2003; 13 9 suppl:S78–86.
- Mensink RP, Katan MB. Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27 trials. Arterioscler Thromb 1992; 12:911–919.
- Appel LJ, Sacks FM, Carey VJ, et al. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA 2005; 294:2455–2464.
- Patterson RE, Kristal A, Rodabough R, et al. Changes in food sources of dietary fat in response to an intensive low-fat dietary intervention: early results from the Women’s Health Initiative. J Am Diet Assoc 2003; 103:454–460.
- Lichtman JH, Roumanis SA, Radford MJ, Riedinger MS, Weingarten S, Krumholz HM. Can practice guidelines be transported effectively to different settings? Results from a multicenter interventional study. Jt Comm J Qual Improv 2001; 27:42–53.
- Jackson M, Berman N, Huber M, et al. Research staff turnover and participant adherence in the Women’s Health Initiative. Control Clin Trials 2003; 24:422–435.
- Willett W, Lenart E. Reproducibility and validity of food-frequency questionnaires. In:Willett W, ed. Nutritional Epidemiology. 2. New York: Oxford University Press, 1998:101–147.
- Subar AF, Kipnis V, Troiano RP, et al. Using intake biomarkers to evaluate the extent of dietary misreporting in a large sample of adults: the OPEN study. Am J Epidemiol 2003; 158:1–13.
- Bowen D, Raczynski J, George V, Feng Z, Fouad M. The role of participation in the women’s health trial: feasibility study in minority populations. Prev Med 2000; 31:474–480.
- Patterson RE, Kristal AR, White E. Do beliefs, knowledge, and perceived norms about diet and cancer predict dietary change? Am J Public Health 1996; 86:1394–1400.
- Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and weight change over 7 years: the Women’s Health Initiative Dietary Modification Trial. JAMA 2006; 295:35–49.
More than 2 years have passed since we published the results of the Women’s Health Initiative (WHI), which caused a storm of information—and misinformation—about the effect of long-term dietary intervention on disease outcomes in postmenopausal women. Now that the dust has long settled, what have we learned from this landmark study?
The WHI results led to numerous additional analyses of all aspects of the study.1–7 What are the implications of all the analyses to clinical practice?
In this article, we summarize key aspects of the clinical trial, including study design, interventions, main results, and future plans. We also discuss potential clinical applications and practical considerations for public health efforts.
WHO WAS ELIGIBLE, WHO WAS NOT
A total of 48,835 postmenopausal women were randomly assigned to either no dietary intervention (n = 29,294) or a dietary intervention (n = 19,541) (see below).7 Participants were followed at 40 clinical centers between 1993 and 2005.4 Their mean age was 62.3 years; 18.6% were members of minorities.
Women were eligible if they were post-menopausal and had a daily dietary fat intake of at least 32% of total calories, based on assessment via a food-frequency questionnaire. They were excluded from the study if they had any of the following: a history of breast cancer, colorectal cancer, or other cancer except skin cancer during the past 10 years; type 1 diabetes; a medical condition in which the predicted survival was less than 3 years; and a potential barrier to adherence to the study regimen, including alcoholism or a lifestyle that involved often eating meals away from home.
THE WHI DIET: LESS FAT, BUT MORE FRUITS, VEGETABLES, GRAINS
The WHI dietary intervention was designed to prevent breast cancer, based on the evidence available when the study was planned. The targets included a total fat intake of less than 20% of energy (in kilocalories), increasing the intake of fruits and vegetables to at least five servings per day, and increasing the intake of grains to at least six servings per day.
Although reduction in saturated fat intake per se was not part of the WHI protocol, we assumed from previous pilot studies8 that the reduction of total fat intake would simultaneously produce a reduction in saturated fat intake to 7% of total calories.
A simpler dietary intervention
Unlike the 2006 American Heart Association guidelines and the US Department of Agriculture’s Dietary Guidelines for Americans 2005, the WHI dietary intervention had no specifications for dietary fiber, specific fatty acids (trans-fatty acids, omega-3 fatty acids, conjugated linoleic acid), complex carbohydrates, whole grains, vegetable protein, or other factors that have emerged as potential risk factors for cardiovascular and other chronic diseases since the study began. The WHI intervention also included no specific recommendation for total calorie intake, nor were patients in the intervention group encouraged to lose weight, as this could have confounded the results of the dietary intervention.
Education and encouragement
Those in the intervention group were each assigned a fat-gram goal, calculated on the basis of height. They were taught how to monitor their intake of total fat, fruits, vegetables, and grains. They attended intensive behavioral modification sessions to encourage them to keep to the dietary program: 18 group sessions in the first year and quarterly maintenance sessions thereafter, touching on a wide variety of nutrition- and behavior-related topics.7,9 Specially trained and certified nutritionists supervised the dietary intervention and the behavioral modification sessions according to the WHI study protocol.
Control-group participants received a copy of the US Department of Agriculture’s Dietary Guidelines for Americans10 and other health-related materials. They had no contact with the study nutritionists.
Other arms of the study
The WHI trial design included several arms,4,11–13 and many participants joined more than one arm: 20,592 postmenopausal women (42.2% of the total enrollment) chose dietary modification only, 8,050 (16.5%) chose diet plus hormone replacement therapy, 25,210 (51.6%) chose diet plus calcium and vitamin D supplementation, and 5,017 (10.3%) enrolled in all three.
Length of follow-up
Participants were followed from enrollment until they died, were lost to follow-up, or requested no further contact, or until the trial’s planned completion date, regardless of adherence to the dietary intervention, according to intention-to-treat analysis. All participants were contacted by clinic staff at 6-month intervals to provide updates on their health outcomes.
Factors assessed
Height, weight, waist circumference, and blood pressure were measured at annual visits using standardized procedures. Fasting blood samples were collected at baseline and at year 1 from all participants and from a subsample of 2,816 women (5.8% of the study population) at years 3 and 6. This subsample was randomly chosen with oversampling of minority women, for whom the odds for selection were six times higher than for white women.
Physical activity was assessed at baseline and at years 1, 3, 6, and 9. Walking and participation in sports and hours of activity per week were calculated for each participant. Physical activity was expressed as metabolic equivalent tasks per week for the analyses.
A food-frequency questionnaire6 to assess average dietary intake in the past 3 months was given at baseline and at year 1 for all participants. A third of all participants completed the questionnaire each year in a rotating sample. Completion rates were 100% at baseline and 81% thereafter. Follow-up data were collected from years 5 through 7. Also, 4-day food records were provided by all women before randomization.
HOW OUTCOMES WERE ASSESSED
The primary assessments of clinical outcome1–3 were mammographic screening, a self-reported medical history documented by a review of medical records, and electrocardiograms digitally obtained every 3 years. Mammograms and electrocardiograms were centrally adjudicated. The diagnosis of acute myocardial infarction was based on an algorithm that included cardiac pain, enzyme levels, and electrocardiographic readings.
OVERALL RESULTS
At 8.1 years, the incidence of breast cancer was 9% lower in the intervention group than in the comparison group (95% confidence interval [CI] = 0.83–1.01; P = .07, P = .09 weighted for length of follow-up).3 Subgroup analysis further showed that women who reported higher intakes of total dietary fat at baseline reduced their risk of breast cancer by 22% (95% CI = 0.64–0.96). Whether extended follow-up will show a significant association has yet to be determined.
Colon cancer rates did not differ between groups, but the number of polyps and adenomas reported was significantly lower in the dietary intervention group.1 The rate of colon cancer will also be included in the extended follow-up study of the WHI.
Risk factors for coronary heart disease in both groups—including levels of serum total cholesterol and serum low-density lipoprotein cholesterol, body weight, body mass index, diastolic blood pressure, and factor VIIc—improved slightly, but at year 3 of the trial, differences in overall rates of coronary heart disease and stroke in the two groups were not statistically significant.2 In addition, the low-fat diet intervention was associated with a reduction in blood estradiol concentrations between baseline and year 1.3 At the end of the study, however, differences in rates of breast cancer, colorectal cancer, and heart disease between the two groups were not statistically significant.
RESULTS OF DIETARY MODIFICATIONS
Fat as a percentage of total calories
At the beginning of the WHI, all participants reported consuming an average of 35% of their caloric intake from fat (Table 1). At 1 year from baseline, the fat intake decreased to 24.3% in the intervention group (short of the study goal of 20%); this level had risen again to 26.7% by year 3 and to 28.8% at the end of the study. Stratified by quartile, women who achieved the greatest reductions in saturated and trans-fatty acids or the largest increases in their intake of fruits and vegetables appeared to have a moderate reduction in the risk of coronary heart disease.2 Women in the comparison group also decreased their fat intake initially, but to a lesser degree, and gradually increased it again thereafter. The mean net difference in self-reported total fat intake between the intervention group and the comparison group at 6 years was 8.2% (P < .001) (study goal, 13%).1–3
Intake of fruits, vegetables, and grains
At baseline, fruit and vegetable intake averaged 3.6 servings per day (Table 1). In the intervention group, this increased to 5.1 servings per day at year 1, and to 5.2 servings at year 3, but at the end of the study it had decreased to 4.9 servings.
Women in the intervention group were eating 4.7 servings of grains per day at baseline. This increased to 5.1 servings at year 1 and then decreased to 4.6 servings at year 3 and to 4.3 servings at the end of the study. It seems that as the women grew older their determination to increase servings of these foods diminished.
Proponents of some currently popular diets blame weight gain on a higher intake of carbohydrates, but the women following the WHI low-fat diet did not gain weight.2
Total fat vs saturated fat
Intake of total fat and saturated fat decreased in the intervention group during the study, but the difference between fat intake in the intervention group and that in the comparison group did not reach the degree expected.
At year 1, total fat as a percentage of total caloric intake was 10.8 percentage points below that of the comparison group, whereas the study expected difference was 13.0. At the end of the trial, the difference was only 8.2 percentage points, whereas the expected difference was 11.0.
Intake of all fatty acids (saturated and unsaturated) decreased at year 1, but then went back up slightly by the end of the trial but did not exceed baseline levels, and saturated fatty acids remained well below baseline levels: 9.5% vs 12.5% of caloric intake at baseline.4
INTERPRETING THE RESULTS
It might be tempting to dismiss the results of the WHI dietary intervention trial as not significant and therefore not meaningful. This would be unfortunate. The trial had some remarkable accomplishments and offers important lessons for future investigations.
The initial reductions in total fat intake were impressive, and women who had the highest total fat intake at baseline achieved the greatest reduction of total fat (to less than 22% of total calories).3 Nonetheless, the dietary intervention goal of less than 20% of calories from fat was not achieved despite intensive dietary counseling and a highly motivated study population. Thus, this dietary fat target may not be reasonable in the general population.
Also, despite the absence of targeted intervention on specific fatty acids, the observed blood cholesterol levels were as expected based on the well-known formula of Mensink and Katan,14 which incorporates information on changes in saturated fat, polyunsaturated fat, and dietary cholesterol intake. The predicted reduction in low-density lipoprotein cholesterol was 2.7 mg/dL; the observed reduction was 2.3 mg/dL.2 This illustrates that with greater modifications in specific known dietary risk factors for cardiovascular disease, such as saturated fatty acids, cholesterol, and unsaturated fatty acids, blood cholesterol levels respond in a predictable fashion. This was presumably not observed in WHI precisely because no goals and objectives were provided to participants for intake of saturated or polyunsaturated fatty acids.
Recent findings from the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart)15 further highlight differences in the total cholesterol response to diets of varying macronutrient (carbohydrate, protein, fat) content compared with the WHI dietary intervention.15 Participants in OmniHeart had reductions in levels of low-density lipoprotein cholesterol that were predictable from the changes reported in intake of saturated fatty acids. Presumably, the results of the WHI intervention would have been similar if the study had included this level of detail.
QUESTIONS REMAIN
Questions from the WHI that need consideration for future clinical applications include whether the study population may have already been “too old” to achieve a benefit from dietary modification, and whether the best timing for dietary intervention might be earlier adulthood with sustained changes in saturated fat, cholesterol, and unsaturated fat intake throughout life. Future subgroup analyses based on age at baseline will need to address these questions. Likewise, a longer follow-up period may be needed for a definitive evaluation of the impact of a regular low-fat diet on different health outcomes.
As reported by Patterson et al,16 the major contributors to total dietary fat intake at baseline were “added fats” such as sauces, gravies, butter, and margarines (25.1% of fat intake), followed by meats (20.9% of fat intake), and desserts (12.8% of fat intake). These findings highlight target areas for future interventions in women of this age group.
Another issue is how to standardize the dietary intervention from one clinical center to another—ie, to minimize differences in how each clinical center manages the study patients. Such differences were noted in WHI and other studies.17 Despite standardized training in delivering the dietary intervention, nutritionists encountered regional and cultural differences that required tailoring the dietary intervention to their patients’ needs. Staff turnover, an unavoidable phenomenon in long-term studies, has previously been reported to negatively influence dietary adherence.18
LIMITATIONS
A major limitation of diet modification research in general is the self-reporting of dietary intake, primarily by a food-frequency questionnaire. Although the use of a questionnaire is the most practical way to obtain dietary data for large studies, systematic biases may exist that obscure true nutrient-outcome relationships.19 Biomarker studies of energy balance suggest that people who are overweight or obese may under-report energy intake to a greater degree than people who are not overweight.20 Also, we still do not know how to get people to follow a healthy diet, although theories and models abound, such as social learning and cognitive-behavioral theory, and a lack of data limits our understanding of factors related to dietary adherence.21,22
FUTURE DIRECTIONS IN WHI
The WHI Extension Study is under way and has been funded through the year 2010. Outcomes ascertainment is the primary focus with no ongoing intervention, although the intervention group participants continue to receive a WHI newsletter that simply reiterates the importance of the study and encourages ongoing participation. As of 2006, an estimated 84% of the cohort, including both observational study and clinical trial participants, are involved. Efforts continue to recruit the remaining 16%, but many of these participants now consider themselves too old or too feeble to respond reliably.
In regard to breast cancer, the results published in 2006 are promising, albeit not statistically significant, and definitive statements cannot yet be made. However, postmenopausal women who are eating the diets highest in fat may have the greatest benefit from reductions in total fat.
Other considerations regarding the lack of statistically significant differences between groups may include the possibility that women in the intervention group may have been at lower risk for breast cancer at baseline. Likewise, although the results of the WHI dietary intervention do not include a statistically significant impact on colorectal cancer outcomes, the significant reduction in polyps and adenomas may later translate into a reduction in invasive cancer risk.
Finally, although no significant reduction was seen in the rate of death due to cardiovascular causes, greater reductions in saturated and trans-fatty acid intake were associated with greater reductions in blood cholesterol and cardiovascular risk.
Numerous subgroup analyses and ongoing assessments of the long-term impact of the diet modification are planned. Further associations are expected to emerge. The current and future results will continue to provide new insights that may lead to new clinical and public health recommendations in the future.
The WHI has raised additional issues that warrant further investigation:
- Will earlier dietary intervention, eg, during premenopausal years or even childhood, alter these results?
- Does the low-fat, high-carbohydrate diet used in WHI facilitate weight maintenance or even weight loss, as proposed by Howard et al23?
- Do quantitative changes in physical activity and weight control attenuate morbidity and mortality rates beyond changes in diet alone?
- Do vitamin and mineral supplements or hormone therapy alter disease outcomes or quality of life?
- Which behavioral approaches are best suited to the recruitment of patients for dietary intervention trials?
More than 2 years have passed since we published the results of the Women’s Health Initiative (WHI), which caused a storm of information—and misinformation—about the effect of long-term dietary intervention on disease outcomes in postmenopausal women. Now that the dust has long settled, what have we learned from this landmark study?
The WHI results led to numerous additional analyses of all aspects of the study.1–7 What are the implications of all the analyses to clinical practice?
In this article, we summarize key aspects of the clinical trial, including study design, interventions, main results, and future plans. We also discuss potential clinical applications and practical considerations for public health efforts.
WHO WAS ELIGIBLE, WHO WAS NOT
A total of 48,835 postmenopausal women were randomly assigned to either no dietary intervention (n = 29,294) or a dietary intervention (n = 19,541) (see below).7 Participants were followed at 40 clinical centers between 1993 and 2005.4 Their mean age was 62.3 years; 18.6% were members of minorities.
Women were eligible if they were post-menopausal and had a daily dietary fat intake of at least 32% of total calories, based on assessment via a food-frequency questionnaire. They were excluded from the study if they had any of the following: a history of breast cancer, colorectal cancer, or other cancer except skin cancer during the past 10 years; type 1 diabetes; a medical condition in which the predicted survival was less than 3 years; and a potential barrier to adherence to the study regimen, including alcoholism or a lifestyle that involved often eating meals away from home.
THE WHI DIET: LESS FAT, BUT MORE FRUITS, VEGETABLES, GRAINS
The WHI dietary intervention was designed to prevent breast cancer, based on the evidence available when the study was planned. The targets included a total fat intake of less than 20% of energy (in kilocalories), increasing the intake of fruits and vegetables to at least five servings per day, and increasing the intake of grains to at least six servings per day.
Although reduction in saturated fat intake per se was not part of the WHI protocol, we assumed from previous pilot studies8 that the reduction of total fat intake would simultaneously produce a reduction in saturated fat intake to 7% of total calories.
A simpler dietary intervention
Unlike the 2006 American Heart Association guidelines and the US Department of Agriculture’s Dietary Guidelines for Americans 2005, the WHI dietary intervention had no specifications for dietary fiber, specific fatty acids (trans-fatty acids, omega-3 fatty acids, conjugated linoleic acid), complex carbohydrates, whole grains, vegetable protein, or other factors that have emerged as potential risk factors for cardiovascular and other chronic diseases since the study began. The WHI intervention also included no specific recommendation for total calorie intake, nor were patients in the intervention group encouraged to lose weight, as this could have confounded the results of the dietary intervention.
Education and encouragement
Those in the intervention group were each assigned a fat-gram goal, calculated on the basis of height. They were taught how to monitor their intake of total fat, fruits, vegetables, and grains. They attended intensive behavioral modification sessions to encourage them to keep to the dietary program: 18 group sessions in the first year and quarterly maintenance sessions thereafter, touching on a wide variety of nutrition- and behavior-related topics.7,9 Specially trained and certified nutritionists supervised the dietary intervention and the behavioral modification sessions according to the WHI study protocol.
Control-group participants received a copy of the US Department of Agriculture’s Dietary Guidelines for Americans10 and other health-related materials. They had no contact with the study nutritionists.
Other arms of the study
The WHI trial design included several arms,4,11–13 and many participants joined more than one arm: 20,592 postmenopausal women (42.2% of the total enrollment) chose dietary modification only, 8,050 (16.5%) chose diet plus hormone replacement therapy, 25,210 (51.6%) chose diet plus calcium and vitamin D supplementation, and 5,017 (10.3%) enrolled in all three.
Length of follow-up
Participants were followed from enrollment until they died, were lost to follow-up, or requested no further contact, or until the trial’s planned completion date, regardless of adherence to the dietary intervention, according to intention-to-treat analysis. All participants were contacted by clinic staff at 6-month intervals to provide updates on their health outcomes.
Factors assessed
Height, weight, waist circumference, and blood pressure were measured at annual visits using standardized procedures. Fasting blood samples were collected at baseline and at year 1 from all participants and from a subsample of 2,816 women (5.8% of the study population) at years 3 and 6. This subsample was randomly chosen with oversampling of minority women, for whom the odds for selection were six times higher than for white women.
Physical activity was assessed at baseline and at years 1, 3, 6, and 9. Walking and participation in sports and hours of activity per week were calculated for each participant. Physical activity was expressed as metabolic equivalent tasks per week for the analyses.
A food-frequency questionnaire6 to assess average dietary intake in the past 3 months was given at baseline and at year 1 for all participants. A third of all participants completed the questionnaire each year in a rotating sample. Completion rates were 100% at baseline and 81% thereafter. Follow-up data were collected from years 5 through 7. Also, 4-day food records were provided by all women before randomization.
HOW OUTCOMES WERE ASSESSED
The primary assessments of clinical outcome1–3 were mammographic screening, a self-reported medical history documented by a review of medical records, and electrocardiograms digitally obtained every 3 years. Mammograms and electrocardiograms were centrally adjudicated. The diagnosis of acute myocardial infarction was based on an algorithm that included cardiac pain, enzyme levels, and electrocardiographic readings.
OVERALL RESULTS
At 8.1 years, the incidence of breast cancer was 9% lower in the intervention group than in the comparison group (95% confidence interval [CI] = 0.83–1.01; P = .07, P = .09 weighted for length of follow-up).3 Subgroup analysis further showed that women who reported higher intakes of total dietary fat at baseline reduced their risk of breast cancer by 22% (95% CI = 0.64–0.96). Whether extended follow-up will show a significant association has yet to be determined.
Colon cancer rates did not differ between groups, but the number of polyps and adenomas reported was significantly lower in the dietary intervention group.1 The rate of colon cancer will also be included in the extended follow-up study of the WHI.
Risk factors for coronary heart disease in both groups—including levels of serum total cholesterol and serum low-density lipoprotein cholesterol, body weight, body mass index, diastolic blood pressure, and factor VIIc—improved slightly, but at year 3 of the trial, differences in overall rates of coronary heart disease and stroke in the two groups were not statistically significant.2 In addition, the low-fat diet intervention was associated with a reduction in blood estradiol concentrations between baseline and year 1.3 At the end of the study, however, differences in rates of breast cancer, colorectal cancer, and heart disease between the two groups were not statistically significant.
RESULTS OF DIETARY MODIFICATIONS
Fat as a percentage of total calories
At the beginning of the WHI, all participants reported consuming an average of 35% of their caloric intake from fat (Table 1). At 1 year from baseline, the fat intake decreased to 24.3% in the intervention group (short of the study goal of 20%); this level had risen again to 26.7% by year 3 and to 28.8% at the end of the study. Stratified by quartile, women who achieved the greatest reductions in saturated and trans-fatty acids or the largest increases in their intake of fruits and vegetables appeared to have a moderate reduction in the risk of coronary heart disease.2 Women in the comparison group also decreased their fat intake initially, but to a lesser degree, and gradually increased it again thereafter. The mean net difference in self-reported total fat intake between the intervention group and the comparison group at 6 years was 8.2% (P < .001) (study goal, 13%).1–3
Intake of fruits, vegetables, and grains
At baseline, fruit and vegetable intake averaged 3.6 servings per day (Table 1). In the intervention group, this increased to 5.1 servings per day at year 1, and to 5.2 servings at year 3, but at the end of the study it had decreased to 4.9 servings.
Women in the intervention group were eating 4.7 servings of grains per day at baseline. This increased to 5.1 servings at year 1 and then decreased to 4.6 servings at year 3 and to 4.3 servings at the end of the study. It seems that as the women grew older their determination to increase servings of these foods diminished.
Proponents of some currently popular diets blame weight gain on a higher intake of carbohydrates, but the women following the WHI low-fat diet did not gain weight.2
Total fat vs saturated fat
Intake of total fat and saturated fat decreased in the intervention group during the study, but the difference between fat intake in the intervention group and that in the comparison group did not reach the degree expected.
At year 1, total fat as a percentage of total caloric intake was 10.8 percentage points below that of the comparison group, whereas the study expected difference was 13.0. At the end of the trial, the difference was only 8.2 percentage points, whereas the expected difference was 11.0.
Intake of all fatty acids (saturated and unsaturated) decreased at year 1, but then went back up slightly by the end of the trial but did not exceed baseline levels, and saturated fatty acids remained well below baseline levels: 9.5% vs 12.5% of caloric intake at baseline.4
INTERPRETING THE RESULTS
It might be tempting to dismiss the results of the WHI dietary intervention trial as not significant and therefore not meaningful. This would be unfortunate. The trial had some remarkable accomplishments and offers important lessons for future investigations.
The initial reductions in total fat intake were impressive, and women who had the highest total fat intake at baseline achieved the greatest reduction of total fat (to less than 22% of total calories).3 Nonetheless, the dietary intervention goal of less than 20% of calories from fat was not achieved despite intensive dietary counseling and a highly motivated study population. Thus, this dietary fat target may not be reasonable in the general population.
Also, despite the absence of targeted intervention on specific fatty acids, the observed blood cholesterol levels were as expected based on the well-known formula of Mensink and Katan,14 which incorporates information on changes in saturated fat, polyunsaturated fat, and dietary cholesterol intake. The predicted reduction in low-density lipoprotein cholesterol was 2.7 mg/dL; the observed reduction was 2.3 mg/dL.2 This illustrates that with greater modifications in specific known dietary risk factors for cardiovascular disease, such as saturated fatty acids, cholesterol, and unsaturated fatty acids, blood cholesterol levels respond in a predictable fashion. This was presumably not observed in WHI precisely because no goals and objectives were provided to participants for intake of saturated or polyunsaturated fatty acids.
Recent findings from the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OmniHeart)15 further highlight differences in the total cholesterol response to diets of varying macronutrient (carbohydrate, protein, fat) content compared with the WHI dietary intervention.15 Participants in OmniHeart had reductions in levels of low-density lipoprotein cholesterol that were predictable from the changes reported in intake of saturated fatty acids. Presumably, the results of the WHI intervention would have been similar if the study had included this level of detail.
QUESTIONS REMAIN
Questions from the WHI that need consideration for future clinical applications include whether the study population may have already been “too old” to achieve a benefit from dietary modification, and whether the best timing for dietary intervention might be earlier adulthood with sustained changes in saturated fat, cholesterol, and unsaturated fat intake throughout life. Future subgroup analyses based on age at baseline will need to address these questions. Likewise, a longer follow-up period may be needed for a definitive evaluation of the impact of a regular low-fat diet on different health outcomes.
As reported by Patterson et al,16 the major contributors to total dietary fat intake at baseline were “added fats” such as sauces, gravies, butter, and margarines (25.1% of fat intake), followed by meats (20.9% of fat intake), and desserts (12.8% of fat intake). These findings highlight target areas for future interventions in women of this age group.
Another issue is how to standardize the dietary intervention from one clinical center to another—ie, to minimize differences in how each clinical center manages the study patients. Such differences were noted in WHI and other studies.17 Despite standardized training in delivering the dietary intervention, nutritionists encountered regional and cultural differences that required tailoring the dietary intervention to their patients’ needs. Staff turnover, an unavoidable phenomenon in long-term studies, has previously been reported to negatively influence dietary adherence.18
LIMITATIONS
A major limitation of diet modification research in general is the self-reporting of dietary intake, primarily by a food-frequency questionnaire. Although the use of a questionnaire is the most practical way to obtain dietary data for large studies, systematic biases may exist that obscure true nutrient-outcome relationships.19 Biomarker studies of energy balance suggest that people who are overweight or obese may under-report energy intake to a greater degree than people who are not overweight.20 Also, we still do not know how to get people to follow a healthy diet, although theories and models abound, such as social learning and cognitive-behavioral theory, and a lack of data limits our understanding of factors related to dietary adherence.21,22
FUTURE DIRECTIONS IN WHI
The WHI Extension Study is under way and has been funded through the year 2010. Outcomes ascertainment is the primary focus with no ongoing intervention, although the intervention group participants continue to receive a WHI newsletter that simply reiterates the importance of the study and encourages ongoing participation. As of 2006, an estimated 84% of the cohort, including both observational study and clinical trial participants, are involved. Efforts continue to recruit the remaining 16%, but many of these participants now consider themselves too old or too feeble to respond reliably.
In regard to breast cancer, the results published in 2006 are promising, albeit not statistically significant, and definitive statements cannot yet be made. However, postmenopausal women who are eating the diets highest in fat may have the greatest benefit from reductions in total fat.
Other considerations regarding the lack of statistically significant differences between groups may include the possibility that women in the intervention group may have been at lower risk for breast cancer at baseline. Likewise, although the results of the WHI dietary intervention do not include a statistically significant impact on colorectal cancer outcomes, the significant reduction in polyps and adenomas may later translate into a reduction in invasive cancer risk.
Finally, although no significant reduction was seen in the rate of death due to cardiovascular causes, greater reductions in saturated and trans-fatty acid intake were associated with greater reductions in blood cholesterol and cardiovascular risk.
Numerous subgroup analyses and ongoing assessments of the long-term impact of the diet modification are planned. Further associations are expected to emerge. The current and future results will continue to provide new insights that may lead to new clinical and public health recommendations in the future.
The WHI has raised additional issues that warrant further investigation:
- Will earlier dietary intervention, eg, during premenopausal years or even childhood, alter these results?
- Does the low-fat, high-carbohydrate diet used in WHI facilitate weight maintenance or even weight loss, as proposed by Howard et al23?
- Do quantitative changes in physical activity and weight control attenuate morbidity and mortality rates beyond changes in diet alone?
- Do vitamin and mineral supplements or hormone therapy alter disease outcomes or quality of life?
- Which behavioral approaches are best suited to the recruitment of patients for dietary intervention trials?
- Beresford SA, Johnson KC, Ritenbaugh C, et al. Low-fat dietary pattern and risk of colorectal cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295:643–654.
- Howard BV, Van Horn L, Hsia J, et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295:655–666.
- Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive breast cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295:629–642.
- The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998; 19:61–109.
- Ritenbaugh C, Patterson RE, Chlebowski RT, et al. The Women’s Health Initiative Dietary Modification trial: overview and baseline characteristics of participants. Ann Epidemiol 2003; 13 9 suppl:S87–97.
- Patterson RE, Kristal AR, Tinker LF, Carter RA, Bolton MP, Agurs-Collins T. Measurement characteristics of the Women’s Health Initiative food frequency questionnaire. Ann Epidemiol 1999; 9:178–187.
- Tinker LF, Burrows ER, Henry H, Patterson RE, Rupp JW, Van Horn LV. The Women’s Health Initiative: overview of the nutrition components. In:Krummel DA, Kris-Etherton PM, editors. Nutrition in Women’s Health. Gaithersburg, MD: Aspen, 1996:510–542.
- Henderson MM, Kushi LH, Thompson DJ, et al. Feasibility of a randomized trial of a low-fat diet for the prevention of breast cancer: dietary compliance in the Women’s Health Trial Vanguard Study. Prev Med 1990; 19:115–133.
- Bowen D, Ehret C, Pedersen M, et al. Results of an adjunct dietary intervention program in the Women’s Health Initiative. J Am Diet Assoc 2002; 102:1631–1637.
- US Department of Agriculture. Dietary Guidelines for Americans. 6. Washington, DC: US Dept of Health and Human Services, 2005.
- Jackson RD, LaCroix AZ, Cauley JA, McGowan J. The Women’s Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol 2003; 13 9 Suppl:S98–106.
- Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321–333.
- Stefanick ML, Cochrane BB, Hsia J, Barad DH, Liu JH, Johnson SR. The Women’s Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol 2003; 13 9 suppl:S78–86.
- Mensink RP, Katan MB. Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27 trials. Arterioscler Thromb 1992; 12:911–919.
- Appel LJ, Sacks FM, Carey VJ, et al. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA 2005; 294:2455–2464.
- Patterson RE, Kristal A, Rodabough R, et al. Changes in food sources of dietary fat in response to an intensive low-fat dietary intervention: early results from the Women’s Health Initiative. J Am Diet Assoc 2003; 103:454–460.
- Lichtman JH, Roumanis SA, Radford MJ, Riedinger MS, Weingarten S, Krumholz HM. Can practice guidelines be transported effectively to different settings? Results from a multicenter interventional study. Jt Comm J Qual Improv 2001; 27:42–53.
- Jackson M, Berman N, Huber M, et al. Research staff turnover and participant adherence in the Women’s Health Initiative. Control Clin Trials 2003; 24:422–435.
- Willett W, Lenart E. Reproducibility and validity of food-frequency questionnaires. In:Willett W, ed. Nutritional Epidemiology. 2. New York: Oxford University Press, 1998:101–147.
- Subar AF, Kipnis V, Troiano RP, et al. Using intake biomarkers to evaluate the extent of dietary misreporting in a large sample of adults: the OPEN study. Am J Epidemiol 2003; 158:1–13.
- Bowen D, Raczynski J, George V, Feng Z, Fouad M. The role of participation in the women’s health trial: feasibility study in minority populations. Prev Med 2000; 31:474–480.
- Patterson RE, Kristal AR, White E. Do beliefs, knowledge, and perceived norms about diet and cancer predict dietary change? Am J Public Health 1996; 86:1394–1400.
- Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and weight change over 7 years: the Women’s Health Initiative Dietary Modification Trial. JAMA 2006; 295:35–49.
- Beresford SA, Johnson KC, Ritenbaugh C, et al. Low-fat dietary pattern and risk of colorectal cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295:643–654.
- Howard BV, Van Horn L, Hsia J, et al. Low-fat dietary pattern and risk of cardiovascular disease: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295:655–666.
- Prentice RL, Caan B, Chlebowski RT, et al. Low-fat dietary pattern and risk of invasive breast cancer: the Women’s Health Initiative Randomized Controlled Dietary Modification Trial. JAMA 2006; 295:629–642.
- The Women’s Health Initiative Study Group. Design of the Women’s Health Initiative clinical trial and observational study. Control Clin Trials 1998; 19:61–109.
- Ritenbaugh C, Patterson RE, Chlebowski RT, et al. The Women’s Health Initiative Dietary Modification trial: overview and baseline characteristics of participants. Ann Epidemiol 2003; 13 9 suppl:S87–97.
- Patterson RE, Kristal AR, Tinker LF, Carter RA, Bolton MP, Agurs-Collins T. Measurement characteristics of the Women’s Health Initiative food frequency questionnaire. Ann Epidemiol 1999; 9:178–187.
- Tinker LF, Burrows ER, Henry H, Patterson RE, Rupp JW, Van Horn LV. The Women’s Health Initiative: overview of the nutrition components. In:Krummel DA, Kris-Etherton PM, editors. Nutrition in Women’s Health. Gaithersburg, MD: Aspen, 1996:510–542.
- Henderson MM, Kushi LH, Thompson DJ, et al. Feasibility of a randomized trial of a low-fat diet for the prevention of breast cancer: dietary compliance in the Women’s Health Trial Vanguard Study. Prev Med 1990; 19:115–133.
- Bowen D, Ehret C, Pedersen M, et al. Results of an adjunct dietary intervention program in the Women’s Health Initiative. J Am Diet Assoc 2002; 102:1631–1637.
- US Department of Agriculture. Dietary Guidelines for Americans. 6. Washington, DC: US Dept of Health and Human Services, 2005.
- Jackson RD, LaCroix AZ, Cauley JA, McGowan J. The Women’s Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Ann Epidemiol 2003; 13 9 Suppl:S98–106.
- Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002; 288:321–333.
- Stefanick ML, Cochrane BB, Hsia J, Barad DH, Liu JH, Johnson SR. The Women’s Health Initiative postmenopausal hormone trials: overview and baseline characteristics of participants. Ann Epidemiol 2003; 13 9 suppl:S78–86.
- Mensink RP, Katan MB. Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27 trials. Arterioscler Thromb 1992; 12:911–919.
- Appel LJ, Sacks FM, Carey VJ, et al. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA 2005; 294:2455–2464.
- Patterson RE, Kristal A, Rodabough R, et al. Changes in food sources of dietary fat in response to an intensive low-fat dietary intervention: early results from the Women’s Health Initiative. J Am Diet Assoc 2003; 103:454–460.
- Lichtman JH, Roumanis SA, Radford MJ, Riedinger MS, Weingarten S, Krumholz HM. Can practice guidelines be transported effectively to different settings? Results from a multicenter interventional study. Jt Comm J Qual Improv 2001; 27:42–53.
- Jackson M, Berman N, Huber M, et al. Research staff turnover and participant adherence in the Women’s Health Initiative. Control Clin Trials 2003; 24:422–435.
- Willett W, Lenart E. Reproducibility and validity of food-frequency questionnaires. In:Willett W, ed. Nutritional Epidemiology. 2. New York: Oxford University Press, 1998:101–147.
- Subar AF, Kipnis V, Troiano RP, et al. Using intake biomarkers to evaluate the extent of dietary misreporting in a large sample of adults: the OPEN study. Am J Epidemiol 2003; 158:1–13.
- Bowen D, Raczynski J, George V, Feng Z, Fouad M. The role of participation in the women’s health trial: feasibility study in minority populations. Prev Med 2000; 31:474–480.
- Patterson RE, Kristal AR, White E. Do beliefs, knowledge, and perceived norms about diet and cancer predict dietary change? Am J Public Health 1996; 86:1394–1400.
- Howard BV, Manson JE, Stefanick ML, et al. Low-fat dietary pattern and weight change over 7 years: the Women’s Health Initiative Dietary Modification Trial. JAMA 2006; 295:35–49.
KEY POINTS
- Colon cancer rates did not differ between the dietary intervention group and the comparison group, but the number of polyps and adenomas reported was significantly lower in the dietary intervention group.
- Risk factors for coronary heart disease improved slightly with the diet, but by trial year 3, differences in overall rates of coronary heart disease and stroke in the two groups were not statistically significant.
- When stratified by quartiles, those who reduced their intake of saturated and trans-fatty acids the most, or who increased their intake of fruits and vegetables the most, appeared to have a moderate reduction in the risk of coronary heart disease.