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Kahwati LC, Weber RP, Pan H, et al. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: An Evidence Review for the U.S. Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018 Apr. (Evidence Synthesis, No. 160.)
Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: An Evidence Review for the U.S. Preventive Services Task Force [Internet].
Show detailsScope and Purpose
The U.S. Preventive Services Task Force (USPSTF) will use this review to update its 2013 recommendation on vitamin D with or without calcium supplementation to prevent fractures in adults.1 The review in support of the 2013 recommendation focused on supplementation with vitamin D alone or in combination with calcium2; the USPSTF did not review the evidence or make a recommendation on supplementation with calcium alone.
This update was scoped to provide the USPSTF with answers to key questions (KQs) about the benefits and harms of supplemental vitamin D alone, calcium alone, or vitamin D combined with calcium to reduce fractures among community-dwelling adult populations typically found in primary care settings. In this context, supplementation refers to the use of vitamin D or calcium supplements without knowledge of a person’s diet, nutritional status, or fracture risk. This review does not focus on the use of vitamin D analogues or preparations used to treat medical conditions (e.g., doxercalciferol) and does not include studies that used vitamin D or calcium supplements as adjunctive medical treatments, such as in treatment of osteoporosis. This review also does not address the use of vitamin D in institutionalized populations, populations known to be at high risk for falls or with vitamin D deficiency, or populations with a prior history of osteoporotic fractures.
Condition Definition
Osteoporotic fractures, also known as fragility, “low-energy,” or “low-trauma” fractures occur most often in the spine, forearm, hip, and proximal humerus. They are defined as fractures sustained because of a fall from standing height or lower and that would not give rise to a fracture in most healthy individuals.3 Osteoporotic fractures occur as a result of bone fragility resulting from bone loss or structural changes.4 Supplementation refers to the untargeted use of supplements, without knowledge of an individual’s diet, nutritional status, or fracture risk. Vitamin D, a fat-soluble prohormone obtained through synthesis in the skin and diet is one of several hormones that regulate calcium and phosphorus levels, which are critical to the mineralization of bone.5 Calcium, a dietary micronutrient, forms the mineral hydroxyapatite, which deposits into the organic skeletal matrix to provide bone structure and strength.5 Although not all osteoporotic fractures may be directly attributable to deficiencies in vitamin D or calcium, these nutrients are important modifiable contributors to optimal bone health.6
Etiology and Natural History
Osteoporotic fractures result when bone structure and composition are unable to be stiff yet flexible enough to absorb energy and resist deformation from loading forces.7 Calcium is essential to bone structure and composition, and an array of hormones—parathyroid, calcitriol (the hormonally active form of vitamin D), and calcitonin—regulate its homeostasis and contribute to bone metabolism.5 Other hormones also influence bone metabolism, including testosterone, estrogen, growth hormone, thyroid hormone, and cortisol. Bone structure and composition, specifically bone mass, is influenced by genes, hormones, underlying medical conditions, physical activity, and diet, and evolves across life stages. These factors influence the ability to develop strong bones as a child or may cause excessive bone resorption or impair the replacement of lost bone in adulthood. As a result, osteoporotic fractures associated with low bone mass can result from different mechanisms; some may result from reduced bone formation, while others may result from increased bone resorption.7 Genes are thought to be the chief determinant of “peak” bone mass; whether accretion, resorption, and remodeling can be influenced through dietary or supplemental calcium and vitamin D intake is not well understood.5, 8 Because of vitamin D production in the skin and the fortification of food and beverages with vitamin D, clinical deficiency manifested as osteomalacia in adults is rare. Clinically overt calcium deficiency is also rare among unselected populations. However, when dietary calcium is insufficient, bone is resorbed to ensure that sufficient circulating levels of calcium are available to support neuromuscular junction functioning, nerve transmission, vasodilation, and hormone secretion.5
Risk Factors
Several studies have demonstrated an association between bone mineral density (BMD) and osteoporotic fracture; this risk of fracture increases 1.5- to 2.5-fold for every standard deviation decrease in BMD.4, 9, 10 Despite this association, fractures can occur in persons with normal bone mass, and no bone mass threshold exists that reliably predicts fractures.10
In addition to low bone mass, advancing age and falls are the major risk factors for incident (i.e., first) osteoporotic fractures, although the precise contribution of each to fracture risk is difficult to determine as these factors are often confounded by comorbid conditions and increased incidence of falls among the elderly.4 Fractures occur in 10 to 15 percent of falls,4 and more than 90 percent of hip fractures are related to falls.11 Other risks for low bone mass and fracture include female sex, smoking, use of glucocorticoids, and use of other medications that impair bone metabolism (e.g., aromatase inhibitors).12, 13
Considerable debate exists about the serum 25-hydroxy vitamin D (25[OH] D) levels associated with optimal bone health (Appendix A Table 1).14-16 Experts agree that serum 25[OH] D levels are the best reflection of the vitamin D supply in the body, which constitutes vitamin D that is ingested and vitamin D that is synthesized in the skin.5 Less clear is whether serum vitamin D levels are directly related to health outcomes. The 2009 and 2014 Agency for Healthcare Research and Quality (AHRQ) Evidence Reports prepared in support of the National Academy of Medicine (NAM, formerly Institute of Medicine) committee charged with updating the vitamin D and calcium Dietary Reference Intakes (DRI) found some evidence of an association between serum vitamin D levels and some bone health outcomes, including falls and bone mineral density (BMD), but the association with fractures in adults was inconsistent (Appendix A and Appendix A Table 2).15, 17 Although results from observational studies suggest an association between vitamin D and bone mass; this relationship has not been supported in randomized controlled trials (RCT).15, 17
The level of 25[OH] D used to define vitamin D deficiency has varied over the previous two decades and large variations in laboratory measurement among different serum assays has presented further challenges to interpreting serum vitamin D data to understand the relationship between vitamin D status and health outcomes.5, 18, 19 To determine threshold serum levels associated with sufficient vitamin D status, researchers have examined the level of 25[OH] D associated with maximal suppression of parathyroid hormone,20-23 maximum calcium absorption,24, 25 and reduced fracture risk.26 The NAM suggests that serum 25[OH]D levels for optimal bone health in individuals have a distribution of values within a population, and no single threshold level can define deficiency.5, 27 Using this perspective, NAM suggests that a distribution of serum levels with a mean of 40 nanomole per liter (nmol/L) and standard deviation (SD) of 5 nmol/L would mean that 70 percent of the population can meet their vitamin D needs for bone health at serum levels between 35 and 45 nmol/L.5, 27
Although most experts generally agree that 25[OH] D levels lower than 50 nmol/L may place some individuals at risk relative to bone health, many will have their needs met at this level.5 Because of this, the specific level that should be promoted as a goal for optimal bone health across a population is not entirely clear, nor is the amount of supplementation that any one individual may require to meet a proposed goal. A goal of 50 nmol/L may label many as deficient, when in fact their needs are being met, and may result in harm to some people who would require supplementation above the tolerable upper intake level.16, 28 Further, some organizations suggest that serum 25[OH] D levels should be greater than 75 nmol/L, particularly in older adults.29-31 Some organizations also suggest that, because of variability in laboratory measurements, targeting a higher 25[OH] D level than the goal level (such as 100 nmol/L) better ensures that all persons meet goal levels. The NAM concluded that there may be a potential U-shaped relationship between 25[OH] D levels and some outcomes (e.g., mortality, cardiovascula disease, selected cancers, falls) at serum levels higher than 125 nmol/L.5
It is unclear whether serum vitamin D levels considered “optimal” for bone and mineral metabolism in whites are the same as those in nonwhite populations. Further, obesity is a confounder in the relationships among race, vitamin D serum levels, BMD, and fracture.32, 33 For example, black postmenopausal women have lower mean serum vitamin D concentrations than white women.34 However, after adjustment for body weight and other risk factors for fracture, black women have a lower fracture risk than white women at every level of BMD.35
Several types of risk factors exist for low vitamin D levels. These include physiological risks related to reduced skin synthesis (dark skin, residence at high latitudes, aging, seasonal reduction in sunlight), decreased bioavailability (malabsorption, sequestration in body fat of obese individuals), increased catabolism (anticonvulsants, antiretrovirals), and decreased conversion (liver or kidney disease).36
No accurate serum measure of whole-body calcium exists (calcium ion concentration is exquisitely regulated in extracellular fluid so that serum level does not increase in response to increases in intake); thus, identifying otherwise healthy individuals who are “calcium deficient” and at risk for bone resorption is not currently feasible. The lack of a measure to assess whole-body calcium stores and the complex interplay between vitamin D and calcium make it difficult to interpret data relative to calcium requirements, excess, and deficiency.5 Chronic inadequate calcium intake may be more common among the following populations: postmenopausal women, amenorrheic women, persons with lactose intolerance or cow’s milk allergy.37, 38
Prevalence and Burden
Prevalence of Osteoporotic Fractures
Worldwide, age-standardized incidence rates of osteoporotic fractures have been decreasing. This decline is hypothesized to be attributed to increasing rates of obesity, increasing use of antiresorptive agents, and birth cohort effects.39 In 2005, approximately 2 million osteoporotic fractures occurred in the United States.40 The majority of fractures (71%) occur among women, and women accounted for more than three quarters of the total cost of incident fractures (>$16.9 billion). The total cost distribution by fracture type is skewed toward hip fractures, which account for 72 percent of total costs but represent only 14 percent of fractures.
Vertebral fractures are the most common fracture associated with low bone mass, accounting for an estimated 700,000 of the 1.5 million osteoporotic fractures annually in the United States.41 Vertebral fractures may present with back pain; however, as many as two-thirds to three-quarters of vertebral fractures are not clinically diagnosed and are only identified because of vertebral body deformities on incidental radiographs (also called morphometric fractures).41 Nearly 74 percent of nonvertebral fractures are in women age 65 years or older.42 The incremental health care cost to Medicare per nonvertebral osteoporotic fracture was estimated to be $13,387 from 1999–2006, with inpatient and long-term care accounting for three quarters of the incremental cost.43 Hip fractures, considered a subset of nonvertebral fractures, accounted for a large proportion of the mortality and morbidity related to fractures. Using Medicare claims data from 1986–2005, the annual rate of hip fractures in women was estimated at 957.3 per 100,000, and the rate in men was estimated at 414.4 per 100,000. The morbidity and mortality associated with hip fractures is high: 20 to 30 percent of patients die within 1 year of a hip fracture, with significantly higher mortality rates after fracture in men than women.42 Nearly 40 percent of those who experience a fracture are unable to walk independently at 1 year, and 60 percent require assistance with at least one essential activity of daily living.10
Prevalence of Vitamin D and Calcium Insufficiency
The NAM selected bone health to serve as the basis for establishing DRIs for vitamin D and calcium.5 These DRIs specify the estimated average requirements and the recommended dietary allowances, which represent the level of intake that will likely meet the bone health needs of 97.5 percent of the population. The DRIs also specify the tolerable upper intake level; these are levels above which the potential for harms increase. Appendix A Table 3 depicts data from the 2011–2012 U.S. National Health and Nutrition Examination Survey (NHANES) regarding vitamin D and calcium intake from dietary and supplement sources along with current Recommended Dietary Allowance for meeting average requirements for adult men and nonpregnant lactating women.5, 44 Based on 1 day of dietary intake data collected in a dietary intake interview, the 2009–2010 NHANES estimated that 42 percent of the U.S. population (age 2 years and older) does not take in the estimated average requirement for calcium.45
Because most vitamin D is produced by the skin—as opposed to being obtained through dietary sources—it is challenging to estimate the proportion of individuals who do not have an adequate level of vitamin D.45, 46 Estimating intake from diet is challenging because of underreporting of calories and amounts of fortified foods.47 For both reasons, estimates of intake from diet or supplements may not adequately reflect adequacy of vitamin D. Although serum 25[OH] D levels can be used to estimate vitamin D deficiency, prevalence estimates remain challenging because rates vary based on how deficiency is defined and the assay used to measure levels.5, 18 The NAM developed a statistical procedure to derive prevalence estimates of nutritional inadequacy. According to this model, 19 percent of the U.S. adult population does not receive the estimated average requirement defined by NAM as a serum 25[OH] D less than 40 nmol/L.48 This prevalence increases to 36 percent if a serum level of 50 nmol/L is used. Based on NHANES 2009–2010 data, 3.5 percent (95% CI, 2.2 to 4.7) of those age 20 to 64 years and 3.9 percent (95% CI, 2.3 to 5.4) of those age 65 or older had 25[OH] D levels less than 25 nmol/L.49 Using this same data source and method, 34.2 percent (95% CI, 30 to 38.3) of adults age 20 to 64 years and 47.5 percent (95% CI, 42 to 53) of adults 65 and older have a 25 [OH] D level of 75 nmol/L or greater.
Prevention Approaches and Rationale
Although the role of vitamin D and calcium in bone metabolism is well-established, uncertainty exists about whether supplementing community-dwelling, unselected adult populations has benefits in terms of fracture prevention. If effective, supplementation, which does not rely on knowledge of a person’s underlying fracture risk, bone mass, vitamin D status, or diet, could be a more efficient approach for fracture prevention than a preventive approach that requires laboratory testing, imaging, or dietary assessment to determine whether treatment with vitamin D or calcium, should be used. At the same time, it is important to understand the harms of supplementation with these agents, such as possible increased risk for cardiovascular events from the use of calcium supplements.50, 51
The NAM recommends a dietary intake between 400 international units (IU) and 800 IU per day of vitamin D for various age groups based on an assumption of minimal sun exposure.5 The NAM suggests that health policy and public health applications of this recommendation may need to adjust the recommended intake based on the level of sunlight exposure within the target population of interest. The proportion of vitamin D obtained through diet is often from foods and beverages that have been fortified, because naturally occurring vitamin D in foods is rare, although recent research suggests animal products (e.g., meat, poultry, eggs) may contain the metabolized form of vitamin D, which is not typically measured when reporting the vitamin D content of food.47 Vitamin D supplements are available for oral or injectable use and are formulated as either vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol). Both forms are generically referred to as calciferol and must undergo further metabolism into calcitriol, the biologically active form of vitamin D. The relationship between vitamin D supplementation and serum 25[OH] D levels appears to be nonlinear5 (Appendix A).
The NAM established DRIs for calcium that vary by age and sex. Currently, the recommended calcium intake for all adults, male or female, ages 19 to 50 is 1,000 mg/day. The daily recommended intake increases to 1,200 mg/day for women age 50 years or older and men age 70 years or older.5 These requirements refer to intake from all sources, including food, beverages, and supplements. Dietary calcium is obtained through foods and beverages that naturally contain calcium or that have been fortified. Calcium supplements are typically formulated as salts; calcium carbonate and calcium citrate are the most common preparations, but other formulations are also available. Dosing is based on the amount of elemental calcium present.
Current Clinical Practice in the United States
Vitamin D and calcium—either alone or in addition to prescription medication and recommendations on physical activity—are often recommended for optimizing “bone health.” Both are components of most multivitamin supplements. Vitamin D and calcium supplements are available over the counter at grocery stores, pharmacies, and other retail outlets. Based on the NHANES, the use of single vitamin D supplements (i.e., vitamin D alone and not as part of a multivitamin supplement) has increased from 5.1 percent of U.S. adults in 1999–2000 to 19 percent in 2011–2012.52 The use of single calcium supplements has slightly decreased over the same time period (38% of U.S. adults in 1999 to 35% in 2011). Appendix A Table 4 summarizes recommendations of professional organizations related to vitamin D and calcium intake.
Previous USPSTF Recommendation
In 2013, the USPSTF recommended against daily supplementation of 400 IU or less of vitamin D3 and 1,000 milligram (mg) or less of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women (D recommendation) because of adequate evidence of no effect on primary prevention of fracture.1 The USPSTF concluded that there was insufficient evidence to recommend vitamin D with or without calcium supplementation for the primary prevention of fractures in premenopausal women and in men. They also found the evidence insufficient to recommend vitamin D at doses greater than 400 IU with or without calcium (at doses greater than 1,000 mg) for noninstitutionalized, postmenopausal women. The USPSTF did not review evidence related to the benefits or harms of supplementation with calcium alone.
Other Related USPSTF Recommendations
The USPSTF has several recommendations related to fracture prevention or vitamin D. These include screening for vitamin D deficiency, screening for osteoporosis, vitamin supplementation to prevent cancer and cardiovascular disease, and falls prevention in older adults. The scope of these related reviews and the corresponding USPSTF recommendation are described in Appendix A Table 5. The review that informed the USPSTF recommendation on screening for vitamin D deficiency found a lack of direct evidence on screening for vitamin D deficiency on health outcomes and no effect on decreasing fractures among studies randomizing ambulatory or institutionalized, vitamin D-deficient individuals to treatment with vitamin D.53 Other nonfracture outcomes were also considered by the USPSTF and they concluded the evidence across all outcomes was insufficient to make a recommendation.54 The review that informed the USPSTF recommendation on screening for osteoporosis found no direct evidence of screening on health outcomes, but found that treatment of individuals with osteoporosis is effective in reducing fractures.55, 56 Thus, the USPSTF recommends screening for osteoporosis in women age 65 or older and in some younger women based on risk (B recommendation). An updated review for the USPSTF of screening for osteoporosis is currently in progress. The review in support of the USPSTF recommendation on vitamin supplementation to prevent cancer or cardiovascular disease found limited evidence about the use of vitamin D as a single or paired supplement, and the USPSTF concluded that the evidence was insufficient to make a recommendation.57, 58 The 2012 review in support of the USPSTF recommendation on Falls Prevention in Older Adults included vitamin D supplementation as an eligible intervention.59 However, the study populations eligible for that review included adults age 65 or older at increased risk for falls, which is a population not included in this review. An update to the Falls Prevention review and updated recommendation for Falls Prevention occurred concurrent to this review.60, 61 The update review found evidence for the effectiveness of exercise interventions and multifactorial interventions to prevent falls but mixed findings, including possible harms, for vitamin D supplementation. As a result, the USPSTF now recommends against vitamin D supplementation to prevent falls in this population (D recommendation).62
- Introduction - Vitamin D, Calcium, or Combined Supplementation for the Primary P...Introduction - Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: An Evidence Review for the U.S. Preventive Services Task Force
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