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Bone Health Contents Summary Overview of Bone Biology Structure and physiology Bone development and growth Determinants of adult bone health Loss of bone mineral and mass Micronutrients Important to Bone Health Minerals Fat-soluble vitamins Micronutrients needed for collagen formation Micronutrients involved in homocysteine metabolism Effects of Lifestyle Factors Smoking Alcohol Physical activity Conclusion Authors and Reviewers References
Micronutrients and Bone Health Summary
The skeleton is an active organ, comprised of tissue and cells in a continual state of activity throughout a lifetime. (More information) Bone development occurs in three general phases that coincide with age: growth, modeling or consolidation, and remodeling. The remodeling phase predominates during adulthood, with bone resorption and formation activities constantly occurring in linked succession. (More information) Accrual of bone mass is the product of both inherited and environmental factors. Diet and exercise can significantly affect the ability to achieve one’s genetically determined peak bone mass. (More information) Beginning around age 34, the rate of bone resorption outpaces that of bone formation, leading to an inevitable loss of bone mass with age. Clinical consequences of low bone mass include osteomalacia, osteopenia, and osteoporosis. (More information) In addition to the classic bone micronutrients calcium and vitamin D, several other minerals and vitamins have essential roles in bone health. (More information) In the elderly and those with suboptimal calcium intake, calcium supplementation improves bone mineral density (BMD) and may reduce the risk of osteoporotic fracture. (More information) Vitamin A excess, typically from supplemental sources, may have a negative effect on bone health and increase the risk of fracture. (More information) Vitamin D intakes of 800 IU or more per day are associated with reduced risk of osteoporotic fracture and falls. (More information) Although vitamin K functionally modifies several bone matrix proteins, there is inconclusive evidence that vitamin K supplementation improves BMD or reduces the risk of osteoporotic fracture. (More information) Vitamin C is essential for collagen synthesis and bone matrix quality, yet few trials have tested the efficacy of vitamin C supplementation on BMD and fracture risk. (More information) Elevated plasma homocysteine (hcy) is associated with increased risk of fracture. Strategies to reduce hcy levels by supplementation with folate, vitamin B12, and vitamin B6 may benefit bone and are under investigation. (More information) Smoking, alcohol consumption, and physical activity significantly affect BMD and risk of osteoporotic fracture. (More information) http://lpi.oregonstate.edu/book/export/html/57
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Overview of Bone Biology Structure and physiology Bone composition and structure. Our skeleton may seem an inert structure, but it is an active organ, made up of tissue and cells in a continual state of activity throughout a lifetime. Bone tissue is comprised of a mixture of minerals deposited around a protein matrix, which together contribute to the strength and flexibility of our skeletons. Sixty-five percent of bone tissue is inorganic mineral, which provides the hardness of bone. The major minerals found in bone are calcium and phosphorus in the form of an insoluble salt called hydroxyapatite (HA) [chemical formula: (Ca)10(PO4)6(OH)2)]. HA crystals lie adjacent and bound to the organic protein matrix. Magnesium, sodium, potassium, and citrate ions are also present, conjugated to HA crystals rather than forming distinct crystals of their own (1). The remaining 35% of bone tissue is an organic protein matrix, 90-95% of which is type I collagen. Collagen fibers twist around each other and provide the interior scaffolding upon which bone minerals are deposited (1). Types of bone. There are two types of bone tissue: cortical (compact) bone and trabecular (spongy or cancellous) bone (2). Eighty percent of the skeleton is cortical bone, which forms the outer surface of all bones. The small bones of the wrists, hands, and feet are entirely cortical bone. Cortical bone looks solid but actually has microscopic openings that allow for the passage of blood vessels and nerves. The other 20% of skeleton is trabecular bone, found within the ends of long bones and inside flat bones (skull, pelvis, sternum, ribs, and scapula) and spinal vertebrae. Both cortical and trabecular bone have the same mineral and matrix components but differ in their porosity and microstructure: trabecular bone is much less dense, has a greater surface area, and undergoes more rapid rates of turnover (see Bone remodeling/turnover). Bone development and growth There are three phases of bone development: growth, modeling (or consolidation), and remodeling (Figure 1). During the growth phase, the size of our bones increases. Bone growth is rapid from birth to age two, continues in spurts throughout childhood and adolescence, and eventually ceases in the late teens and early twenties. Although bones stop growing in length by about 20 years of age, they change shape and thickness and continue accruing mass when stressed during the modeling phase. For example, weight training and body weight exert mechanical stresses that influence the shape of bones. Thus, acquisition of bone mass occurs during both the growth and modeling/consolidation phases of bone development. The remodeling phase consists of a constant process of bone resorption (breakdown) and formation that predominates during adulthood and continues throughout life. Beginning around age 34, the rate of bone resorption exceeds that of bone formation, leading to an inevitable loss of bone mass with age (3).
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Peak bone mass
Bone mass refers to the quantity of bone present, both matrix and mineral. Bone mass increases through adolescence and peaks in the late teen years and into our twenties. The maximum amount of bone acquired is known as peak bone mass (PBM) (see Figure 1 above) (4, 5). Achieving one’s genetically determined PBM is influenced by several environmental factors, discussed more extensively below (see Determinants of adult bone health). Technically, we cannot detect the matrix component of bone, so bone mass cannot be measured directly. We can, however, detect bone mineral by using dual X-ray absorptiometry (DEXA). In this technique, the absorption of photons from an X-ray is a function of the http://lpi.oregonstate.edu/book/export/html/57
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amount of mineral present in the path of the beam. Therefore, bone mineral density (BMD) measures the quantity of mineral present in a given section of bone and is used as a proxy for bone mass (6). Although BMD is a convenient clinical marker to assess bone mass and is associated with osteoporotic fracture risk, it is not the sole determinant of fracture risk. Bone quality (architecture, strength) and propensity to fall (balance, mobility) also factor into risk assessment and should be considered when deciding upon an intervention strategy (see Osteoporosis). Bone remodeling/turnover
Bone tissue, both mineral and organic matrix, is continually being broken down and rebuilt in a process known as remodeling or turnover. During remodeling, bone resorption and formation are always “coupled” — osteoclasts first dissolve a section of bone and osteoblasts then invade the newly created space and secrete bone matrix (6). The goal of remodeling is to repair and maintain a healthy skeleton, adapt bone structure to new loads, and regulate calcium concentration in extracellular fluids (7). The bone remodeling cycle, which refers to the time required to complete the entire series of cellular events from resorption to final mineralization, lasts approximately 40 weeks (8, 9). Additionally, remodeling units cycle at staggered stages. Thus, any intervention that influences bone remodeling will affect newly initiated remodeling cycles at first, and there is a lag time, known as the “bone remodeling transient,” until all remodeling cycles are synchronized to the treatment exposure (8). Considering the bone remodeling transient and the length of time required to complete a remodeling cycle, a minimum of two years is needed to realize steady-state treatment effects on BMD (10). The rates of bone tissue turnover differ depending on the type of bone: trabecular bone has a faster rate of turnover than cortical bone. Osteoporotic fracture manifests in trabecular bone, primarily as fractures of the hip and spine, and many osteoporotic therapies target remodeling activities in order to alter bone mass (11). Bone cells
The cells responsible for bone formation and resorption are osteoblasts and osteoclasts, respectively. Osteoblasts prompt the formation of new bone by secreting the collagen-containing component of bone that is subsequently mineralized (1). The enzyme alkaline phosphatase is secreted by osteoblasts while they are actively depositing bone matrix; alkaline phosphatase travels to the bloodstream and is therefore used as a clinical marker of bone formation rate. Osteoblasts have receptors for vitamin D, estrogen, and parathyroid hormone (PTH). As a result, these hormones have potent effects on bone health through their regulation of osteoblastic activity. Once they have finished secreting matrix, osteoblasts either die, become lining cells, or transform into osteocytes, a type of bone cell embedded deep within the organic matrix (9, 12). Osteocytes make up 90-95% of all bone cells and are very long-lived (up to decades) (12). They secrete soluble factors that influence osteoclastic and osteoblastic activity and play a central role in bone remodeling in response to mechanical stress (9, 12, 13). Osteoclasts erode the surface of bones by secreting enzymes and acids that dissolve bone. More specifically, enzymes degrade the organic matrix and acids solubilize bone mineral salts (1). Osteoclasts work in small, concentrated masses and take approximately three weeks to http://lpi.oregonstate.edu/book/export/html/57
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dissolve bone, at which point they die and osteoblasts invade the space to form new bone tissue. In this way, bone resorption and formation are always “coupled.” End products of bone matrix breakdown (hydroxyproline and amino-terminal collagen peptides) are excreted in the urine and can be used as convenient biochemical measures of bone resorption rates. Determinants of adult bone health Maximum attainment of peak bone mass
The majority of bone mass is acquired during the growth phase of bone development (see Figure 1 above) (4, 6). Attaining one’s peak bone mass (PBM) (i.e., the maximum amount of bone) is the product of genetic, lifestyle, and environmental factors (5, 14). Sixty to 80% of PBM is determined by genetics, while the remaining 20-40% is influenced by lifestyle factors, primarily nutrition and physical activity (15). In other words, diet and exercise are known to contribute to bone mass acquisition but can only augment PBM within an individual’s genetic potential. Acquisition of bone mass during the growth phase is sometimes likened to a “bone bank account” (4, 5). As such, maximizing PBM is important when we are young in order to protect against the consequences of age-related bone loss. However, improvements in bone mineral density (BMD) generally do not persist once a supplement or exercise intervention is terminated (16, 17). Thus, attention to diet and physical activity during all phases of bone development is beneficial for bone mass accrual and skeletal health. Rate of bone loss with aging
Bone remodeling is a lifelong process, with resorption and formation linked in space and time. Yet the scales tip such that bone loss outpaces bone gain as we age. Beginning around age 34, the rate of bone resorption exceeds the rate of bone formation, leading to an inevitable loss of bone mass with age (see Figure 1 above) (18). Age-related estrogen reduction is associated with increased bone remodeling activity — both resorption and formation — in both sexes (13). However, the altered rate of bone formation does not match that of resorption; thus, estrogen deficiency contributes to loss of bone mass over time (9, 13). The first three to five years following the onset of menopause ('early menopause') are associated with an accelerated, self-limiting loss of bone mass (3, 18, 19). Subsequent postmenopausal bone loss occurs at a linear rate as we age (3). As we continue to lose bone, we near the threshold for osteoporosis and are at high-risk for fractures of the hip and spine. Loss of bone mineral and mass Osteomalacia
Osteomalacia, also known as “adult rickets,” is a failure to mineralize bone. Stereotypically, osteomalacia results from vitamin D deficiency (serum 25-hydroxyvitamin D levels <20 nmol/L or <8 ng/mL) and the associated inability to absorb dietary calcium and phosphorus across the small intestine. Plasma calcium concentration is tightly controlled, and the body has a number of mechanisms in http://lpi.oregonstate.edu/book/export/html/57
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place to adjust to fluctuating blood calcium levels. In response to low blood calcium, PTH levels increase and vitamin D is activated. The increase in PTH stimulates bone remodeling activity — both resorption and formation, which are always coupled. Thus, osteoclasts release calcium and phosphorus from bone in order to restore blood calcium levels, and osteoblasts mobilize to replace the resorbed bone. During osteomalacia, however, the deficiency of calcium and phosphorus results in incomplete mineralization of the newly secreted bone matrix. In severe cases, newly formed, unmineralized bone loses its stiffness and can become deformed under the strain of body weight. In addition to vitamin D deficiency, osteomalacia can result from fluoride toxicity, cadmium poisoning, and genetic disorders of phosphate homeostasis (hypophosphatemia) (20). Osteopenia
Simply put, osteopenia and osteoporosis are varying degrees of low bone mass. Whereas osteomalacia is characterized by low-mineral and high-matrix content, osteopenia and osteoporosis result from low levels of both. As defined by the World Health Organization (WHO), osteopenia precedes osteoporosis and occurs when one’s bone mineral density (BMD) is between 1 and 2.5 standard deviations (SD) below that of the average young adult (30 years of age) woman (see Figure 1 above). Osteoporosis
Osteoporosis is a condition of increased bone fragility and susceptibility to fracture due to loss of bone mass. Clinically, osteoporosis is defined as a BMD that is greater than 2.5 SD below the mean for young adult women (see Figure 1 above). It has been estimated that fracture risk in adults is approximately doubled for each SD reduction in BMD (6). Common sites of osteoporotic fracture are the hip, femoral neck, and vertebrae of spinal column — skeletal sites rich in trabecular bone. BMD, the quantity of mineral present per given area/volume of bone, is only a surrogate for bone strength. Although it is a convenient biomarker used in clinical and research settings to predict fracture risk, the likelihood of experiencing an osteoporotic fracture cannot be predicted solely by BMD (6). The risk of osteoporotic fracture is influenced by additional factors, including bone quality (microarchitecture, geometry) and propensity to fall (balance, mobility, muscular strength). Other modifiable and non-modifiable factors also play into osteoporotic fracture risk, and they are generally additive (21). The WHO Fracture Risk Assessment Tool was designed to account for some of these additional risk factors. Once you have your BMD measurement, visit the WHO website to calculate your 10year probability of fracture, taking some of these additional risk factors into account. Paying attention to modifiable risk factors for osteoporosis is an important component of fracture prevention strategies. For more details about individual dietary factors and osteoporosis, see the Micronutrient Information Center's Disease Index.
Micronutrients Important to Bone Health Micronutrient supply plays a prominent role in bone health. Several minerals have direct roles in hydroxyapatite (HA) crystal formation and structure; other nutrients have indirect roles as cofactors or as regulators of cellular activity (22, 23). http://lpi.oregonstate.edu/book/export/html/57
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Table 1 lists the dietary reference intakes (DRIs) for micronutrients important to bone health. The average dietary intake of Americans (aged 2 years and older) is also provided for comparative purposes (24). Table 1. DRIs for Micronutrients Important to Bone Health RDA or AI*
UL (≥19 y)
Mean Intake (≥2 y, all food sources) (24)
Men: 1,000 mg/d (19-70y) 1,200 mg/d (>70y) Women: 1,000 mg/d (19-50y) 1,200 mg/d (>50y)
Men & Women: 2,500 mg/d (19-50y) 2,000 mg/d (>50y)
939 mg/d
Phosphorus
Men & Women: 700 mg/d
Men & Women: 4 g/d (19-70y) 3 g/d (>70y)
1,326 mg/d
Fluoride
Men: 4 mg/d* Women: 3 mg/d*
Men & Women: 10 mg/d
Not reported
Men: 400 mg/d (19-30y) 420 mg/d (>31y) Women: 310 mg/d (19-30y) 320 mg/d (>31y)
Men & Women: 350 mg/da
276 mg/d
Men & Women: 1.5 g/d (19-50y) 1.3 g/d (51-70y) 1.2 g/d (>70y)
Men & Women: 2.3 g/d
Not reported
Men & Women: 15 mcg (600 IU)/d (19-70y) 20 mcg (800 IU)/d (>70y)
Men & Women: 100 mcg (4,000 IU)/d
4.9 mcg (200 IU)/d
Micronutrient
Calcium
Magnesium
Sodium
Vitamin D
Men: http://lpi.oregonstate.edu/book/export/html/57
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900 mcg (3,000 IU)/db Women: 700 mcg (2,333 IU)/db
Men & Women: 3,000 mcg (10,000 IU)/db
601 mcg/d
Vitamin K
Men: 120 mcg/d* Women: 90 mcg/d*
ND
80 mcg/d
Vitamin C
Men: 90 mg/d Women: 75 mg/d
Men & Women: 2,000 mg/d
85 mg/d
Vitamin B6
Men: 1.3 mg/d (19-50y) 1.7 mg/d (>50y) Women: 1.3 mg/d (19-50y) 1.5 mg/d (>50y)
Men & Women: 100 mg/d
1.9 mg/d
Folate
Men & Women: 400 mcg/dc
Men & Women: 1,000 mcg/dc
543 mcg/d
Vitamin B12
Men & Women: 2.4 mcg/d
ND
5.3 mcg/d
Vitamin A
Abbreviations: DRI, dietary reference intake; RDA, recommended dietary allowance; AI, adequate intake; UL, tolerable upper intake level; y, years; d, day; g, gram; mg, milligram; mcg, microgram; IU, international units; ND, not determinable aApplies only to the supplemental form bApplies only to preformed retinol cApplies to the synthetic form in fortified foods and supplements Minerals Calcium http://lpi.oregonstate.edu/book/export/html/57
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Calcium is the most common mineral in the human body. About 99% of the calcium in the body is found in bones and teeth, while the other 1% is found in blood and soft tissues. Calcium levels in the blood must be maintained within a very narrow concentration range for normal physiological functioning, namely muscle contraction and nerve impulse conduction. These functions are so vital to survival that the body will demineralize bone to maintain normal blood calcium levels when calcium intake is inadequate. In response to low blood calcium, parathyroid hormone (PTH) is secreted. PTH targets three main axes in order to restore blood calcium concentration: (1) vitamin D is activated (see the section on vitamin D), (2) filtered calcium is retained by the kidneys, and (3) bone resorption is induced (1). It is critical to obtain enough dietary calcium in order to balance the calcium taken from our bones in response to fluctuating blood calcium concentrations. Several randomized, placebo-controlled trials (RCTs) have tested whether calcium supplementation reduces age-related bone loss and fracture incidence in postmenopausal women. In the Women’s Health Initiative (WHI), 36,282 healthy, postmenopausal women (aged 50 to 79 years; mean age 62 years) were randomly assigned to receive placebo or 1,000 mg calcium carbonate and 400 IU vitamin D3 daily (25). After a mean of seven years of follow-up, the supplement group had significantly less bone loss at the hip. A 12% reduction in the incidence of hip fracture in the supplement group did not reach statistical significance, possibly due to the low rates of absolute hip fracture in the 50 to 60 year age range. The main adverse event reported in the supplement group was an increased proportion of women with kidney stones. Another RCT assessed the effect of 1,000 mg of calcium citrate versus placebo on bone density and fracture incidence in 1,472 healthy postmenopausal women (aged 74±4 years) (26). Calcium had a significant beneficial effect on bone mineral density (BMD) but an uncertain effect on fracture rates. The high incidence of constipation with calcium supplementation may have contributed to poor compliance, which limits data interpretation and clinical efficacy. Hip fracture was significantly reduced in an RCT involving 1,765 healthy, elderly women living in nursing homes (mean age 86±6 years) given 1,200 mg calcium triphosphate and 800 IU vitamin D3 daily for 18 months (27). The number of hip fractures was 43% lower and the number of nonvertebral fractures was 32% lower in women treated with calcium and vitamin D3 supplements compared to placebo. While there is a clear treatment benefit in this trial, the institutionalized elderly population is known to be at high risk for vitamin deficiencies and fracture rates and may not be representative of the general population. Overall, the majority of calcium supplementation trials (and meta-analyses thereof) show a positive effect on BMD, although the size of the effect is modest (3, 7, 28, 29). Furthermore, the response to calcium supplementation may depend on habitual calcium intake and age: those with chronic low intakes will benefit most from supplementation (7, 29), and women within the first five years after menopause are somewhat resistant to calcium supplementation (7, 10). The current recommendations in the US for calcium are based on a combination of balance data and clinical trial evidence, and they appear to be set at levels that support bone health (see Table 1 above) (30, 31). Aside from the importance of meeting the RDA, calcium is a critical adjuvant for therapeutic regimens used to treat osteoporosis (7, 11). The therapy (e.g., estrogen replacement, pharmaceutical agent, and physical activity) provides a bone-building stimulus that must be matched by raw materials (nutrients) obtained from the diet. Thus, calcium supplements are a necessary component of any osteoporosis treatment strategy. A recent meta-analysis (32) and prospective study (33) have raised concern over the safety of calcium supplements, either alone or with http://lpi.oregonstate.edu/book/export/html/57
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vitamin D, on the risk of cardiovascular events. Although these analyses raise an issue that needs further attention, there is insufficient evidence available at this time to definitely refute or support the claims that calcium supplementation increases the risk of cardiovascular disease. For more extensive discussion of this issue, visit the LPI Spring/Summer 2012 Research Newsletter or the LPI News Article. Phosphorus
More than half the mass of bone mineral is comprised of phosphorus, which combines with calcium to form HA crystals. In addition to this structural role, osteoblastic activity relies heavily on local phosphate concentrations in the bone matrix (11, 34). Given its prominent functions in bone, phosphorus deficiency could contribute to impaired bone mineralization (34). However, in healthy individuals, phosphorus deficiency is uncommon, and there is little evidence that phosphorus deficiency affects the incidence of osteoporosis (23). Excess phosphorus intake has negligible affects on calcium excretion and has not been linked to a negative impact on bone (35). Fluoride
Fluoride has a high affinity for calcium, and 99% of our body fluoride is stored in calcified tissues, i.e., teeth and bones (36). In our teeth, very dense HA crystals are embedded in collagen fibers. The presence of fluoride in the HA crystals (fluoroapatite) enhances resistance to destruction by plaque bacteria (1, 36), and fluoride has proven efficacy in the prevention of dental caries (37). While fluoride is known to stimulate bone formation through direct effects on osteoblasts (38), high-dose fluoride supplementation may not benefit BMD or reduce fracture rates (39, 40). The presence of fluoride in HA increases the crystal size and contributes to bone fragility; thus, uncertainties remain about the quality of newly formed bone tissue with fluoride supplementation (9, 23). Chronic intake of fluoridated water, on the other hand, may benefit bone health (9, 36). Two large prospective studies comparing fracture rates between fluoridated and non-fluoridated communities demonstrate that long-term, continuous exposure to fluoridated water (1 mg/L) is safe and associated with reduced incidence of fracture in elderly individuals (41, 42). Magnesium
Magnesium (Mg) is a major mineral with essential structural and functional roles in the body. It is a critical component of our skeleton, with 50-60% of total body Mg found in bone where it colocalizes with HA, influencing the size and strength of HA crystals (23). Mg also serves a regulatory role in mineral metabolism. Mg deficiency is associated with impaired secretion of PTH and end-organ resistance to the actions of PTH and 1,25-dihydroxyvitamin D3 (43). Low dietary intake of Mg is common in the US population (24), and it has therefore been suggested that Mg deficiency could impair bone mineralization and represent a risk factor for osteoporosis. However, observational studies of the association between Mg intake and bone mass or bone loss have produced mixed results, with most showing no association (34). The effect of Mg supplementation on trabecular bone density in postmenopausal women was assessed in one controlled intervention trial (44). Thirty-one postmenopausal women (mean age, 57.6±10.6 years) received two to six tablets of 125 mg http://lpi.oregonstate.edu/book/export/html/57
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each magnesium hydroxide (depending on individual tolerance levels) for six months, followed by two tablets daily for another 18 months. Twenty-three age-matched osteoporotic women who refused treatment served as controls. After one year of Mg supplementation, there was either an increase or no change in bone density in 27 out of 31 patients; bone density was significantly decreased in controls after one year. Although encouraging, this is a very small study, and only ten Mg-supplemented patients persisted into the second year. Sodium
Sodium is thought to influence skeletal health through its impact on urinary calcium excretion (34, 45). Sodium excretion (a proxy for sodium intake) is accompanied by calcium excretion by the kidneys: for every 1-gram (g) of sodium (equivalent to 2.5 g of salt) excreted, approximately 26.3 milligrams (mg) of calcium is excreted into the urine (46). Theoretically, if the urinary calcium loss is not compensated for by increased intestinal absorption from dietary sources, bone calcium will be mobilized and could potentially affect skeletal health. Any negative effects of habitual, high-sodium intake on bone may be influenced by concurrent calcium intake: at the recommended levels or more of calcium intake, high-sodium intake (approximately 3,000 mg/day) does not appear to be detrimental to bone health, but at low levels of calcium intake, high-sodium intake may negatively influence calcium balance and bone health (47). Some cross-sectional studies have observed that the combination of high-sodium and low-calcium intakes are associated with decreased bone mineral density (BMD) at the hip (48) and increased concentration of C-terminal telopeptides of type 1 collagen, a marker of bone resorption (49). A two-year longitudinal study in postmenopausal women found increased urinary sodium excretion (an indicator of increased sodium intake) to be associated with decreased BMD at the hip (50). Linear regression analysis estimated that BMD could be maintained by reducing sodium intake to recommended levels (2,300 mg/day) and by increasing calcium intake to 1,200 mg/day. A second longitudinal study in postmenopausal women found that habitual high-sodium intake (approximately 3,000 mg/day) was not detrimental to BMD over three years of follow-up (51). Notably, the average calcium intake in this study population was 1,300 to 1,500 mg/day. Although these results do not clarify the long-term impact of high-sodium intake on bone health, it is clear that most Americans consume too much sodium and too little calcium (52). Thus, striving to lower sodium intake while increasing calcium intake to the recommended levels is a good strategy for supporting bone health. Fat-soluble vitamins Vitamin A
Both vitamin A deficiency and excess can negatively affect skeletal health. Vitamin A deficiency is a major public health concern worldwide, especially in developing nations. In growing animals, vitamin A deficiency causes bone abnormalities due to impaired osteoclastic and osteoblastic activity (53). These abnormalities can be reversed upon vitamin A repletion (54). In animals, vitamin A toxicity (hypervitaminosis A) is associated with poor bone growth, loss of bone mineral content, and increased rate of fractures (22). Case studies in humans have indicated that extremely high vitamin A intakes (100,000 IU/day or more, several fold above the tolerable upper intake level [UL] (see Table 1 above) are associated with hypercalcemia and bone resorption (55-57). http://lpi.oregonstate.edu/book/export/html/57
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The question remains, however, if habitual, excessive vitamin A intake has a negative effect on bone (22, 58, 59). There is some observational evidence that high vitamin A intake (generally in supplement users and at intake levels >1,500 mcg [5,000 IU]/day) is associated with an increased risk of osteoporosis and hip fracture (60-62). However, methods to assess vitamin A intake and status are notoriously unreliable (63), and the observational studies evaluating the association between vitamin A status or vitamin A intake with bone health report inconsistent results (64, 65). At this time, striving for the recommended dietary intake (RDA) for vitamin A (see Table 1 above) is an important and safe goal for optimizing skeletal health. Vitamin D
The primary function of vitamin D is to maintain calcium and phosphorus absorption in order to supply the raw materials of bone mineralization (9, 66). In response to low blood calcium, vitamin D is activated and promotes the active absorption of calcium across the intestinal cell (66). In conjunction with PTH, activated 1,25-dihydroxyvitamin D3 retains filtered calcium by the kidneys. By increasing calcium absorption and retention, 1,25-dihydroxyvitamin D3 helps to offset calcium lost from the skeleton. Low circulating 25-hydoxyvitamin D3 (the storage form of vitamin D3) triggers a compensatory increase in PTH, a signal to resorb bone. The Institute of Medicine determined that maintaining a serum 25-hydroxyvitamin D3 level of 50 nmol/L (20 ng/ml) benefits bone health across all age groups (31). However, debate remains over the level of serum 25-hydroxyvitamin D3 that corresponds to optimum bone health. Based on a recent review of clinical trial data, the authors concluded that serum 25-hydroxyvitamin D3 should be maintained at 75110 nmol/L (30-44 ng/ml) for optimal protection against fracture and falls with minimal risk of hypercalcemia (67). The level of intake associated with this higher serum 25-hydroxyvitamin D3 range is 1,800 to 4,000 IU per day, significantly higher than the current RDA (see Table 1 above) (67). As mentioned in the Calcium section above, several randomized controlled trials (and meta-analyses) have shown that combined calcium and vitamin D supplementation decreases fracture incidence in older adults (29, 68-70). The efficacy of vitamin D supplementation may depend on habitual calcium intake and the dose of vitamin D used. In combination with calcium supplementation, the dose of vitamin D associated with a protective effect is 800 IU or more per day (29, 71). In further support of this value, a recent dosing study performed in 167 healthy, postmenopausal, white women (aged 57 to 90 years old) with vitamin D insufficiency (15.6 ng/mL at baseline) demonstrated that 800 IU/d of vitamin D3 achieved a serum 25-hydoxyvitamin D3 level greater than 20 ng/mL (72). The dosing study, which included seven groups ranging from 0 to 4,800 IU per day of vitamin D3 plus calcium supplementation for one year, also revealed that serum 25hydroxyvitamin D3 response was curvilinear and plateaued at approximately 112 nmol/L (45 ng/mL) in subjects receiving more than 3,200 IU per day of vitamin D3. Some trials have evaluated the effect of high-dose vitamin D supplementation on bone health outcomes. In one RCT, high-dose vitamin D supplementation was no better than the standard dose of 800 IU/d for improving bone mineral density (BMD) at the hip and lumbar spine (73). In particular, 297 postmenopausal women with low bone mass (T-score ≤-2.0) were randomized to receive high-dose (20,000 IU vitamin D3 twice per week plus 800 IU per day) or standard-dose (placebo plus 800 IU per day) for one year; both groups also received http://lpi.oregonstate.edu/book/export/html/57
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1,000 mg elemental calcium per day. After one year, both groups had reduced serum PTH, increased serum 25-hydroxyvitamin D3, and increased urinary calcium/creatinine ratio, although to a significantly greater extent in the high-dose group. BMD was similarly unchanged or slightly improved in both groups at all measurement sites. In the Vital D study, 2,256 elderly women (aged 70 years and older) received a single annual dose of 500,000 IU of vitamin D3 or placebo administered orally in the autumn or winter for three to five years (74). Calcium intake was quantified annually by questionnaire; both groups had a median daily calcium intake of 976 mg. The vitamin D group experienced significantly more falls and fractures compared to placebo, particularly within the first three months after dosing. Not only was this regimen ineffective at lowering risk, it suggests that the safety of infrequent, high-dose vitamin D supplementation warrants further study. The RDAs for calcium and vitamin D go together, and the requirement for one nutrient assumes that the need for the other nutrient is being met (31). Thus, the evidence supports the use of combined calcium and vitamin D supplements in the prevention of osteoporosis in older adults. Vitamin K
The major function of vitamin K1 (phylloquinone) is as a cofactor for a specific enzymatic reaction that modifies proteins to a form that facilitates calcium-binding (75). Although only a small number of vitamin-K-dependent proteins have been identified, four are present in bone tissue: osteocalcin (also called bone GLA protein), matrix GLA protein (MGP), protein S, and Gas 6 (75, 76). The putative role of vitamin K in bone biology is attributed to its role as cofactor in the carboxylation of these glutamic acid (GLA)-containing proteins (77). There is observational evidence that diets rich in vitamin K are associated with a decreased risk of hip fracture in both men and women; however, the association between vitamin K intake and BMD is less certain (77). It is possible that a higher intake of vitamin K1, which is present in green leafy vegetables, is a marker of a healthy lifestyle that is responsible for driving the beneficial effect on fracture risk (75, 77). Furthermore, a protective effect of vitamin K1 supplementation on bone loss has not been confirmed in randomized controlled trials (76-78). Vitamin K2 (menaquinone) at therapeutic doses (45 mg/day) is used in Japan to treat osteoporosis (see the Micronutrient Information Center’s Disease Index). Although a 2006 meta-analysis reported an overall protective effect of menaquinone-4 (MK-4) supplementation on fracture risk at the hip and spine (79), more recent data have not corroborated a protective effect of MK-4 and may change the outcome of the meta-analysis if included in the dataset (77). A double-blind, placebo-controlled intervention performed in 2009 observed no effect of either vitamin K1 (1 mg/d) or MK-4 (45 mg/d) supplementation on markers of bone turnover or BMD among healthy, postmenopausal women (N=381) receiving calcium and vitamin D supplements (76). In the Postmenopausal Health Study II, the effect of supplemental calcium, vitamin D, and vitamin K (in fortified dairy products) and lifestyle counseling on bone health was examined in healthy, postmenopausal women (80, 81). One hundred fifty women (mean age 62 years) were randomly assigned to one of four groups: (1) 800 mg calcium plus 10 mcg vitamin D3 (N=26); (2) 800 mg calcium, 10 mcg vitamin D3, plus 100 mcg vitamin K1 (N=26); (3) 800 mg calcium, 10 mcg vitamin D3, plus 100 mcg MK-7 (N=24); and http://lpi.oregonstate.edu/book/export/html/57
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(4) control group receiving no dietary intervention or counseling. Supplemental nutrients were delivered via fortified milk and yogurt, and subjects were advised to consume one portion of each on a daily basis and to attend biweekly counseling sessions during the one-year intervention. BMD significantly increased in all three treatments compared to controls. Between the three diet groups, a significant effect of K1 or MK-7 on BMD remained only at the lumbar spine (not at hip and total body) after controlling for serum vitamin D and calcium intake. Overall, the positive influence on BMD was attributed to the combined effect of diet and lifestyle changes associated with the intervention, rather than with an isolated effect of vitamin K or MK-7 (80). Micronutrients needed for collagen formation We often discuss the mineral aspect of bone, but the organic matrix is also an integral aspect of bone quality and health. Collagen makes up 90% of the organic matrix of bone. Type I collagen fibers twist around each other in a triple helix and become the scaffold upon which minerals are deposited. Vitamin C is a required cofactor for the hydroxylation of lysine and proline during collagen synthesis by osteoblasts (82). In guinea pigs, vitamin C deficiency is associated with defective bone matrix production, both quantity and quality (83). Unlike humans and guinea pigs, rats can synthesize ascorbic acid on their own. Using a special strain of rats with a genetic defect in ascorbic acid synthesis (Osteogenic Disorder Shionogi [ODS] rats), researchers can mimic human scurvy by feeding these animals a vitamin C-deficient diet (84). Ascorbic acid-deficient ODS rats have a marked reduction in bone formation with no defect in bone mineralization (85). More specifically, ascorbic acid deficiency impairs collagen synthesis, the hydroxylation of collagenous proline and lysine residues, and osteoblastic adhesion to bone matrix (85). In observational studies, vitamin C intake and status is inconsistently associated with bone mineral density and fracture risk (22). A double-blind, placebo-controlled trial was performed with the premise that improving the collagenous bone matrix will enhance the efficacy of mineral supplementation to counteract bone loss (82). Sixty osteopenic women (35 to 55 years of age) received a placebo comprised of calcium and vitamin D (1,000 mg calcium carbonate plus 250 IU vitamin D) or this placebo plus CB6Pro (500 mg vitamin C, 75 mg vitamin B6, and 500 mg proline) daily for one year. In contrast to controls receiving calcium plus vitamin D alone, there was no bone loss detected in the spine and femur in the CB6Pro group. Micronutrients involved in homocysteine metabolism High levels of a metabolite known as homocysteine (hcy) are an independent risk factor for cardiovascular disease (CVD) (see the Disease Index) and may also be a modifiable risk factor for osteoporotic fracture (22). A link between hcy and the skeleton was first noted in studies of hyperhomocysteinuria, a metabolic disorder characterized by exceedingly high levels of hcy in the plasma and urine. Individuals with hyperhomocysteinuria exhibit numerous skeletal defects, including reduced bone mineral density (BMD) and osteopenia (86). In vitro studies indicate that a metabolite of hcy inhibits lysyl oxidase, an enzyme involved in collagen cross-linking, and that elevated hcy itself may stimulate osteoclastic activity (87-89). http://lpi.oregonstate.edu/book/export/html/57
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The effect of more subtle elevations of plasma hcy on bone health is more difficult to demonstrate, and observational studies in humans report conflicting results (86, 90). Some report an association between elevated plasma hcy and fracture risk (91-93), while others find no relationship (94-96). A recent meta-analysis of 12 observational studies reported that elevated plasma homocysteine is associated with increased risk of incident fracture (97). Folate, vitamin B12, and vitamin B6 help keep blood levels of hcy low; thus, efforts to reduce plasma hcy levels by meeting recommended intake levels for these vitamins may benefit bone health (90). Few intervention trials evaluating hcy-lowering therapy on bone health outcomes have been conducted. In one trial, 5,522 participants (aged 55 years and older) in the Heart Outcomes Prevention Evaluation (HOPE) 2 trial were randomized to receive daily hcy level-lowering therapy (2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12) or placebo for a mean duration of five years (98). Notably, HOPE 2 participants were at high-risk for cardiovascular disease and have preexisting CVD, diabetes mellitus, or another CVD risk factor. Although plasma hcy levels were reduced in the treatment group, there were no significant differences between treatment and placebo on the incidence of skeletal fracture. A randomized, double-blind, placebocontrolled intervention is under way that will assess the effect of vitamin B12 and folate supplementation on fracture incidence in elderly individuals (99). During the B-PROOF (B-vitamins for the Prevention Of Osteoporotic Fracture) trial, 2,919 subjects (65 years and older) with elevated hcy (≥12 micromol/L) will receive placebo or a daily tablet with 500 mcg B12 plus 400 mcg folic acid for two years (both groups also receive 15 mcg [600 IU] vitamin D daily). The first results are expected in 2013 and may help clarify the relationship between hcy, B-vitamin status, and osteoporotic hip fracture.
Effects of Lifestyle Factors on Bone Health: Smoking, Alcohol, and Exercise Smoking Cigarette smoking has an independent, negative effect on bone mineral density (BMD) and fracture risk in both men and women (100, 101). Several meta-analyses have been conducted to assess the relationship between cigarette smoking and bone health. After pooling data from a number of similar studies, there is a consistent, significant reduction in bone mass and increased risk of fracture in smokers compared to non-smokers (102-104). The effects were dose-dependent and had a strong association with age. Smoking cessation may slow or partially reverse the bone loss caused by years of smoking. Unhealthy lifestyle habits and low body weight present in smokers may contribute to the negative impact on bone health (100, 101). Additionally, smoking leads to alterations in hormone (e.g., 1,25-dihydroxyvitamin D3 and estrogen) production and metabolism that could affect bone cell activity and function (100, 101). The deleterious effects of smoking on bone appear to be reversible; thus, efforts to stop smoking will benefit many aspects of general health, including bone health. Alcohol Chronic light alcohol intake is associated with a positive effect on bone density. If one standard drink contains 10 g ethanol, then this level of intake translates to one drink per day for women and two drinks per day for men. The effect of higher alcohol intakes (11-30 g ethanol http://lpi.oregonstate.edu/book/export/html/57
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per day) on BMD is more variable and may depend on age, gender, hormonal status, and type of alcoholic beverage consumed. At the other end of the spectrum, chronic alcoholism has a documented negative effect on bone and increases fracture risk (105). Alcoholics consuming 100-200 g ethanol per day have low bone density, impaired osteoblastic activity, and metabolic abnormalities that compromise bone health (105, 106). Physical activity Physical activity is highly beneficial to skeletal health across all stages of bone development. Regular resistance exercise helps to reduce osteoporotic fracture risk for two reasons: it both directly and indirectly increases bone mass, and it reduces falling risk by improving strength, balance, and coordination (107). Physical activity increases bone mass because mechanical forces imposed on bone induce an adaptive osteogenic (bone-forming) response. Bone adjusts its strength in proportion to the degree of bone stress (1), and the intensity and novelty of the load, rather than number of repetitions or sets, matter for building bone mass (108). Exercise recommendations for adults to maintain bone health are listed in Table 2 (107). Table 2. Exercise Recommendations for Bone Health According to the American College of Sports Medicine Mode
Weight-bearing endurance activities
Tennis, stair climbing, jogging
Activities that involve jumping
Volleyball, basketball
Resistance exercise
Weight lifting
Intensity
Moderate to high
Frequency
Weight-bearing endurance activities
3-5 times per week
Resistance exercise
2-3 times per week
30-60 minutes per day
Combination of weight-bearing endurance activities, activities that involve jumping, and resistance exercise that targets all major muscle groups
Duration
Additionally, the ability of the skeleton to respond to physical activity can be either constrained or enabled by nutritional factors. For example, calcium insufficiency diminishes the effectiveness of mechanical loading to increase bone mass, and highly active people who are malnourished are at increased fracture risk (2, 107). Thus, exercise can be detrimental to bone health when the body is not receiving the nutrients it needs to remodel bone tissue in response to physical activity. http://lpi.oregonstate.edu/book/export/html/57
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Conclusion Micronutrients play a prominent role in bone health. The emerging theme with supplementation trials seems to be that habitual intake influences the efficacy of the intervention. In other words, correcting a deficiency and meeting the RDAs of micronutrients involved in bone health will improve bone mineral density (BMD) and benefit the skeleton (see Table 1 above). To realize lasting effects on bone, the intervention must persist throughout a lifetime. At all stages of life, high impact and resistance exercise in conjunction with adequate intake of nutrients involved in bone health are critical factors in maintaining a healthy skeleton and minimizing bone loss. The propensity of clinical trial data supports supplementation with calcium and vitamin D in older adults as a preventive strategy against osteoporosis. Habitual, high intake of vitamin A at doses >1,500 mcg (5,000 IU) per day may negatively impact bone. Although low dietary vitamin K intake is associated with increased fracture risk, RCTs have not supported a direct role for vitamin K1 (phylloquinone) or vitamin K2 (menaquinone) supplementation in fracture risk reduction. The other micronutrients important to bone health (phosphorus, fluoride, magnesium, sodium, and vitamin C) have essential roles in bone, but clinical evidence in support of supplementation beyond recommended levels of intake to improve BMD or reduce fracture incidence is lacking. Many Americans, especially the elderly, are at high risk for deficiencies of several micronutrients (24). Some of these nutrients are critical for bone health, and the LPI recommends supplemental calcium, vitamin D, and magnesium for healthy adults (see the LPI Rx for Health).
Authors and Reviewers Written in August 2012 by: Giana Angelo, Ph.D. Linus Pauling Institute Oregon State University Reviewed in August 2012 by: Connie M. Weaver, Ph.D. Distinguished Professor and Department Head Department of Nutrition Science Purdue University This article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland. Last updated 8/6/15 Copyright 2012-2015 Linus Pauling Institute
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58. Barker ME, Blumsohn A. Is vitamin A consumption a risk factor for osteoporotic fracture? Proc Nutr Soc. 2003;62:845-850. (PubMed) 59. Genaro Pde S, Martini LA. Vitamin A supplementation and risk of skeletal fracture. Nutr Rev. 2004;62:65-67. (PubMed) 60. Melhus H, Michaelsson K, Kindmark A, et al. Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med. 1998;129:770-778. (PubMed) 61. Promislow JH, Goodman-Gruen D, Slymen DJ, Barrett-Connor E. Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. J Bone Miner Res. 2002;17:1349-1358. (PubMed) 62. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002;287:47-54. (PubMed) 63. Ribaya-Mercado JD, Blumberg JB. Vitamin A: is it a risk factor for osteoporosis and bone fracture? Nutr Rev. 2007;65:425-438. (PubMed) 64. Ballew C, Galuska D, Gillespie C. High serum retinyl esters are not associated with reduced bone mineral density in the Third National Health And Nutrition Examination Survey, 1988-1994. J Bone Miner Res. 2001;16:2306-2312. (PubMed) 65. Lim LS, Harnack LJ, Lazovich D, Folsom AR. Vitamin A intake and the risk of hip fracture in postmenopausal women: the Iowa Women's Health Study. Osteoporos Int. 2004;15:552-559. (PubMed) 66. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689S-1696S. (PubMed) 67. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC. Benefit-risk assessment of vitamin D supplementation. Osteoporos Int. 2010;21:1121-1132. (PubMed) 68. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005;293:2257-2264. (PubMed) 69. 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;169:551-561. (PubMed) 70. Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P. Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab. 2007;92:1415-1423. (PubMed) 71. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012;367:40-49. (PubMed) http://lpi.oregonstate.edu/book/export/html/57
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