Clinical Nutrition

Sorting Dietary Advice for Bone Health

Weaver, Connie M. PhD; Wallace, Taylor C. PhD, CFS, FACN, FAND; Cao, Sisi PhD

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Nutrition Today 59(4):p 149-167, 7/8 2024. | DOI: 10.1097/NT.0000000000000691

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Abstract

Healthcare professionals are consistently bombarded with conflicting messages about the role of diet in bone health. Yet, few resources are available that compile the broad scope of dietary factors that influence bone health. This article evaluates the evidence on the association of diet and exercise with bone health, with the aim to provide a resource for healthcare professionals and researchers in the field. This review also highlights gaps in knowledge, provides dialogue around why some studies exhibit conflicting outcomes, and showcases why many remaining questions likely cannot be answered with the current evidence to date. The best evidence to date supports obtaining recommended dairy and calcium intakes for building bone in early life and mitigating bone loss with age. However, nutrients do not solely work in isolation, and there is growing evidence that many other nutrients and dietary bioactives play a synergistic role in supporting bone health. Large randomized controlled trials, particularly in traditionally underserved subpopulations (eg, people of color, transgender individuals, older adults, etc), are needed to fully elucidate the effects of diet and exercise on bone health across the lifespan.

INTRODUCTION

Healthcare professionals are consistently being bombarded with conflicting messages about the role of diet in bone health. Yet, few resources are available that compile the broad scope of dietary factors that influence bone health. This article reviews important questions for clinicians to consider when counseling patients on nutritional strategies for improving their bone health:

• What nutrients are needed and when are they needed?

• Should we recommend dietary patterns, essential nutrients, bioactives, all of these, or none of them?

• What are the benefits and risks of whole foods, fortified foods, and supplements?

• What do we know about physical activity recommendations for bone health?

• When are lifestyle choices alone sufficient for supporting long-term bone health, and at what point should they be accompanied by pharmaceutical and medical interventions?

Although dairy, calcium, and vitamin D have received the most attention as nutritional strategies to promote bone health and mitigate bone loss, several other classic nutrients, bioactive compounds, foods, and dietary patterns now present increasingly compelling research that warrants consideration when counseling patients. For example, novel metabolomics technologies have shown that higher berry intakes are protective against bone deterioration and osteoporosis in humans.¹ Several small clinical trials have demonstrated conflicting results around the role of various forms of vitamin K in maintaining bone density. Diets that alter acid-base balance offer some promise, particularly those derived from a more acidic Western dietary pattern, but additional research is needed to fully elucidate their effects. Additional evidence is also needed to inform public policy and health recommendations around most bioactive ingredients, foods, and dietary patterns in regard to bone health. However, the risk of encouraging patients to meet recommended nutrient intakes through healthful dietary patterns and modest supplementation (when needed) is low, recognizing that no individual component of the diet can act as a “magic pill.”

Conflicting information and misinterpretations in the news media (Box 1) make it difficult even for health professionals to know what dietary advice to provide clients and patients on managing their bone health. This article evaluates the evidence of the association of bone health with diet and exercise, with the aim to provide a resource for healthcare professionals and researchers in the field. This review also highlights gaps in knowledge, provides dialogue around why some studies exhibit conflicting outcomes, and showcases why many remaining questions likely cannot be answered with the current evidence to date.

Box 1. Examples of Confusion About Appropriate Dietary Advice for Bone Health.

The motivation for this article stems from seemingly conflicting information on nutrition and misinterpretations of research reported in the news media, which make it difficult even for health professionals to know what dietary advice to provide clients and patients on managing their bone health. The information is often confusing even for dietary components long known to promote bone health, like calcium, vitamin D, and dairy foods. For example, the Dietary Reference Intakes recommend adequate intake of calcium and vitamin D for bone health,² preferably from food sources. A 2018 US Preventive Services Task Force (USPSTF) report recommended against daily supplementation with 10 μg/d or less of vitamin D and 1000 mg/d or less of calcium for the primary prevention of fractures in community-dwelling postmenopausal women (grade D).³ The USPSTF concluded that there was insufficient evidence to assess the benefits and harms of daily supplementation above these levels in community-dwelling postmenopausal women (grade I). The USPSTF’s 2018 report also stated that the evidence was insufficient to assess the balance of benefits and harms of vitamin D supplementation in men and postmenopausal women (grade I).⁴ However, baseline vitamin D and calcium status of community-dwelling older people was not mentioned; if these individuals are not deficient to begin with, no effect of D or calcium would be expected.

In a recent large ancillary study (N = 25 871) of the Vitamin D and Omega-3 Trial (VITAL), daily supplementation with 50 μg (2000 IU) of vitamin D₃ did not result in a significantly lower risk of fracture among generally healthy midlife and older adults.⁵ Of note, interpretations of the VITAL trial reports often failed to mention that most patients had baseline serum levels of 25(OH)D within the normal range, and only 2.4% had levels associated with deficiency, so it is likely that many were not deficient to begin with.⁵

Over the last decade, media reports have selectively presented a minority of studies claiming that calcium supplementation is associated with heart attack and other adverse cardiovascular events; however, the many studies that failed to show such associations are not mentioned. (See the commentary by Wallace and Weaver for a summary of the evidence.)⁶ Consumers and health professionals today are consistently bombarded by confusing interpretations of research, with headlines seeming to suggest that foods traditionally associated with bone health are actually harmful. For example, data from large Swedish cohorts recently led researchers to suggest that milk intake was associated with increased risk of hip fracture and all-cause mortality in women.⁷ Despite these recommendations, no scientific professional society has found sufficient evidence to warrant a reversal of longstanding recommendations around the positive effects of calcium supplementation on bone health among individuals with inadequate intakes. Thus, reports are often conflicting, confusing, and oversensationalized in the media.

DIET AND BONE HEALTH

Calcium

The adult human body contains approximately 1 kg of calcium, on average, with more than 99% residing in the bone as hydroxyapatite [Ca₁₀(PO₄)₆(OH)₂]. Calcium influences bone strength through its effect on bone mass.

Getting enough dietary calcium and regular exercise is likely the most protective modifiable dietary factor for maintaining bone health and preventing osteoporotic fractures in individuals with adequate serum 25(OH)D status.

Dietary demand for calcium changes throughout the lifespan. Bone calcium accretion during childhood and adolescence represents a major determinant of peak bone mass that is associated with the risk of osteoporosis and related fractures in late life.^8,9 It has been estimated that a 5% to 10% difference in peak bone mass influences the risk of hip fracture by 25% to 50% later in life.⁸ Postattainment of peak bone mass during the third decade of life is maintained without much change for about 20 years. Age-related bone loss begins during middle age, with a loss of approximately 0.5% to 1% per year for both men and women. The menopause transition represents a dynamic time in which bone calcium and bone mass are known to deteriorate more rapidly at a rate of 2% to 3% per year.¹⁰ This deterioration is mostly due to estrogen deficiency that leads to decreased intestinal calcium uptake, decreased renal calcium reabsorption, increased parathyroid hormone (PTH) secretion, and increased bone resorption.^11–19 Recent data from the Study of Women’s Health Across the Nation cohort suggested that the menopause transition, which generally occurs during the fifth and sixth decades of life in women, might represent a nutrition-sensitive timepoint where initiation of calcium supplementation during the premenopausal period was associated with decreased rates of bone loss across the transition.²⁰

Pregnancy and lactation both exert a significant demand on the mother to provide sufficient calcium (among other nutrients) to the fetus and neonate. Calcium metabolism during pregnancy must adapt to increased demand created by the fetus and placenta. Likewise, calcium metabolism must adapt in the lactating woman to supply sufficient calcium to breast milk. Potential adaptations include increased dietary intake, enhanced intestinal uptake, mobilization of minerals from bone, and increased renal conservation. These hormone-mediated adaptations satisfy the needs of the fetus and neonate, causing short-term depletion of skeletal reserves that resolves without long-term detriment to bone under conditions of calcium and vitamin D adequacy.²¹

Serum levels of calcium are largely regulated by PTH, estrogen, vitamin D, and phosphorous. Vitamin D works in tandem (see the Vitamin D section) by increasing intestinal calcium absorption and both osteoblast proliferation and differentiation.^22–24 When dietary calcium intake is insufficient, osteoclasts increase release of mineral from bone to be utilized in physiological functions such as blood vessel contraction and dilation, muscle function, blood clotting, nerve transmission, and hormonal secretions.² A number of randomized controlled trials (RCTs) have examined the Co-supplementation effects of calcium supplementation (most with vitamin D cosupplementation) on bone mineral density (BMD) and fracture.^16,25–28 These trials showed that in middle-aged to older people (50+ years) with a baseline calcium intake of 500 to 1000 mg/d, increasing intake can prevent bone loss. A 2016 meta-analysis from the Bone Health and Osteoporosis Foundation (formerly the National Osteoporosis Foundation) reported that calcium with vitamin D supplementation reduces the risk of total and hip fractures by 14% and 39%, respectively.^29,30

Calcium and Cardiovascular Disease

The relationship between calcium supplements and cardiovascular events has garnered recent attention in the mainstream media and among consumers, due to publication of a handful of epidemiological analyses indicating an increased risk.^6,31 However, these few epidemiological analyses conflict with results from clinical trials and systematic reviews, utilized cohorts not designed with CVD endpoints as a primary outcome, and/or failed to adjust for known CVD risk factors.⁶ A clinical guideline from the Bone Health and Osteoporosis Foundation and the American College for Preventive Cardiology found moderate-quality evidence that calcium with or without vitamin D intake from food or supplements has no relationship (beneficial or harmful) with the risk of cardiovascular disease, based on a commissioned independent systematic review.^32,33 A 2023 systematic review reinforced these findings, showing no effects of supplementation on heart attack, coronary heart disease, coronary heart disease–related death, or stroke.³⁴ In a previous comprehensive and critical evaluation of the scientific literature, researchers concluded that there was a general lack of evidence or biological plausibility linking calcium supplements to any increased risks of cardiovascular events or outcomes, which was in line with guidelines from leading scientific societies.^6,33

In the United States, 70% of calcium in the diet comes from dairy products, and 49% of calcium comes from milk globally.^2,35 The US Dietary Guidelines for Americans³⁶ recommend that individuals consume 3 servings of low-fat or nonfat milk (or equivalent) daily to obtain the recommended amount of calcium, potassium, magnesium, and other nutrients important for bones. For every glass of milk or equivalent dairy product not consumed, the 300 mg of calcium from each serving needs to be replaced with fortified foods or supplements. However, there are benefits to bone from consuming dairy products beyond their contribution of calcium and other nutrients. Rat studies have shown the dairy matrix or whole foods benefit growing bone over diets that provide all the nutrients required as isolated compounds.^37,38 Alternative natural food sources to dairy products are unable to provide the amount of absorbable calcium that dairy products provide as they have much lower calcium concentrations and/or they have inhibitors of calcium absorption.³⁹ Some fortified foods such as calcium-fortified orange juice and soymilk are comparable in calcium absorption to dairy products.³⁹ Plant-based milk alternative beverages except for soymilk have not been studied for calcium absorption.

Vitamin D co-standard

Vitamin D is costandard therapy with calcium for preventing and treating osteoporosis. At a routine wellness visit, it is becoming more common to measure a patient’s vitamin D status (serum 25-hydroxyvitamin D [25(OH)D]). Vitamin D status should be within the normal reference range of 50 to 125 nmol/L (20-50 ng/mL) for maintenance of bone and overall health in healthy individuals, according to the National Academy of Medicine (formerly the Institute of Medicine) under the National Academies of Sciences, Engineering, and Medicine (Table 1).²

TABLE 1 - Serum 25(OH)D Levels and Health²

If a patient’s serum 25(OH)D status falls even slightly below 50 nmol/L (20 ng/mL), a supplementation regimen is often initiated to raise levels to the normal range. Serum 25(OH)D levels can be expected to increase by approximately 2.5 nmol/L (1 ng/mL) for every 2.5 μg of additional vitamin D each day.⁴⁰

Groups at risk of vitamin D inadequacy include the following:

• Exclusively breastfed infants, as human milk does not enable them to meet vitamin D requirements⁴¹

• Older adults, due to the skin’s decreased ability to synthesize vitamin D when exposed to the sun⁴²

• People with limited sun exposure⁴³

• People with dark skin, because the pigment melanin reduces the skin’s ability to produce vitamin D from sun exposure²

• People with conditions that limit fat absorption, as vitamin D is fat-soluble and its absorption depends on the gut’s ability to absorb fat⁴⁴

• Individuals with a body mass index of 30 kg/m² or greater, who are more likely to have a lower serum status because subcutaneous fat stores sequester vitamin D⁴⁵

• Those who have undergone gastric bypass surgery, because the part of the upper small intestine where vitamin D is absorbed is bypassed^46,47

Numerous studies suggest that populations around the world are deficient in vitamin D. For example, a recent systematic review and meta-analysis of 96 studies with a total of 227 758 participants reported a 34.76% prevalence of vitamin D deficiency in South America.⁴⁸ It is important to note, however, that the estimated prevalence of vitamin D deficiency depends on the cutoff value of serum 25(OH)D chosen. The aforementioned meta-analysis⁴⁸ used a cutoff value for deficiency of serum 25(OH)D below 50 nmol/L (20 ng/mL), citing the NAM panel who set the last Dietary Reference Intakes (DRIs) for vitamin D and calcium in the United States and Canada.⁴⁹ In fact, the NAM defined vitamin D deficiency as serum 25(OH)D below 30 nmol/L (<12 ng/mL) and inadequacy as serum 25(OH)D between 30 and 50 nmol/L (12-20 ng/mL). Therefore, the cutoff used in the meta-analysis⁴⁸ was the upper end of inadequacy as defined by the NAM, not the cutoff for deficiency. The estimated prevalence of vitamin D deficiency would be much lower with a cutoff of 30 nmol/L (12 ng/mL) compared with 50 nmol/L (20 ng/mL). Cutoffs vary throughout the literature, making it difficult to understand the prevalence of vitamin D deficiency. For example, the Endocrine Society cutoff for vitamin D deficiency is serum 25(OH)D below 50 nmol/L (<20 ng/mL), and insufficiency is defined as 52.5 to 72.5 nmol/L (21-29 ng/mL).⁵⁰ These higher cutoffs are guidelines for clinicians treating patients to maximize the effect of vitamin D on calcium, bone, and muscle metabolism.

While monitoring both serum 25(OH)D and PTH levels. Additional confusion regarding assessing vitamin D adequacy of a population relates to serum 25(OH)D assay standardization. As part of the Vitamin D Initiative, the NIH Office of Dietary Supplements established the Vitamin D Standardization Program in 2010 and coordinated its efforts and concluded in 2018, following a meeting held in November 28 to 30, 2017, that assessed program achievements and outlined future partner-driven efforts, including evaluation of VDSP performance criteria for 25(OH)D, the promotion of standardization of 24,25(OH)2D3 and vitamin D–binding protein measurements, and the development of the rickets registry.^51,52

Adequacy of vitamin D status for individuals would be better assessed if linked to a functional outcome measure such as bone density. Unfortunately, the health consequences of low vitamin D status are unclear. The NAM cutoff for deficiency is based on bone outcome measures. Vitamin D is most often associated with adequate calcium absorption. Yet, calcium absorption efficiency is not compromised until serum 25(OH)D levels fall below 10 nmol/L (4 ng/mL).⁵³ For reference, only 2.4% of a large cohort of more than 25 871 Americans in the Vitamin D and Omega-3 Trial (VITAL) had vitamin D levels below 12 ng/mL.⁵ The VITAL investigators thus found no benefit to bone, as described in Box 1.⁵ Therefore, unless vitamin D status is extremely low, vitamin D supplementation may increase serum 25(OH)D levels without increasing calcium absorption efficiency. Similarly, in a study of pubertal Black children and White children, vitamin D supplementation during the winter increased serum 25(OH)D levels without increasing fractional calcium absorption.⁵⁴ Nevertheless, low fractional calcium absorption efficiency has been linked to hip fracture risk.⁵⁵

Vitamin D also promotes bone growth and remodeling by acting on osteoblasts and osteoclasts. A recent systematic review and meta-analysis showed a beneficial dose-response effect of vitamin D₃ supplementation compared with placebo at the lumbar spine, total hip, and femoral neck.⁵⁶ Paradoxically, serum 25(OH) levels have been reported to be lower in Black individuals compared with White individuals, yet BMD is higher, and fracture risk is lower among Black individuals.⁵⁷ We await the explanation for this apparent discrepancy, but it may be related to a vitamin D–binding protein, which determines the amount of free vitamin D.⁵⁸

In the United States, most vitamin D in the diet comes from fortified foods, including milk and some breakfast cereals, infant formulas,⁵⁹ yogurt, cheese, and juices. Vitamin D bioavailability is not typically modified by incorporation into fortified food products.⁶⁰ Irradiated foods such as mushrooms and yeast, which can produce vitamin D, have come onto the market but are not yet widely available to consumers. Vitamin D from irradiated yeast appears not to be bioaccessible.^61,62 Animal sources of 25(OH) vitamin D may contribute 15% to 30% of vitamin D intake requirements.⁶³

Cutaneous synthesis of vitamin D under ultraviolet radiation exposure can be an important source of vitamin D, but endogenous production may fluctuate depending on the season, latitude, sunscreen use, outdoor activity, age, and clothing. Some researchers have suggested that approximately 5 to 30 minutes of sun exposure (particularly between 10:00 am and 4:00 pm) to the face, arms, hands, and legs without sunscreen either daily or at least twice a week may lead to sufficient endogenous vitamin D synthesis.^64–66 Moderate use of commercial tanning beds that emit 2% to 6% ultraviolet B radiation is also effective^64,67 ; however, use of indoor tanning beds and booths is not recommended as authoritative groups such as the International Agency for Research on Cancer and the American Academy of Dermatology have classified indoor tanning devices as carcinogenic to humans.^68,69 Dietary supplements provide bioactive forms of both vitamins D₂ (plant sources) and D₃ (animal sources), with the latter being more predominant on the US market.

Magnesium

Recent systematic reviews and meta-analyses have identified the importance of magnesium for bone health in older adults.^70,71 Magnesium is linked to bone health in several physiological ways. Magnesium is a skeletal component, with approximately 60% of the body’s magnesium stored in bone.⁷² In experimental studies, osteoclasts increased in number and activity under low magnesium conditions.^73–79 Magnesium deficiency contributes to abnormal hydroxyapatite crystals and increases production of several proinflammatory cytokines known to enhance osteoclast activity, lower PTH, and deplete serum 25(OH)D levels.⁸⁰ Magnesium has also been shown to stimulate osteoblast activity and promote a healthier bone matrix because it is a key cofactor for alkaline phosphatase, which is involved in hydroxyapatite deposition and bone mineralization.^81–83 Thus, it is not surprising that the authors of a recent systematic review found higher dietary magnesium intake to be associated with increased hip and femoral neck BMD in older adults.⁷⁰ A separate systematic review demonstrated that lower serum magnesium levels were strongly associated with higher incident bone fracture risk in older adults.⁷¹ However, evidence is still fairly limited as to whether higher dietary magnesium intakes impact BMD at other bone sites.

Dietary surveys consistently show that many individuals consume less than the recommended amounts of magnesium. For example, data from the 2013-2016 National Health and Nutrition Examination Survey showed that approximately 48% of Americans fail to meet the estimated average requirement for magnesium, with adult men 71 years or older and adolescents being the most likely to have low intakes.⁸⁴ It should be noted from a clinical standpoint that absorption of magnesium from different kinds of dietary supplements can vary substantially. Small studies have shown that magnesium aspartate, citrate, lactate, and chloride forms are more completely absorbed and bioavailable, as are most other organic magnesium salts. Magnesium oxide (the predominant form sold on the market) and most other inorganic salts, aside from chloride, are known to be minimally absorbed by the body and exhibit much lower bioavailability.^85–89 More research is needed on this neglected nutrient and its associations with bone health.

Potassium

Adequate potassium intake can have positive effects on bone health. A few theories have proposed the potential mechanisms of potassium benefit to bone,⁹⁰ but the most promoted hypothesis is that potassium acts via its effect on acid-base balance.^91,92 Diets high in added sugars, refined grains, and meat, common in Western cultures, contribute to increased dietary acid load, leading to metabolic acidosis. This acidic environment may result in bone loss, as alkaline calcium salts derived from bone are utilized to buffer the increased acidity. Potassium salts, obtained from potassium supplements or metabolism of fruits and vegetables, may play a role in maintaining pH homeostasis and may protect against bone resorption.⁹⁰ In a previous study, potassium supplementation in an animal model did not ameliorate bone resorption induced by an acidogenic diet.⁹³ However, another study reported that potassium supplementation improved calcium balance in humans.⁹⁴

Studies investigating the relationship between potassium and bone health have assessed bone turnover biomarkers, calcium retention and homeostasis, and BMD. The evidence on potassium and bone health was also reviewed in the 2019 DRI recommendations for potassium and sodium in the context of adequate potassium intake in decreasing risk reduction.⁹⁵ Cross-sectional observational studies show a consistent benefit to bone from high intakes of fruits and vegetables associated with increased potassium levels in adolescents,^96–98 older men and women,^99,100 and premenopausal¹⁰¹ and postmenopausal women.⁹⁷

Evidence from potassium supplementation trials suggests that potassium alkali treatment decreases bone resorption markers of C-telopeptide, N-telopeptide, and procollagen type I N-terminal propeptide in older men and women.^102,103 A highly cited study¹⁰⁴ showed that potassium bicarbonate decreased excretion of urinary hydroxyapatite (a bone resorption marker) and increased serum osteocalcin (a bone formation marker) in postmenopausal women and had positive effects on improved calcium balance. Calcium metabolic studies also demonstrated the association of potassium intake as potassium citrate or bicarbonate salts with reduced urinary calcium excretion across sexes and life stages.^105,106 In a recent clinical trial with a crossover design, Stone et al¹⁰⁷ also suggested that potassium gluconate (3300 mg/d) significantly lowered urinary calcium excretion in prehypertensive to hypertensive adults. However, randomized clinical trials examining the impact of potassium supplementation on BMD yielded mixed findings, with some reporting improvement^108,109 and others showing null results.^110,111 In addition to trials involving potassium supplementation, only one food, that is, potato, has been evaluated in clinical trials; potato is the highest source of potassium among all foods.⁹⁰ A short-term controlled feeding study suggests that the bioavailability of potassium from potatoes is comparable to that from potassium gluconate supplements.¹¹² Overall, among individuals consuming a Western diet, a bone-beneficial effect of potassium supplementation was primarily observed at high doses (2300-3500 mg/d; 60-90 mmol/d).⁹⁰ Potassium amounts in almost all dietary supplements are extremely low (usually <99 mg or 25 of the Daily Value) because of the concerns related to potassium-containing drugs.^113–115

Vitamin K

Vitamin K acts as a cofactor to the γ-glutamyl carboxylase enzyme that catalyzes glutamic acid residues to γ-carboxyglutamic acid (Gla) to form γ-carboxyglutamic acid–containing proteins, also known as vitamin K–dependent proteins (VKDPs). Inadequate dietary intake of vitamin K can impair VKDPs from becoming fully active, which results in detrimental effects on both bone metabolism and ectopic calcification of soft tissues.^116,117 The 2 naturally occurring forms of vitamin K are phylloquinones (vitamin K₁) and menaquinones (vitamin K₂). Vitamin K₁ occurs ubiquitously in various green vegetables and plant oils and is the primary dietary source of vitamin K.¹¹⁸ Vitamin K₂ has a variable side-chain length of 4 to 15 isoprene units; each form is referred to as menaquinone-n (MK-n), where n denotes the number of isoprene units. Vitamin K₂ has greater γ-carboxylation activity, which is key for maintaining the structure of osteocalcin—the most important noncollagenic skeletal VKDP. γ-Carboxylated osteocalcin corresponds to active osteocalcin that can effectively bind calcium to bone hydroxyapatite crystals.¹¹⁹ The NAM defines the adequate intake of vitamin K as 120 and 90 μg/d for men and women, respectively, based on the maintenance of normal blood coagulation.¹²⁰

Data on the effectiveness of vitamin K for prevention of fractures and BMD loss are emerging but insufficient to draw firm conclusions for most patient groups. An older systematic review and meta-analysis by Fang et al¹²¹ showed modest effects of vitamin K supplementation on BMD at the lumbar spine but not at the femoral neck. An updated systematic review by Mott et al¹²² reported vitamin K supplementation to be effective at reducing clinical fractures by 28% (odds ratio, 0.72; 95% confidence interval, 0.55-0.95) but not vertebral fractures or BMD at any site in postmenopausal patients or individuals with osteoporosis. The results of Mott et al¹²² differ from the earlier systematic review by Fang et al,¹²¹ due to the inclusion of newer large RCTs of MK-4 that showed null effects. Mott et al¹²² concluded that there is limited evidence, and thus no conclusions can be drawn on the clinical benefit of vitamin K in these groups. It should be noted that neither systematic review considered potential differences in how various forms of vitamin K may affect bone health outcomes.

Both vitamin K₁ and MK-4 have demonstrated the ability to decrease osteocalcin γ-carboxylation at doses obtainable through dietary or supplemental intake in humans. In one study, serum osteocalcin concentrations were significantly altered after healthy postmenopausal Japanese women were supplemented with MK-4 (1.5 mg/d) for 4 weeks.¹²³ In another study, MK-4 supplementation (≥5 mg/d for 3 weeks) provided to postmenopausal women with osteoporotic fractures decreased undercarboxylated osteocalcin (high concentrations are associated with osteoporotic fractures) to levels typical of healthy, premenopausal women.¹²⁴ It is worth noting that gene expression of osteocalcin is enhanced by 1,25 (OH)₂D, after which osteocalcin undergoes posttranslational modification by vitamin K.¹²⁵ Therefore, one could hypothesize that a synergistic effect of vitamins D and K may exist.

Most recently, vitamin K₂ (MK-7) has been proposed to exhibit unique bone-protective effects, although clinical interventions have yielded mixed results. MK-7 is thought to have higher efficacy due to its higher bioavailability and longer half-life compared with other vitamin K homologs.^117,126 In one study, treatment with MK-7 (180 μg/d) as an add-on to calcium and vitamin D supplementation increased carboxylation of osteocalcin but did not affect bone turnover markers, BMD, or bone microarchitecture after 3 years.¹²⁷ In another study, postmenopausal women supplemented with MK-7 (45 mg/d) for 3 years did not show any improvement in BMD, although bone quality indices of the femur increased.¹²⁸ However, in a separate RCT in healthy postmenopausal women, the same investigators showed that MK-7 (180 μg/d) inhibited BMD and bone mineral content (BMC) loss at the femoral neck over a 3-year period.¹²⁹ MK-7 may also be able to increase collagen production in the bone matrix.^117,130 Intake of natto, a fermented soybean product produced by Bacillus subtilis and high in MK-7 (200-400 μg/serving), was inversely associated with fracture risk in a prospective cohort study of postmenopausal Japanese women.¹³¹ More research on this topic is needed.

Vitamins C and E

Vitamin C seems to exert a positive effect on trabecular bone formation by influencing expression of bone matrix genes within the osteoblast. Vitamin C is a critical modulator of collagen production and an important cofactor for many prolyl and lysyl hydroxylases, which actively participate in collagen maturation.^132,133 Analyses of several epidemiological and rodent models have suggested beneficial effects of vitamin C on bone.^134–136

Vitamin E is the collective name of a lipid-soluble group of tocopherols and tocopherols, whose main role is to act as an antioxidant. α-Tocopherol is the only form of vitamin E recognized to meet human requirements. The liver preferentially resecretes only α-tocopherol and excretes the other forms. Hence, the majority of research has been somewhat limited to the α-tocopherol form until recently. The underlying mechanism of action of vitamin E on bone is a topic of current investigation, with many studies indicating potential molecular targets of bone metabolism, as recently summarized by Wong et al.¹³⁷ Vitamin E supplementation has been shown to protect against bone loss and to restore bone strength in the aged mouse and ovariectomized rat using validated osteopenic models.^{134,138–140} In a previous study, osteoporotic postmenopausal women (T score ≤2.5) were reported to have a lower mean serum α-tocopherol/lipid ratio compared with those with normal bone density.¹⁴¹

There is a dearth of clinical evidence assessing isolated effects of vitamins C and E on bone health with aging. However, a small number of RCTs reported findings from coadministration of the 2 nutrients. Supplementation with vitamin E (600 mg/d) and vitamin C (1000 mg/d) versus placebo for 6 months was shown to protect postmenopausal women (n = 34) against lumbar spine BMD loss in a pilot study.¹⁴² Older patients (n = 90) supplemented with vitamin C (500 or 1000 mg/d) and α-tocopherol (400 IU/d) versus placebo for 1 year showed beneficial effects of antioxidant vitamins as a coadjuvant in preventing and treating osteoporosis.¹⁴³ The combination of calcium with vitamin D supplements and collagen-related nutrients, such as vitamin C (500 mg/d), vitamin B₆ (75 mg/d), and proline (500 mg/d), was shown to deter BMD loss at all sites and decrease markers of bone turnover after 1 year in women (n = 60) with osteopenia.¹⁴⁴ In contrast, supplementation with vitamin C (1000 mg/d) and vitamin E as α-tocopherol (235 mg/d) during a 12-week supervised strength training study blunted some of the favorable skeletal effects of strength training.¹⁴⁵ Administration of mixed tocotrienols (400 IU/d) blunted changes in C-terminal telopeptide, a marker of bone resorption, after 12 weeks in postmenopausal women with osteopenia enrolled in a double-blind RCT (n = 52).¹⁴⁶ In another study, annatto-extracted tocotrienol supplementation decreased bone resorption and improved bone remodeling in postmenopausal women (n = 89) with osteopenia.¹⁴⁷ The authors suggested that modulation of oxidative stress may be involved in the purported effects.¹⁴⁷ In human and animal studies, higher doses of vitamin E decreased inflammatory cytokines, such as C-reactive protein, which have been shown to influence bone metabolism.¹⁴⁸

Vitamin A

The current evidence yields inconsistent results on the effects of vitamin A and provitamin A in preventing osteoporosis and related fractures. Yee et al¹⁴⁹ provided an expert review of the current evidence. Vitamin A is known to influence multiple stages of osteogenesis through enhancing early osteoblast differentiation and by inhibiting bone mineralization via retinoic acid receptor (RAR) signaling and modulation of osteocyte- and osteoblast-related bone peptides. Provitamin A analogs (carotene and β-cryptoxanthin) may also exert protective effects on bone as antioxidants and by serving as a precursor for retinoids, specifically all-trans-retinoic acid, which serves as a ligand for RAR signaling.

The relationship between vitamin A intake and vitamin A status and bone health is inconsistent among human observational studies.¹⁴⁹ To date, only one single-blind, placebo-controlled study of healthy younger to middle-aged men (n = 80) showed null effects of retinol palmitate (7576 μg/d; 25 000 IU/d) on bone-specific alkaline phosphatase, N-telopeptide of type-1 collagen, and osteocalcin after 6 weeks.¹⁵⁰ Some studies have suggested that the beneficial relationship between vitamin A intake and bone health is more pronounced among individuals with vitamin D deficiency.^149,151 Retinoic acid and 1,25-hydroxyvitamin D share a common nuclear receptor following their interaction with the RAR and the vitamin D receptor. Hence, high vitamin A blood status has been shown to antagonize the calcium response to vitamin D.¹⁵² Animal studies suggest a detrimental association between high retinol intake and cortical bone.¹⁵³ High doses suppress bone formation stimulated by external factors, such as mechanical loading.¹⁵⁴

There is limited evidence on the role of provitamin A in bone health, with most studies showing a beneficial effect and a small number showing a null effect. To our knowledge, no observed detrimental effects of provitamin A have been documented in human or animal studies.¹⁴⁹ However, there is evidence of increased risk of lung cancer with very high-dose beta-carotene supplements in people who smoke or have smoked or been exposed to asbestos.^155,156

B Vitamins and Choline

Current research on B vitamins and bone health primarily focuses on their influence over plasma homocysteine levels.¹⁵⁷ According to recent literature reviews, vitamin B₆, vitamin B₁₂, and folate have the potential to affect bone metabolism and physiology,¹⁵⁷ as inadequate intakes of vitamins that play a role in 1-carbon metabolism are known to cause increases in total plasma homocysteine concentrations.^157,158 However, the precise link between plasma homocysteine levels and bone health requires further exploration to confirm their effects on BMD, bone metabolism, and fracture risk.^157,158

Two clinical trials showed that multisupplementation of B vitamins involved in 1-carbon metabolism (vitamin B₆, vitamin B₁₂, and folate) is linked to increased lumbar spine BMD, to reduced serum homocysteine levels, and to more optimal biomarkers of bone turnover.^159,160 A recent narrative review recommended evaluating homocysteine levels in older adults and supplementing those with hyperhomocysteinemia with folic acid (500 μg) to improve BMD¹⁶¹ ; however, these recommendations have not been universally accepted by authoritative bodies or the scientific community. The specific links between each B vitamin and bone health are detailed next.

Vitamin B₁ (Thiamine)

Limited research exists on the role of thiamine in bone health. Studies from the 1980s and 1990s suggested a connection between thiamine deficiency and fall and fracture risk in older adults.^157,162,163 Biologically, thiamine may play a role in bone health through its essential role in amino acid metabolism.¹⁶⁴

Vitamin B₂ (Riboflavin)

Riboflavin is a cofactor for multiple enzymes in 1-carbon metabolism, including methylenetetrahydrofolate reductase (MTHFR). A recent literature review identified 5 studies linking riboflavin to bone health.¹⁵⁷ Two studies identified positive associations between dietary riboflavin intake and femoral neck and lumbar spine BMD, one of which linked genotype-associated low MTHFR activity in women with increased BMD and fracture risk, likely due to low riboflavin affinity.^157,165 Other studies reported a positive association between riboflavin status and femoral neck BMD in women with the MTHFR TT genotype, suggesting that a small portion of the population may benefit from supplementation to increase MTHFR activity.^166–168 Low MTHFR enzyme activity can increase homocysteine levels, which has been suggested to detrimentally affect bone health.¹⁶⁵ The current emerging evidence also suggests that older adults are at greater risk of riboflavin deficiency, which may further exacerbate poor bone health.

Vitamin B₃ (Niacin)

Niacin plays a crucial role in redox reactions, energy metabolism, cellular repair, and DNA formation.¹⁵⁷ Niacin is suspected to detrimentally affect BMD via its stimulating effects on prostaglandin D₂, whereas niacin’s beneficial effects on BMD are thought to be due to its role in increasing SIRT1 gene expression and reducing inflammation.²⁰ A recent review identified 2 studies reporting a beneficial relationship of niacin intake with BMD in postmenopausal Caucasian women and premenopausal Japanese women.¹⁵⁷ In contrast, a study in Chinese men and women found no association between niacin intake and fracture risk.¹⁶⁹ A 2019 longitudinal analysis in US adults 65 years or older reported that both the lowest and highest quartiles of niacin intake were associated with increased risk of hip fracture.¹⁷⁰

Vitamin B₆ (Pyridoxine)

Vitamin B₆ contributes to various enzymatic and metabolic processes, including amino acid metabolism, neurotransmitter production, and 1-carbon metabolism.¹⁷¹ Vitamin B₆ is also involved in the regulation of estrogen and is a coenzyme for lysyl oxidase, the enzyme responsible for collagen cross-linking.¹⁵⁷ One study reported a dose-dependent inverse relationship of vitamin B₆ intake with hip fracture risk, exclusively in women.¹⁶⁹ Although some studies have suggested a link among vitamin B₆ intake, BMD, bone turnover markers, and fracture risk, more comprehensive prospective studies and clinical trials are needed.^{165,172–174}

Vitamin B₉ (Folate)

Folate is a critical component of 1-carbon metabolism. Low dietary folate contributes to reduced conversion of homocysteine to methionine. In this scenario, homocysteine levels are elevated, and low methionine contributes to megaloblastic changes in cell division and proliferation that affect bone marrow and tissue.¹⁵⁷ As with vitamin B₆, evidence to suggest whether folate supplementation affects BMD and fracture risk is mixed and scarce. Although beneficial effects have been observed with multisupplementation of vitamin B₆, vitamin B₁₂, and folate, the effect of supplementation alone remains unclear.¹⁵⁷ A recent review highlighted that older adults with low serum folate levels exhibited increased BMD and reduced fracture risk upon supplementation, and the authors emphasized the importance of blood folate screening for older adults and those with pernicious anemia.¹⁶¹ The authors also recommended supplementation with folic acid (500 μg/d) for individuals with hyperhomocysteinemia for the purpose of improving BMD¹⁶¹ ; however, these recommendations have not been universally accepted by authoritative bodies or the scientific community.

Vitamin B₁₂ (Cobalamin)

Vitamin B₁₂ may play a role in bone health with dual actions on DNA/RNA synthesis and circulating homocysteine levels. Inadequate dietary intakes of vitamin B₁₂ have been noted among vegetarians, vegans, and older adults. The risk of vitamin B₁₂ deficiency in older adults is heightened due to reduced absorption with age and is compounded by medications that affect vitamin B₁₂ absorption, which are more commonly used in this subpopulation. A recent review reported that evidence from 8 of 17 cross-sectional studies showed beneficial effects of increased vitamin B₁₂ intake on bone mass in adults.¹⁵⁷ In addition, 5 of 12 longitudinal studies and 6 of 9 intervention studies reported a beneficial relationship between vitamin B₁₂ intake and various biomarkers of bone health or fracture risk.¹⁵⁷ In a placebo-controlled trial, vitamin B₁₂ supplementation was shown to increase lumbar spine BMD and reduce circulating homocysteine levels in a subset of patients with osteoporosis and hyperhomocysteinemia.¹⁶⁰ These data may indicate a need to evaluate homocysteine and vitamin B₁₂ status in older individuals with osteoporosis and supplementation when appropriate.

Choline

Limited research exists on the link between dietary choline intake and bone health. Choline’s involvement in 1-carbon metabolism, particularly in regulating homocysteine levels, is an emerging area of research that has been gaining attention among the scientific community. Choline is the precursor to betaine, which provides a methyl group for the conversion of homocysteine to methionine; therefore, adequate choline intakes may influence circulating levels of homocysteine.¹⁷⁵ Data from animal studies also pinpoint a potential role of the choline-containing phospholipid, phosphatidylcholine, in regulating bone metabolism through activation of peroxisome proliferator–activated receptor α.¹⁷⁶ A recent cross-sectional analysis of US adults enrolled in the 2005-2010 National Health and Nutrition Examination Survey showed a dose-dependent inverse relationship between dietary choline intake and risk of osteoporosis.¹⁷⁷ Another cross-sectional analysis of the Hordaland Health Study reported lower dietary choline intake and status to be associated with low-femoral neck BMD in middle-aged and older adults.¹⁷⁸ Although the mediating link among choline intake, circulating homocysteine levels, and increased BMD has not been examined directly, emerging evidence suggests that choline supplementation has a potential role in reducing plasma homocysteine levels.¹⁷⁹ Further research is needed to ascertain the effects of dietary choline intake and supplementation on BMD, fracture risk, and osteoporosis within a clinical context.

Protein

Protein comprises approximately 50% of bone volume and about one-third of bone mass. Loss of both bone and muscle mass that occurs with age is closely related, and lifestyle factors that influence muscle anabolism, including protein intake, also affect bone health.¹⁸⁰ Protein plays a multifactorial role in bone health, including its involvement in collagen synthesis, calcium absorption, and modulation of insulinlike growth factor 1 (IGF-1). Amino acids, particularly those rich in proline, glycine, and lysine, are essential for collagen synthesis.^180,181 These amino acids are incorporated in collagen molecules, where they facilitate the formation of cross-links that are critical for the stability and integrity of bone tissue. When bone is remodeled, many amino acids cannot be reused due to the posttranslational modification process during collagen cross-linking.¹⁸⁰ IGF-1 enhances bone growth but decreases with age.¹⁸² Low protein intake is associated with a decrease in IGF-1, potentially further exacerbating bone loss.¹⁸⁰ However, research in this area is somewhat sparse. Previously, higher protein intake was thought to lead to increased bone resorption due to higher urinary calcium excretion, as demonstrated in early calcium balance studies.¹⁸³ Current evidence from modern dual stable calcium isotope studies demonstrates that, in fact, higher urinary calcium excretion occurs when dietary protein intakes increase, due to a concurrent increase in intestinal calcium absorption or decrease in endogenous secretion that overcompensates for any increased loss in the urine.^184–186

In the most recent position statement and systematic review from the Bone Health and Osteoporosis Foundation on lifestyle factors that affect peak bone mass attainment, a positive association was observed between protein intake and bone in children across prospective studies.⁹ In another systematic review and meta-analysis from the Bone Health and Osteoporosis Foundation, higher protein intake was shown to beneficially affect. There was not sufficient lumbar spine BMD and BMC in adults, whereas the trend for other bone sites was nonsignificant.^187,188 There was no sufficient evidence to support the effects of protein intake and site-specific or overall fracture risk.¹⁸⁷ A separate systematic review evaluating varying levels of protein intake found a 16% decrease in hip fractures between high versus low protein intake.¹⁸³ Regarding protein source, a recent meta-analysis from the Bone Health and Osteoporosis Foundation concluded that limited evidence suggests no significant difference between intake of soy protein versus animal protein (and vice versa) on total body, total hip, lumbar spine, or femoral neck BMD or total BMC.¹⁸⁸ Overall, the evidence suggests that protein intake above the current Recommended Dietary Allowance is likely beneficial for maintaining BMD in adults, although large RCTs are needed to fully confirm these findings.¹⁸³ The current Recommended Dietary Allowance for protein is 0.8 grams per kilogram of body weight (g/Kg BW), as most recently published by the NAM in 2005.¹⁸⁹ However, recent studies utilizing more novel and advanced technologies suggest that protein requirements may differ, depending on factors such as life stage and level of activity. Healthy children 6-11 years of age were recently demonstrated to have a protein requirement in the range of 1.2 to 1.5 mg/kg.¹⁹⁰ The European Geriatric Medicine Society–led PROT-AGE Study Group now recommends older adults >65 years consume 1.0-1.2 mg of protein/kg body weight for maintaining and regaining lean body mass and function.¹⁹¹ A recent study employing a similar whey protein–augmented diet demonstrated beneficial effects on body composition in older adults (60-80 years old) on bed rest for more than 7 days.¹⁹² Supplementing daily meals with small quantities of the amino acid leucine (~3 to 4 g per meal) offers modest benefits to skeletal muscle loss that occurs during states of catabolism in adults (eg, bed rest).¹⁹³ The Academy of Nutrition and Dietetics, Dietitians of Canada and American College of Sports Medicine all recommend protein ingestion for athletes in the range of 1.2-2.0 g/kg,¹⁹⁴ whereas the International Society of Sports Nutrition recommends 1.4-2.0 g/kg.¹⁹⁵ The exception to these recommendations is in those with or at risk for chronic kidney disease (CKD), such as those with diabetes, obese patients with microalbuminuria, and those with a solitary kidney.^196,197 Glomerular hyperfiltration associated with higher protein intakes may lead to a higher risk of de novo CKD or may accelerate the progression of preexisting CKD, whereas persons with healthy intact kidneys are not affected by high protein intake.¹⁹⁷

^{SEE PART #2 for the rest of this article https://www.live4today.me/p/sorting-dietary-advice-for-bone-health-part-2}