Sage Journals: Discover world-class research

Abstract

Bone fragility is the susceptibility to fracture due to poor bone strength. This condition is usually associated with aging, comorbidities, disability, poor quality of life, and increased mortality. International guidelines for the management of patients with bone fragility include a nutritional approach, mainly aiming at optimal protein, calcium, and vitamin D intakes. Several biomechanical features of the skeleton, such as bone mineral density (BMD), trabecular and cortical microarchitecture, seem to be positively influenced by micro- and macronutrient intake. Patients with major fragility fractures are usually poor consumers of dairy products, fruit, and vegetables as well as of nutrients modulating gut microbiota. The COVID-19 pandemic has further aggravated the health status of patients with skeletal fragility, also in terms of unhealthy dietary patterns that might adversely affect bone health. In this narrative review, we discuss the role of macro- and micronutrients in patients with bone fragility during the COVID-19 pandemic.

Keywords

bone fragility COVID-19 fragility fractures macronutrients micronutrients osteoporosis

Background

Good nutrition is a major determinant of health and can help prevent or control most chronic diseases.

Nutrition is associated with bone health at multiple levels, being involved in bone metabolism, structural (e.g. bone geometry and matrix mineralization) and density (i.e. bone mineral density, BMD) changes as well as in functional issues (i.e. fall risk). Therefore, inadequate nutrition patterns might contribute to an increased risk of fragility fractures.^1–3 Besides vitamin D and calcium, other micronutrients seem to bring benefits to bone health, including fluorine, magnesium, potassium, vitamin B6, vitamin C, vitamin K, and zinc.^4,5

The COVID-19 pandemic significantly impacted the mental and physical well-being of the worldwide population. Psychological discomforts led people to assume wrong habits, including low levels of physical activity and an unhealthy diet, as evidenced by the increase in the consumption of alcohol and foods rich in sugars, leading to an altered ratio between caloric intake and energy expenditure.^6,7 Moreover, it is expected that the impact of the sedentary lifestyle adopted during the pandemic also due to the prolonged and repeated lockdown, might have affected bone health, both in young and elderly people, increasing the risk for fragility fractures.⁸

COVID-19 seems to have a detrimental effect on the musculoskeletal system also at the biological level. Indeed, a key role regards the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and angiotensin-converting enzyme 2 (ACE2). This enzyme is widely expressed in a variety of human tissues in addition to the lungs, where acts as a host cell receptor.⁹ For example, low levels of ACE2 were found on human bone marrow-derived stem/progenitor cells (BMSPCs), where monocytes/macrophages, the osteoclast precursors, synthesize also other RAS (renin-angiotensin system) components as Mas receptor (MasR), a class of G-protein-coupled receptor. Moreover, osteoblasts and osteoclasts synthesise ACE2 and MasR.¹⁰ In this context, ACE2 promotes AngII degradation and synthetizes Ang-(1–7), which acts via MasR promoting skeletal repair through the ACE2/Ang-(1–7)/Mas axis. More specifically, the activation of this pathway increases osteocalcin and collagen 1A mRNA levels promoting osteoblast activity and, at the same time, it reduces RANK and IL-1β mRNA levels decreasing osteoclast differentiation.¹¹

Therefore, the downregulation of ACE2 induced by SARS-CoV-2 infection may affect bone homeostasis, causing bone fragility.

Among the other potential factors that may influence bone metabolism in COVID-19 patients, it was observed that the ‘cytokine storm’ and other inflammatory factors, as well as depletion of B and T lymphocytes, contribute to the receptor activator of nuclear factor-kappa B ligand (RANKL) upregulation, increasing bone resorption. It seems that Ang-(1–7) can decrease the expression of pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF), that are directly involved in bone resorption in a wide range of inflammatory conditions;^11–13 therefore, the depletion of ACE2 and the high levels of cytokine caused by SARS-CoV-2 infection might act synergistically inducing osteoclastogenesis in COVID-19 patients.

Evidence also suggested a putative role of oxidative stress in bone remodeling in SARS-CoV-2 infected patients, through the amplification and perpetuation of biological events, such as cytokine storm, coagulopathy, and cellular hypoxia, and the association with excessive levels of reactive oxygen species (ROS).¹⁴ The ROS are involved in the regulation of RANKL-dependent osteoclast differentiation and seems to influence the process of bone resorption with a dual role. At physiological levels, ROS production induced by osteoclasts regulates RANKL signaling pathways, essential for osteoclast differentiation through the recruitment of TNF receptor-associated factor (TRAF) 6, Rac1, and NADPH (nicotinamide adenine dinucleotide phosphate) oxidase (Nox) 1.¹⁵ On the other hand, at higher concentrations, as those observed in aging or inflammatory states like in COVID-19, ROS lead to cell death and bone loss.^16,17 In this scenario, adequate intake of nutrients is essential for an optimal immune response able to prevent infections, and to counteract inflammatory state and oxidative stress, strengthening a relationship between nutrition and individual response to disease burden.^18,19 Consistent with this concept, a recent cross-sectional study showed the importance of adequate levels of vitamin D and zinc for their immunomodulatory and direct antiviral effects during SARS-CoV-2 infection. Similarly, these nutrients are noteworthily required for normal skeletal growth and bone homeostasis,^20,21 further supporting their adequate intake during COVID-19 to prevent bone loss.

Finally, hypoxemia and subsequent acidosis observed in the severe COVID-19 inhibits osteoprotective factors like osteoprotegerin (OPG) through hypoxia-inducible factor (HIF)-1α and further upregulated RANKL and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) disrupting bone homeostasis.²²

Considering all the above-mentioned potential risks for bone health during the pandemic, we provide an overview to address how inadequate micro- and macronutrient intakes could contribute to bone fragility during the COVID-19 pandemic.

Bone fragility and nutrition: what does it matter?

Bone fragility is an umbrella term that includes quantitative (e.g. density) and qualitative (e.g. geometry, microarchitecture, material composition) changes that modify the internal stress state of bone tissue predisposing to fragility fractures.²³ All structural and material changes characterizing bone fragility are potentially related to nutritional factors, including water, macronutrients, micronutrients, and trace elements.²⁴

Macronutrients and micronutrients

Correct nutrition consists of the ingestion of macronutrients, as proteins, lipids, and carbohydrates,²⁵ as well as micronutrients, such as vitamins and minerals contained in food and in water (minerals). Water can be considered an essential food, with several roles in the human body, from building material to solvent and carrier for nutrients.²⁶ Bone has a complex structure and consists of water for 10–20% of total volume, available as free within pores and matrix bounded, the latter as an essential component for the integration of hydroxyapatite and collagen to modulate mechanical behavior of bone tissue in terms of better ductility.²⁷ Collagen conformation change (i.e. from triple helix to partially unfolded fragments) expected occurring in aging leads to poor water adsorption mode, strength, and density on hydroxyapatite with consequent bone fragility.²⁸ It should be underlined that calcium bioavailability of mineral water rich in calcium is comparable with that of dairy products,²⁹ and that bicarbonate-rich alkaline water decreases serum parathyroid hormone (PTH) and C-telopeptides (CTX).³⁰

Proteins are among the main components of bone, accounting for about 50% of bone volume.³¹ These nutrients influence bone health particularly because of their positive effects on insulin-like growth factor-1 (IGF-1) production.^32–34 Low dietary protein intake reduces intestinal calcium absorption³⁵ and negatively affects the activation of calcium-sensing receptor³⁶ leading to increased serum PTH.³⁷ On the other side, an excess of dietary protein intake increases intestinal calcium absorption with increased urinary excretion of calcium.³⁸ In a healthy pediatric population, high daily dietary protein intake (1.5–2 g/kg body weight) usually observed for growth requirements, is associated with greater periosteal circumference, cortical area, bone mineral content, and strength-strain index.³⁹ Interestingly, those consuming high sulfur-containing aminoacids (i.e. methionine and cysteine) did not report a significant association between protein intake and bone fragility components, suggesting the relevance of the quality of proteins for bone health. It has been suggested that alanine, lysine, arginine, leucine, and glutamine support osteoblast growth and differentiation by stimulating insulin secretion,^40–42 and lysine and arginine seem to contribute to type I collagen synthesis.⁴³ Furthermore, a finite element analysis (FEA) demonstrated a positive association between bone strength and animal protein intake, while no significant finding was reported in people consuming vegetable-derived proteins.^44,45

Several meta-analyses investigated the association between daily dietary protein intake and BMD, reporting that 0.8–1.2 g/kg body weight of protein consumption accounted for 2–4% of BMD variance.^46–49 On the other side, no randomized controlled trials (RCTs) evaluated the efficacy of dietary protein on fracture risk,²⁴ and observational data suggest that intake over the recommended dietary allowance (RDA) might be able to reduce hip fracture risk up to –16% compared with lower intake,⁴⁸ without adverse effect on bone quality.⁴⁶

It is key to note that the benefits of proteins on bone health seem to be significantly affected by their interaction with calcium supplementation. Indeed, significantly higher fracture risk (+51%) was reported in patients receiving high dietary proteins but low calcium intake (<400 mg/1000 kcal).⁵⁰

Lipids are essential macronutrients accounting for 20–35% of daily energy intake and contribute to the absorption of fat-soluble vitamins, including vitamin D.⁵¹ High-fat diet (HFD), especially saturated fatty acids (SFAs), might reduce BMD, impair bone microarchitecture^52–54 reduce marker of bone formation (serum osteocalcin, procollagen type 1 amino-terminal propeptide, P1NP, carboxy-terminal propeptide of type 1 procollagen, P1CP), increase bone resorption markers (cross-linked N-telopeptides of bone type I collagen, NTx, urine pyridinoline, Pyr, and deoxypyridinoline, Dpyr),⁵⁵ and increase fracture risk.⁵² In animal models, trabecular bone volume fraction, mineral content, trabecular number, and bone strength significantly decreased after HFD, without recovery after weight loss, despite reduced marrow adipose tissue accumulation.⁵⁴ Moreover, increased bone marrow adiposity in response to HFD has deleterious effect on the skeleton, and the progenitor cells exhaustion due to continuous recruitment to adipogenesis reduced recruitment to osteoblastic cells, and decreased bone formation.⁵⁶

Several mechanisms have been proposed for the negative effects of lipids on bone health. High dietary fat intake induces hyperinsulinemia that led to high urinary calcium and magnesium excretion, along with poor calcium absorption and increased retinol intake that stimulates bone resorption.⁵⁷ Furthermore, high lipid intake enhances sclerostin expression and damages the osteocyte network.⁵⁸

In clinical studies, a high intake of SFAs is associated with reduced femoral neck BMD and increased hip fracture risk (+31%).^59,60

Carbohydrates are macronutrients widely available in Mediterranean and Western diets as mono- and disaccharides, oligosaccharides, polysaccharides, and soluble dietary fibers.⁶¹ Diets with a high intake of carbohydrates, particularly monosaccharides (i.e. glucose) and disaccharides (i.e. sucrose), seem to reduce BMD.⁶² Basic research suggests that high concentrations of glucose impair osteoblast proliferation and differentiation,⁶³ while sucrose-fed animal models reported lower bone strength in long bones.⁶⁴ High fructose intake reduces calcitriol-dependent intestinal and renal calcium transport,⁶⁵ and the insulin spike triggered by high glucose ingestion is proportional to urinary calcium.⁶⁶ The increased glucose intake induces lactic acid formation in osteoclasts resulting in the dissolution of calcium and magnesium from the bone surfaces.⁶⁶ The consumption of sugar-sweetened beverages, a major source of carbohydrates, is associated with poor calcium intake,⁶⁷ increased urinary calcium excretion, presumably due to kidney damage (i.e. glomerular congestion and intertubular bleeding), low BMD,⁶⁸ and poor bone quality.⁶⁹ On the other hand, increased intestinal calcium absorption (up to 58%)⁷⁰ and BMD have been reported after the consumption of fruits and vegetables rich in water-soluble fibers containing inulin.^71,72

Micronutrients and trace elements

Micronutrients and trace elements with effects on bone fragility are calcium, fluoride, magnesium, potassium, phosphorus, vitamin B group, vitamin C, vitamin D, vitamin K, boron, copper, manganese, selenium, silicon (Si), strontium, and zinc.

Calcium contributes to bone strength by being stored for more than 99% in the skeleton to form hydroxyapatite crystals.^34,73 Calcium is largely contained in milk, yogurt, cheeses, legumes, nuts, and sardines.^74,75 The bioavailability of this element is superior when taken through dairy products and mineral waters.²⁴ A decreased calcium intake might adversely affect bone health by promoting bone remodeling through secondary hyperparathyroidism.²⁴ Different studies investigated the effects of calcium intake through nutrition or supplementation on BMD improvements, reporting similar benefits in trials of increased intake of calcium through diet or calcium supplements. Considering the mild and nonprogressive BMD change, the authors concluded that increased calcium intake is unlikely to lead to a reduction in fracture risk.⁷⁶ However, in a study conducted on an Italian outpatient population, higher fracture risk was correlated with a lower calcium intake, particularly in individuals with vertebral fractures.⁷⁷ To prevent fragility fractures, it has been recommended 1 g/day of calcium in postmenopausal women.⁷⁸

Fluoride is available particularly in tea, seafood, and fruits and vegetables.⁷⁹ The daily supplementation of approximately 5 mg of fluoride might be effective in enlarging osteoblasts volume, bone formation, and BMD.⁸⁰ However, literature is not univocal on this topic as reported in an RCT showing no beneficial effect of fluoride on cortical BMD and fracture risk.^81,82 The improvement of bone metabolism by fluoride administration was reported in a double-blinded and placebo-controlled trial in which 180 postmenopausal women with osteopenia received 2.5, 5, or 10 mg of fluoride. Compared with placebo, the groups treated with 5 and 10 mg of active intervention reported a significant increase of the P1NP (p < 0.04 and p < 0.005, respectively), suggesting a modulation of bone formation.⁸³

Magnesium (Mg) contributes to PTH secretion and potassium homeostasis.⁸⁴ Foods containing an adequate amount of Mg are nuts, leafy green vegetables, and dairy products.²⁴ About 50% of Mg present in our body is accumulated in the bone where Mg modulates the size and formation of hydroxyapatite crystals. Mg deficiency may inhibit osteoblasts and activate osteoclasts,^85,86 and promotes vitamin D production.⁸⁷ A lower Mg intake seems associated with a lower hip BMD.⁸⁸ On the other hand, a higher Mg intake than the recommended dose is associated with a higher risk for wrist fracture.⁸⁸ Otherwise, more recently, it has been reported significant association between high Mg intake and low fracture incidence both in women (–62%) and men (–53%).⁸⁹

Potassium dietary intake has a protective action on age-related bone loss.^90,91 Foods with a high content of potassium are potatoes, milk, cereals, and coffee⁹² Potassium salts seem to have a positive effect on bone by lowering renal extraction of calcium and acids and significantly reduce NTX.⁹³ A prospective cohort study on 266 older women reported that those consuming food rich in potassium (3676 mg daily) had significantly higher BMD at different sites compared with women in the lowest quartile of potassium intake.⁹⁴ It was also noted that an adequate potassium intake was related to an increase of BMD in postmenopausal women but not in men over 50 years.⁹⁵ In a large observational study conducted in Korea, a decreased risk for low BMD at the lumbar spine (–32%) in postmenopausal women, but not in men, was reported in people with an adequate potassium intake.⁹⁶ The most accredited hypothesis for potential benefits of dietary potassium on bone health is its effect on modulation of acid–base equilibrium. Western diet rich in meats and cereal grains but poor of fruits and vegetables predisposes to metabolic acidosis that worsens with age due to renal function decline.⁹⁷ Buffering of this acidic serum pH by the alkaline calcium salts in the skeleton may enhance bone resorption. Thus, alkaline potassium salts intake from fruits and vegetables or potassium supplements may prevent bone resorption.

Another important ion is phosphorus, which is present in dairy products, meats, beans, nuts, lentils, and cereals.⁹⁸ Phosphorus is a structural component of bones and teeth,^99,100 and it is important for the optimal mineralization of cartilage and for osteoblasts activity¹⁰¹ with the recommended daily administration of 700 mg for adults and 1250 mg for adolescents.⁹⁸ An adequate level of phosphorus is required to ensure apoptosis of mature chondrocytes to trigger the invasion of blood vessels and generation of new bone, thus preventing rickets and delayed growth.¹⁰² A high intake of phosphorus increases bone mineral content and BMD.¹⁰³

B vitamins (i.e. folate, B6, and B12) seem to improve bone health by regulating plasma homocysteine concentrations (tHcy). Serum levels of vitamin B9 (folic acid) and B12 are inversely correlated with serum tHcy.¹⁰⁴ Meta-analyses, cross-sectional, and cohort studies suggest a role of vitamin B12 on fracture risk reduction but not on BMD changes.¹⁰⁵ In a 1-year double-blind placebo-controlled trial B-vitamins administration did not affect bone turnover nor BMD in patients with osteoporosis, except in those with hyperhomocysteinemia, in which B vitamins supplementation increased lumbar spine BMD.^106,107

Vitamin C is an important nutrient for bone health by contributing to collagen production in the bone matrix and counteracting the production of ROS.¹⁰⁸ Foods that provide the highest level of vitamin C are tomatoes, potatoes, and citrus fruits, such as limes, oranges, and lemons.¹⁰⁹ This vitamin appears to modulate osteoclastogenesis and osteoblastogenesis¹¹⁰ and stimulate the production of type 1 collagen by osteoblasts.¹¹¹ Increased vitamin C intake has been associated with a reduced risk of hip fragility fractures as well as an increase in BMD at the femoral neck and lumbar spine.^111,112

Vitamin D is a fat-soluble vitamin involved in calcium metabolism and bone health.¹¹³ Vitamin D status mainly depends on sun exposure, although it can also be influenced by diet by consuming fatty fish, mushrooms, and eggs and, also, vitamin D-fortified foods, such as low-fat cheeses and biofortified eggs, seem to be useful for increasing intake.^75,114 It has been reported that the combined administration of calcium and vitamin D is more effective than the administration of the two elements alone, as confirmed by the efficacy of this intervention in reducing the risk of hip fractures and non-vertebral fractures in osteoporotic patients compared with placebo.^115,116 Moreover, vitamin D deficiency needs to be corrected to guarantee the effectiveness of anti-osteoporotic drugs.¹¹⁷

Vitamin K has been attributed benefits in preventing vascular calcification and cancer as well as in improving insulin sensitization and bone formation.¹¹⁸ There are two different kinds of vitamin K produced by plants (K1) and bacteria (K2). Vitamin K1 is the most present in food while vitamin K2 is contained only in some cheeses.¹¹⁹ Vitamin K favors the gamma-carboxylation of osteocalcin thus promoting bone mineralization.¹²⁰ However, clinical studies not reported low BMD in patients with low vitamin K intake.^121,122 A RCT including 244 post-menopausal women showed that vitamin K supplementation for 3 years significantly improves BMD compared with those receiving placebo,¹²³ whereas a meta-analysis showed that vitamin K supplementation has little effect on BMD changes with favorable effect for clinical fragility fractures of the spine.¹¹⁹

Several studies evidence the relationship between single vitamins in monotherapy and the percentage of fracture, but only a few studies have investigated the role of multivitamins on bone health. In a study conducted in an Australian care setting multivitamin supplementation significantly increased serum 25(OH)D, folate, and vitamin B12 along with higher BMD and reduced fall risk.¹²⁴ Moreover, in a meta-analysis, multivitamins intake has been associated with a decreased probability of hip fracture [odds ratio (OR) = 0.49, 95% confidence interval (CI): 0.32–0.77].¹²⁵

Boron contributes to bone health by reducing calcium excretion and influencing the metabolism of steroid hormones, including vitamin D.¹²⁶ Boron protects from rickets regulating bone remodeling and improving bone stiffness.¹²⁷ In animal studies, an optimal intake of boron seems to have a positive effect on bone trabecular microarchitecture and cortical bone strength.¹²⁸

Copper functions as an enzymatic cofactor and removes bone free radicals imputable to osteoclasts activation.¹²⁹ In in vitro study, copper appears to block osteoclastic resorption,¹³⁰ while in experimental animal models, a lower intake of copper leads to reduced bone strength.¹³¹ Moreover, a significant correlation between low serum copper and the occurrence of hip fractures in elderly subjects has been reported.¹³²

Manganese is an osteotropic element. It favors bone matrix formation and stimulates calcification. In a study conducted on 40 post-menopausal women, it has been found a positive relationship between serum manganese and BMD, and a negative association between serum manganese and the number of fragility fractures.¹³³

Selenium seems to bring benefits in terms of BMD improvement and fracture risk reduction,^134,135 likely by a mechanism linked to high osteoclasts activation in low antioxidative status.

Interestingly, studies in rodents show that selenium deficiency increases bone resorption and damages bone microarchitecture,¹³⁶ and low levels of selenium lead to osteopenia in young animals.¹³⁷

Si is highly concentrated as bound to glycosaminoglycans in connective tissues, particularly in bone, playing a key role in the crosslinks between collagen and proteoglycans.^138,139 Si concentration progressively reduces from osteoid tissue to mature bone mineral, suggesting a putative role in bone mineralization,¹⁴⁰ as also suggested by poor growth, cortical thinning, and skeletal fragility in animal models with low dietary Si intake.¹⁴¹ Most bioavailable sources of Si are mineral water and beer, where it is present as orthosilicic acid, and vegetables.^142,143 It has been estimated that the adequate daily intake of this element for bone health is about 25 mg.¹⁴⁴ Si seems to contribute to bone mineralization, type 1 collagen synthesis, osteoblast differentiation, and osteoclasts inhibition presumably by reducing the RANKL/OPG ratio and antagonizing the activation of nuclear factor kappa B (NF-κB),^{138,145–148} In animal studies, dietary Si intake is associated with increased bone content of calcium and phosphorus, enhanced activity of alkaline phosphatase, structural rigidity, and quantity of force absorbed before breaking at femur compared with lower Si intake.^149,150 Moreover, low serum Si seems to inhibit growth plate closure resulting in higher longitudinal growth.¹⁵¹

In human studies, high dietary Si intake resulted in increased femoral BMD, not spine BMD, in pre-menopausal women and adult men, whereas no significant BMD change was reported in post-menopausal women.^152,153

Strontium is chemically related to calcium and is almost completely stored in bone and teeth after ingestion.¹⁵⁴ The administration of this element as the salt of ranelic acid has been widely studied for osteoporosis treatment. Strontium is adsorbed onto the mineral surface of the new bone, particularly the trabecular component, and increases structural properties of the skeleton, such as bone volume and trabecular thickness, without affecting hydroxyapatite crystal features (i.e. mineralization).^155,156

Zinc is required for normal skeletal growth and bone homeostasis as well as for promoting bone healing.¹⁵⁷ However, the cellular and molecular pathways through which zinc promotes these effects are poorly understood. Zinc can positively affect osteoblast functions while inhibiting osteoclast activity, consistent with a beneficial role in bone homeostasis and regeneration.¹⁵⁷ In a murine model, zinc deficiency increased serum PTH through a reduction of serum calcium resulting in bone fragility,¹⁵⁸ but human studies to understand if zinc deficiency predisposes to osteoporosis are still lacking.

Table 1 synthetizes evidence about the role of nutrients on bone health.

Table 1.

Benefits of nutrients on bone fragility in adults.

Nutrients	Daily dietary reference intakes^a	Bone metabolism	Parameters of bone strength	Fragility fracture
Water (calcium- and bicarbonate-rich)	2.7 (women) – 3.7 (men) L	Reduces serum PTH and CTX	Improve ductility by integrating hydroxyapatite and collagen	N/A
Proteins (particularly containing alanine, lysine, arginine, leucine, and glutamine)	46 (women)–56 (men) g	Increase IGF-1 secretion, which enhances calcitriol synthesis leading to enhanced intestinal absorption of calcium and phosphate and kidney reabsorption of phosphate. Stimulate osteoblast growth and differentiation by enhancing insulin secretion	Contribute to type I collagen synthesis; increase periosteal circumference, cortical area, BMC, BMD, and strength-strain index	Reduce hip fracture risk (−16%; observational study)
Lipids (i.e. MUFAs and α-linoleic acid)	Not defined; 1.1 (women)–1.6 (men) g for α-linoleic acid	N/A	Improve trabecular and cortical volumetric BMD	Reduce hip fracture risk (−80%, observational study)
Carbohydrates (i.e. fruits and vegetables rich in water-soluble fibers containing inulin)	130 g	Increase intestinal calcium absorption (+58%)	Increase BMD	N/A
Calcium (i.e. in dairy products and mineral waters)	1–1.2 g	99% stored in the skeleton	Forms hydroxyapatite crystals; improves BMD	Reduces the risk of fragility fractures (combined with vitamin D)
Fluoride	3 (women)–4 (men) mg	Increases the procollagen propeptide type 1 N (P1NP)	Improves spine BMD	N/A
Magnesium	310 (women)–420 (men) mg	50% stored in bone to increase formation and size of hydroxyapatite crystals; increases osteoblast proliferation and vitamin D production	Increases hip BMD	Reduces fracture risk (−62%; observational study)
Potassium	2600 (women)–3400 (men) mg	Reduces NTX	Increases BMD	N/A
Phosphorus	700 mg	Structural component of bones and teeth; modulates cartilage mineralization and osteoblasts activity	Increases BMD	N/A
Vitamin B12	2.4 µg	N/A	Increases spine BMD (only in patients with hyperhomocysteinemia)	N/A
Vitamin C	75 (women)–90 (men) mg	Stimulates the production of type 1 collagen by osteoblasts	Increases BMD at the spine and femoral neck	Reduces hip fracture risk (observational studies)
Vitamin D	15–20 µg	Regulates differentiation and mineralization of osteoblasts. Increases the production of type 1 collagen and non-collagenous proteins (e.g. osteocalcin) Increases the expression of RANKL in osteoblasts and inhibits the expression of OPG, stimulating osteoclastogenesis Stimulates intestinal calcium absorption, and calcium and phosphate reabsorption in the kidneys, from the tubular fluid into the blood	Increases BMD and bone mineralization	Reduces the risk of fragility fractures (combined with calcium)
Vitamin K	90 (women)–120 (men) µg	Increases gamma-carboxylation of osteocalcin	Promotes bone mineralization	Reduces clinical fragility fractures
Boron	N/A	Reduces calcium excretion	Improves bone stiffness	N/A
Copper	900 µg	Reduces osteoclasts resorption	N/A	Reduces hip fracture risk (observational study)
Manganese	1.8 (women)–2.3 (men) mg	N/A	Increases bone matrix formation and stimulates calcification. Increases BMD	Reduces fragility fracture risk (observational study)
Selenium	55 µg	Reduces bone resorption	Improves bone microarchitecture (trabecular bone volume, trabecular number, and trabecular separation)	Reduces fragility fracture risk (observational study)
Silicon	25 mg	Increases osteoblast differentiation, and inhibits osteoclasts by reducing the RANKL/ OPG Enhances alkaline phosphatase activity	Contributes to crosslinks between collagen and proteoglycans and to bone mineralization. Increases structural rigidity and quantity of force absorbed before breaking at the femur	N/A
Strontium	N/A	N/A	Increases bone volume and trabecular thickness, without affecting hydroxyapatite mineralization	Reduces fragility fracture risk
Zinc	8 (women)–11 (men) mg	N/A	N/A	N/A

BMC: bone mineral content; BMD, bone mineral density; CTX, C-telopeptides; IGF, growth factor-1; N/A, not available; OPG, osteoprotegerin; PTH, parathyroid hormone; RANKL, receptor activator of nuclear factor-kappa B ligand; MUFA, monounsaturated fatty acid.

Dietary reference intakes according to the National Institutes of Health. Office of Dietary Supplements.¹⁵⁹

Risks of the overintake of micronutrients

The evidence seems to be clear about the damages related to an insufficiency of micronutrient intake and the benefits of supplementation when needed. On the other side, pending questions remain about the potential harms of overintake of these substances, particularly on bone. It is key to note that few studies have investigated this issue. Considering vitamin D, severe hypercalcemia and confusion, abdominal pain, vomiting, and dehydration, occur in patients with vitamin D toxicity (VDT).¹⁶⁰ However, this condition is rare and is usually caused by the intake of extremely high doses of pharmacological preparations of vitamin D (exogenous VDT) as well as other diseases that produce the calcitriol (i.e. granulomatous disorders) (endogenous VDT).

Poor evidence reported the effects on bone of an overintake of calcium. However, overuse of calcium supplementation could lead to cardiovascular diseases and malignancy. Some studies, including a meta-analysis, estimated that calcium supplements have up to 30% increased risk for myocardial infarction and mortality, particularly in men.^161,162

An overconsumption of proteins seems to have indirect effects on bone.¹⁶³ Indeed, an excess of protein intake increases glomerular filtration rate and urinary calcium. Negative calcium imbalance could negatively affect bone turnover, as demonstrated by increased urinary N-telopeptide excretion.¹⁶⁴

Similarly, sugar consumption impacts negatively bone tissue and is associated with low BMD. A meta-analysis found that sugar-sweetened beverages significantly reduce bone density, increasing the risk of fracture.¹⁶⁵ This condition seems to be related to several mechanisms, such as the increased renal excretion of calcium, but also the reduction of intestinal calcium absorption, unbalancing osteoblast, and osteoclast activity promoting bone resorption.¹⁶⁶

Also, excess vitamin A intake seems to have negative effects on bone health. An observational study found that increased dietary retinol intake promotes a reduction of BMD at the femoral neck, Ward’s triangle, trochanter region of the proximal femur, lumbar spine, and total body with an increased hip fracture risk.¹⁶⁷ Recently, an animal study observed that a massive dose of vitamin A suppresses the loading-induced gain of bone mass decreasing cortical bone area by 12%, marrow area by 19%, endocortical perimeter by 10%, and periosteal perimeter by 8%. This effect seems to be related to the suppression of osteoblastic genes Sp7, Alpl, and Col1a1 caused by vitamin A.¹⁶⁸ High concentration of vitamin A and its active form, all-trans retinoic acid (ATRA), inhibits both bone differentiation and mineralization.¹⁶⁹

Even the overconsumption of B vitamins seems to be associated with poor bone health. Particularly, it has been demonstrated that higher dosages of niacin (vitamin B3) reduce bone strength with an unclear mechanism.¹⁷⁰ Moreover, a clinical study suggests a putative role in increasing the incidence of hip fracture in men with higher intake of niacin.¹⁷¹

These data raise further questions considering the abuse of multivitamin supplementation in clinical practice not carefully taking into account the potential negative consequences. During theCOVID-19 pandemic, the intake of these substances has been sometimes excessive, adding an additional risk factor for the occurrence of fragility fracture.

Bone damage due to the COVID-19 pandemic

Bone damage due to SARS-CoV-2 infection

Severe COVID-19 patients may be affected by pulmonary and extrapulmonary manifestations, including neurological, gastrointestinal, and musculoskeletal complications, in both acute and long-term care (i.e. long COVID).^172–174 Long-COVID-19 is ‘the persistence of signs and symptoms that develop following an infection consistent with COVID-19 which continue for more than 12 weeks and are not explained by an alternative diagnosis’.¹⁷⁵ In this syndrome, malnutrition, dysphagia, appetite loss, taste/smell alterations, gut microbiota changes, and sarcopenia have been reported, requiring an adequate nutritional approach.^176–178 On the other side, inadequate nutrition might be associated with long-COVID-19.¹⁷⁹

More recently, new insights are emerging about the role of SARS-CoV-2 infection as a contributor to bone fragility. Clinical data showed that COVID-19 patients that received intensive care reported lower BMD compared with those treated in other settings,¹⁸⁰ and that spine BMD seems to be a predictor of mortality in this population.¹⁸¹ Follow-ups for patients recovering from COVID-19 are usually focused on cardiorespiratory and neurological alterations rather than skeletal disorders, despite these clinical issues typically occurring in the long term. On the other side, severe COVID-19 commonly affects older people and patients with comorbidities, on corticosteroid and immunosuppressive therapy, therefore, the identification of COVID-19-related bone damage in these patients is challenging.¹⁸² Metabolic bone disorder can be observed in chronic inflammatory diseases, such as chronic obstructive pulmonary disease (COPD),¹⁸³ and the degree of inflammatory response is associated with bone loss that persists even if the inflammatory disease is well treated.¹⁸⁴ In COVID-19, it has been demonstrated that the inflammatory patterns are closely correlated with the clinical manifestations, so that, severe diseases are characterized by higher serum pro-inflammatory cytokines than mild COVID-19 (‘cytokine storm’).^185,186 It is well known that inflammation negatively affects bone metabolism by enhancing bone resorption and persisting inflammation in bone marrow has been reported in COVID-19 survivors after recovery.^187,188 A recent study characterized the effects of SARS-CoV-2 infection on bone metabolism in the acute and post-recovery periods in an animal model.¹⁸² The microcomputerized tomography (μCT) and histological analysis of golden Syrian hamsters showed an early and progressive bone loss particularly in the trabecular component in terms of bone volume (–50% than noninfected hamsters), density and trabecular thickness, and number at the distal femur and proximal tibia from 4 days after infection to post-acute (1 month), and the recovery phase (2 months), while cortical component was poorly affected. The same skeletal alterations were detected in the lumbar vertebrae at 1 month, and bone density did not improve during the recovery period (2 months). These pathological changes were sustained by increased bone resorption because a higher number (almost doubled) of tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts expressing NFATc1 were found in the trabecular bone of all the skeletal sites examined, and the RANKL expression was triplicated in infected compared with healthy animals. Finally, this study excluded the direct involvement of bone tissue due to SARS-CoV-2 infection by reporting little to no expression of ACE2 in the bone marrow.

Like SARS, it is presumable that also SARS-CoV-2 could impact negatively bone metabolism, with a direct effect of stimulating and activating osteoclasts and upregulating their activity through the so-called ‘cytokine storm’.¹³ During the pandemic, clear evidence about BMD loss and the increased risk of fragility fracture in patients with osteoporosis is not available. However, in this period, healthcare systems had to face a dramatic condition that inevitably reduced the cure for other pathological conditions including osteoporosis. Particularly, physicians were forced to quickly treat and previously discharge patients with hip fractures, neglecting the consequent needs of the patients, such as pharmacological therapy for secondary prevention of fragility fractures and postsurgical rehabilitation.

COVID-19 patients that need intensive care may also be affected by other conditions that could result in poor bone health, including prolonged immobilization and sarcopenia, as well as they often receive some medications, such as corticosteroids and anticoagulants, that are associated with bone loss.¹⁸⁹ Optimizing nutritional intake in patients in intensive care is a critical issue that needs an individualized approach, ensuring the correct assumption of protein and micronutrients. For example, vitamin D deficiency is frequently found in these patients, and it is associated with musculoskeletal disorders and poor clinical outcomes.¹⁹⁰ An appropriate intake of vitamin D is fundamental in patients at risk for vitamin D deficiency, with a daily supplementation up to 2000 IU.¹⁹¹

During the pandemic, a change in lifestyle has been observed, even in nutritional habits. During self-isolation at home, people of low- and middle-income countries (LMICs) had a limited food intake, whereas people in developed countries increased their caloric intake,¹⁹² particularly in terms of processed and cheaper food with a low nutritional value¹⁹³ Moreover, an increased risk of malnutrition was reported in hospitalized COVID 19 patients, regardless of country.¹⁹⁴

Nutritional issues during the COVID-19 pandemic and their consequences on bone health

The COVID-19 pandemic has slowed down the population in buying fresh foods, leading to adopt wrong nutritional habits as well as sedentary behavior with physical inactivity, an increase in body weight, and, often, mental health problems.¹⁹⁵ The pandemic has led to an increase in the number of snacks, especially at night, and this is highly deleterious since there is a tight correlation between this behavior and the incidence of metabolic syndrome.^196–205 Also, several studies have shown an increase in the consumption of foods during the COVID-19 pandemic that did not require a high set-up time, such as foods of animal origin and canned foods.^206–208 Other studies have shown an extreme reduction in the consumption of fruits and vegetables for reasons related to greater stress evoked by the quarantine, the reduced possibility of freely enjoying these products, and their raised prices, leading to poor adherence to the Mediterranean diet.^209–214

Another wrong habit linked to changes in the dietary model and increased psychological disorders was increased alcohol consumption.^197,215 High doses of alcohol (more than two units) can increase the risk of fractures.^216,217 Interestingly, a gain in body weight has emerged in several studies,^200,201,211 as the study by Pellegrini et al.²⁰⁰ who found a significant increased body weight among obese adults during the COVID-19 pandemic, confirming that subjects with a higher body mass index (BMI) have a higher risk of harmful dietary profiles during the lockdown. People who did not change their eating habits took a lower amount of alcohol and used an important number of supplements.¹⁹⁵ In contrast, positive habits have also emerged during the pandemic. Indeed, several studies have reported increased consumption of fruits and vegetables in adolescents, and this could be explained by the increase in home-cooked foods and an increase in awareness from the World Health Organization (WHO) on the relevance of fruits and vegetables during quarantine^{196,199,206,208–211,218,219} Since it has been impossible to eat at the restaurant during the first period of the COVID-19 pandemic, home-cooking rich in starchy foods is increased.^28,220 It has also been reported a lower intake of alcohol among young people and this could also be related to the quarantine rules, since they had less opportunity to buy alcohol and interact with friends.^220–226 A purchase increase during pandemic was also noted for specific supplements, such as vitamin C supplements to cope with COVID-19.²¹⁵

Interestingly, a recent study reported that post-COVID-19 patients consumed significantly fewer calories and less than 40% met the 1.2 g/kg/day optimal protein intake proposed by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).⁷⁸ Moreover, daily protein distribution was skewed, considering that only 3% consumed proteins at all meals, and over 30% did not meet the recommended threshold at any meal.

Another study investigating changes in food choice during lockdown reported a reduction of 2.5% in the fresh milk intake. At the same time, during the COVID-19 lockdown, it was observed a minor prescription for calcium supplements.^221,222

No study investigated the association between fluoride intake changes and bone health during the COVID-19 pandemic, except a trial conducted on a pediatric population that showed an increased risk for caries due to inadequate fluoride intake during the lockdown.²²³ It should be hypothesized that fluoride deficiency linked to unhealthy eating habits may influence bone health but further studies focusing on bone fragility are needed.

During the pandemic, a reduction in the consumption of fresh vegetables and an increase in canned or frozen ones were reported.²²⁴ This may have reduced potassium intake throughout the diet. On the other hand, a recent study on dietary supplements showed an increase in the potassium content in supplements produced during the pandemic.²²⁵ However, the clinical implications of this intervention in terms of compensation for the reduced dietary intake have not been studied and fully characterized so far.

An observational study reported that low serum phosphorus is more prevalent in severe than moderate COVID-19 patients and that serum calcium and phosphorus combined with lymphocyte count could be considered clinical biomarkers to discriminate severe COVID-19 patients.²²⁶ Moreover, poor food intake during infectious diseases implies higher ATP requirements of activated immune cells mainly covered by mobilization of phosphate and Mg stored in bones and muscles.²²⁷

It has been suggested laboratory investigation for serum tHcy and B9/B12 in all patients affected by COVID-19 during hospitalization, for potential benefits of relative supplementation of micronutrients in terms of disease severity and vascular complications.²²⁸ However, no supporting evidence for the potential detrimental effects of hyperhomocysteinemia on bone fragility in COVID-19 patients as well as of putative benefits of its correction by B9/B12 vitamins supplementation in terms of fragility fracture prevention is available so far.

As mentioned earlier, during the COVID-19 pandemic, an increased intake of vitamin C through the diet was advised, especially by increasing the consumption of kiwifruit, broccoli, and citrus fruits, particularly aiming to increase the synthesis of alpha and beta interferons for stimulating the immune response.²²⁹ However, clinical data about the effectiveness of vitamin C supplementation did not confirm any significant benefits on mortality reduction, intubation rate, and length of stay. Moreover, no data about the potential benefits of this intervention on bone health during the COVID-19 pandemic are available.

During the COVID-19 pandemic, vitamin D status was compromised considering the change in diet and the lack of sunlight exposure due to quarantine, as well as, in inpatients, to prolonged intensive care.^230,231 Moreover, vitamin D deficiency and increased serum PTH were more common among patients with more severe COVID-19. The incidence of vertebral fragility fractures significantly increased in COVID-19 patients with vitamin D deficiency.²³² Despite few data are available about the efficacy of vitamin D supplementation on bone health in COVID-19 patients, a recent position paper recommends this intervention as mandatory in those with serum 25(OH)D lower than 20 ng/ml,²³³ while a joint statement, issued from the Endocrine Society, American Society for Bone and Mineral Research (ASBMR), American Association of Clinical Endocrinologists (AACE), European Calcified Tissue Society (ECTS), and National Osteoporosis Foundation (NOF), recommended 400–1000 IU vitamin D daily in the COVID-19 pandemic, especially during quarantine for bone protection.²³⁴

During COVID-19, it has been observed that deficiencies of both vitamins K and D are associated with increased COVID-19 disease severity, implying a presumable synergistic action of these vitamins.²³⁵ However, a recent study reported that only vitamin K deficiency was associated with serum IL-6 increase and worse outcomes in COVID-19 patients. Considering that both vitamins K and D reduce IL-6 production, a cytokine involved in bone loss,²³⁶ it has been hypothesized a protective role for skeletal involvement by combined administration of these vitamins, although no data are available about this intervention.²³⁷

The largest observational study on COVID-19 and nutraceuticals has shown a significant association between users of multivitamin supplements and a lower risk of testing positive for infection with SARS-CoV-2.²³⁸ The putative effects of multivitamins administration on bone health in COVID-19 patients have not been investigated so far.

COVID-19 patients experienced trace element deficiency before and after the disease course.²³⁹ It has been claimed that trace element assessment at hospital admission may contribute to a better stratification of COVID-19 patients to support therapeutic interventions and adjuvant supplementation needs.²⁴⁰ However, it is not known if the biological effects of trace elements might be useful to prevent bone loss in COVID-19 patients.²⁴¹

In Figure 1 are reported the key messages of this article.

Figure 1.

Bone fragility, nutrition, and COVID-19: highlights.

Conclusion

Several macro- and micronutrients play pivotal roles in the homeostasis of bone health, and their adequate intakea, such as food or dietary supplements, have biological plausibility for the management of bone fragility. The COVID-19 pandemic upsets lifestyle habits, including nutrition and dietary patterns, increasing the risk of skeletal fragility. In this context, the comprehensive management of COVID-19-related complications, including bone fragility, should provide an adequate intake of nutrients, starting from waters rich in calcium and bicarbonate to macronutrients, such as proteins rich in lysine and arginine, monounsaturated fatty acids (MUFAs), and water-soluble fibers containing inulin, and micronutrients, such as calcium, magnesium, vitamin C, vitamin D, vitamin K, copper, Si, and strontium, although, for some of these nutrients, no evidence is available so far.

On the other hand, during the COVID-19 pandemic, the number of consumers of dietary supplements significantly increased.

In conclusion, beyond the putative benefits of these substances, it is necessary to carefully consider that their safety profile is not systematically monitored and that not all nutraceuticals are approved by regulatory agencies, while advertising for these products is often not based on strong evidence and sometimes misleading. Finally, some dietary supplements are claimed as effective (e.g. to cure COVID-19) despite a lack of consistent data or negative findings drawn from clinical trials.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Antimo Moretti

Marco Paoletta

Silvia Migliaccio

Giovanni Iolascon

References

Syed

AC.

The pathophysiology of the aging skeleton. Curr Osteoporos Rep 2010; 8: 235–240.

Rizzoli

Bianchi

Garabédian

, et al. Maximizing bone mineral mass gain during growth for the prevention of fractures in the adolescents and the elderly. Bone 2010; 46: 294–305.

Ferrari

Rizzoli

Manen

, et al. Vitamin D receptor gene start codon polymorphisms (FokI) and bone mineral density: interaction with age, dietary calcium, and 3’-end region polymorphisms. J Bone Miner Res 1998; 13: 925–930.

Iolascon

Gimigliano

Bianco

, et al. Are dietary supplements and nutraceuticals effective for musculoskeletal health and cognitive function? A revision of the scope. J Nutr Health Aging 2017; 21: 527–538.

Rizzoli

Nutritional aspects of bone health. Best Pract Res Clin Endocrinol Metab 2014; 28: 795–808.

Mattioli

Sciomer

Cocchi

, et al. Quarantine during the COVID-19 epidemic: changes in diet and physical activity increase the risk of cardiovascular disease. Nutr Metab Cardiovasc Dis 2020; 30: 1409–1417.

Cheval

Sivaramakrishnan

Maltagliati

, et al. Relationships between changes in self-reported physical activity, sedentary behaviour and health during the coronavirus (COVID-19) pandemic in France and Switzerland. J Sports Sci 2021; 39: 699–704.

Kotsalou

Zafeirakis

Kotsalou

The COVID-19 pandemic as a threatening for bone health. Med Sci Discov 2021; 8: 143–146.

Zhang

, et al. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty 2020; 9: 45.

10.

Queiroz-Junior

Santos

ACPM

Galvão

, et al. The angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor axis as a key player in alveolar bone remodeling. Bone 2019; 128: 115041.

11.

Khajah

Fateel

Ananthalakshmi

, et al. Anti-inflammatory action of angiotensin 1–7 in experimental colitis may be mediated through modulation of serum cytokines/chemokines and immune cell functions. Dev Comp Immunol 2017; 74: 200–208.

12.

Rodrigues Prestes

Rocha

Miranda

, et al. The anti-inflammatory potential of ACE2/angiotensin-(1-7)/MAS receptor axis: evidence from basic and clinical research. Curr Drug Targets 2017; 18: 1301–1313.

13.

Khajeh Pour

Ranjit

Summerill

, et al. Anti-inflammatory effects of ang-(1–7) bone-targeting conjugate in an adjuvant-induced arthritis rat model. Pharmaceuticals 2022; 15: 1157.

14.

Cecchini

AL.

SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Med Hypotheses 2020; 143: 110102.

15.

Lee

Choi

Baik

, et al. A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation. Blood 2005; 106: 852–859.

16.

Agidigbi

Kim

Reactive oxygen species in osteoclast differentiation and possible pharmaceutical targets of ROS-mediated osteoclast diseases. Int J Mol Sci 2019; 20: 3576.

17.

Mohiuddin

Kasahara

The emerging role of oxidative stress in complications of COVID-19 and potential therapeutic approach to diminish oxidative stress. Respir Med 2021; 187: 106605.

18.

Golabi

Adelipour

Mobarak

, et al. The association between vitamin D and zinc status and the progression of clinical symptoms among outpatients infected with SARS-CoV-2 and potentially non-infected participants: a cross-sectional study. Nutrients 2021; 13: 3368.

19.

Golabi

Ghasemi

Adelipour

, et al. Oxidative stress and inflammatory status in COVID-19 outpatients: a health center-based analytical cross-sectional study. Antioxidants 2022; 11: 606.

20.

Fung

Kwiatkowski

Huang

, et al. Zinc supplementation improves bone density in patients with thalassemia: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 2013; 98: 960–971.

21.

Iolascon

Paoletta

Liguori

, et al. Bone fragility: conceptual framework, therapeutic implications, and COVID-19-related issues. Ther Adv Musculoskelet Dis 2022; 14: 1759720X221133429.

22.

Zheng

Zhang

, et al. COVID-19 and the bone: underestimated to consider. Eur Rev Med Pharmacol Sci 2020; 24: 10316–10318.

23.

Marcus

Chapter 45 – osteoporosis in adults. In: Coulston

Boushey

Ferruzzi

(eds) Nutrition in the prevention and treatment of disease. Cambridge, MA: Academic Press, 2017, pp. 991–1009.

24.

Rizzoli

Biver

Brennan-Speranza

TC.

Nutritional intake and bone health. Lancet Diabetes Endocrinol 2021; 9: 606–621.

25.

Martiniakova

Babikova

Mondockova

, et al. The role of macronutrients, micronutrients and flavonoid polyphenols in the prevention and treatment of osteoporosis. Nutrients 2022; 14: 523.

26.

Jéquier

Constant

Water as an essential nutrient: the physiological basis of hydration. Eur J Clin Nutr 2010; 64: 115–123.

27.

Granke

Does

Nyman

JS.

The role of water compartments in the material properties of cortical bone. Calcif Tissue Int 2015; 97: 292–307.

28.

Vaissier Welborn

. Environment-controlled water adsorption at hydroxyapatite/collagen interfaces. Phys Chem Chem Phys 2021; 23: 13789–13796.

29.

Bohmer

Müller

Resch

KL.

Calcium supplementation with calcium-rich mineral waters: a systematic review and meta-analysis of its bioavailability. Osteoporos Int 2000; 11: 938–943.

30.

Wynn

Krieg

Aeschlimann

, et al. Alkaline mineral water lowers bone resorption even in calcium sufficiency: alkaline mineral water and bone metabolism. Bone 2009; 44: 120–124.

31.

Heaney

RP.

Protein and calcium: antagonists or synergists?

Am J Clin Nutr 2002; 75: 609–610.

32.

Rizzoli

Bonjour

. Physiology of calcium and phosphate homeostases. In: Seibel

Robins

Bilezikian

(eds) Dynamics of bone and cartilage metabolism. 2nd ed. San Diego, CA: Academic Press, 2006, pp. 345–360.

33.

Dawson-Hughes

Harris

Rasmussen

, et al. Comparative effects of oral aromatic and branched-chain amino acids on urine calcium excretion in humans. Osteoporos Int 2007; 18: 955–961.

34.

Lorincz

Manske

Zernicke

Bone health: part 1, nutrition. Sports Health 2009; 1: 253–260.

35.

Kerstetter

O’Brien

Insogna

KL.

Dietary protein affects intestinal calcium absorption. Am J Clin Nutr 1998; 68: 859–865.

36.

Conigrave

Brown

Rizzoli

Dietary protein and bone health: roles of amino acid-sensing receptors in the control of calcium metabolism and bone homeostasis. Annu Rev Nutr 2008; 28: 131–155.

37.

Kerstetter

Caseria

Mitnick

, et al. Increased circulating concentrations of parathyroid hormone in healthy, young women consuming a protein-restricted diet. Am J Clin Nutr 1997; 66: 1188–1196.

38.

Weaver

Proulx

Heaney

Choices for achieving adequate dietary calcium with a vegetarian diet. Am J Clin Nutr 1999; 70(Suppl.): 543S–548S.

39.

Alexy

Remer

Manz

, et al. Long-term protein intake and dietary potential renal acid load are associated with bone modeling and remodeling at the proximal radius in healthy children. Am J Clin Nutr 2005; 82: 1107–1114.

40.

Liu

Jeppesen

Gregersen

, et al. Dose- and glucose-dependent effects of amino acids on insulin secretion from isolated mouse islets and clonal INS-1E beta-cells. Rev Diabet Stud 2008; 5: 232–244.

41.

Yang

Zhang

Wang

, et al. Insulin stimulates osteoblast proliferation and differentiation through ERK and PI3K in MG-63 cells. Cell Biochem Funct 2010; 28: 334–341.

42.

Jennings

MacGregor

Spector

, et al. Amino acid intakes are associated with bone mineral density and prevalence of low bone mass in women: evidence from discordant monozygotic twins. J Bone Miner Res 2016; 31: 326–335.

43.

Fini

Torricelli

Giavaresi

, et al. Effect of L-lysine and L-arginine on primary osteoblast cultures from normal and osteopenic rats. Biomed Pharmacother 2001; 55: 213–220.

44.

Durosier-Izart

Biver

Merminod

, et al. Peripheral skeleton bone strength is positively correlated with total and dairy protein intakes in healthy postmenopausal women. Am J Clin Nutr 2017; 105: 513–525.

45.

Langsetmo

Peters

Burghardt

, et al. Volumetric bone mineral density and failure load of distal limbs predict incident clinical fracture independent HR-pQCT BMD and failure load predicts incident clinical fracture of FRAX and clinical risk factors among older men. J Bone Miner Res 2018; 33: 1302–1311.

46.

Darling

Millward

Torgerson

, et al. Dietary protein and bone health: a systematic review and meta-analysis. Am J Clin Nutr 2009; 90: 167492.

47.

Shams-White

Chung

, et al. Dietary protein and bone health: a systematic review and meta-analysis from the National Osteoporosis Foundation. Am J Clin Nutr 2017; 105: 1528–1543.

48.

Wallace

Frankenfeld

CL.

Dietary protein intake above the current RDA and bone health: a systematic review and metaanalysis. J Am Coll Nutr 2017; 36: 481–496.

49.

Darling

Manders

RJF

Sahni

, et al. Dietary protein and bone health across the life-course: an updated systematic review and meta-analysis over 40 years. Osteoporos Int 2019; 30: 741–761.

50.

Dargent-Molina

Sabia

Touvier

, et al. Proteins, dietary acid load, and calcium and risk of postmenopausal fractures in the E3N French women prospective study. J Bone Miner Res 2008; 23: 1915–1922.

51.

Bajželj

Laguzzi

Röös

The role of fats in the transition to sustainable diets. Lancet Planet Health 2021; 5: e644–e653.

52.

Kato

Toniolo

Zeleniuch-Jacquotte

, et al. Diet, smoking and anthropometric indices and postmenopausal bone fractures: a prospective study. Int J Epidemiol 2000; 29: 85–92.

53.

Romero Márquez

Varela López

Navarro Hortal

, et al. Molecular interactions between dietary lipids and bone tissue during aging. Int J Mol Sci 2021; 22: 6473.

54.

Scheller

Khoury

Moller

, et al. Changes in skeletal integrity and marrow adiposity during high-fat diet and after weight loss. Front Endocrinol 2016; 7: 102.

55.

Xiao

Cui

, et al. Dyslipidemic high-fat diet affects adversely bone metabolism in mice associated with impaired antioxidant capacity. Nutrition 2011; 27: 214–220.

56.

Tencerova

Figeac

Ditzel

, et al. High-fat diet-induced obesity promotes expansion of bone marrow adipose tissue and impairs skeletal stem cell functions in mice. J Bone Miner Res 2018; 33: 1154–1165.

57.

Karpouzos

Diamantis

Farmaki

, et al. Nutritional aspects of bone health and fracture healing. J Osteoporos 2017; 2017: 4218472.

58.

Kim

Henneicke

Caavanagh

, et al. Osteoblastic glucocorticoid signaling exacerbates high-fat-diet-induced bone loss and obesity. Bone Res 2021; 9: 40.

59.

Corwin

Hartman

Maczuga

, et al. Dietary saturated fat intake is inversely associated with bone density in humans: analysis of NHANES III. J Nutr 2006; 136: 159–165.

60.

Orchard

Cauley

Frank

, et al. Fatty acid consumption and risk of fracture in the women’s health initiative. Am J Clin Nutr 2010; 92: 1452–1460.

61.

Kiely

Hickey

RM.

Characterization and analysis of food-sourced carbohydrates. Methods Mol Biol 2022; 2370: 67–95.

62.

Cohen

Hazell

Vanstone

, et al. A family-centered lifestyle intervention to improve body composition and bone mass in overweight and obese children 6 through 8 years: a randomized controlled trial study protocol. BMC Public Health 2013; 13: 383.

63.

Terada

Inaba

Yano

, et al. Growth-inhibitory effect of a high glucose concentration on osteoblast-like cells. Bone 1998; 22: 17–23.

64.

Tjäderhane

Larmas

A high sucrose diet decreases the mechanical strength of bones in growing rats. J Nutr 1998; 128: 1807–1810.

65.

Douard

Sabbagh

Lee

, et al. Excessive fructose intake causes 1,25-(OH)(2)D(3)-dependent inhibition of intestinal and renal calcium transport in growing rats. Am J Physiol Endocrinol Metab 2013; 304: 1303–1313.

66.

Ericsson

Angmar-Månsson

Flores

Urinary mineral ion loss after sugar ingestion. Bone Miner 1990; 9: 233–237.

67.

Vartanian

Schwartz

Brownell

KD.

Effects of soft drink consumption on nutrition and health: a systematic review and meta-analysis. Am J Public Health 2007; 97: 667–675.

68.

Tsanzi

Light

Tou

JC.

The effect of feeding different sugar-sweetened beverages to growing female Sprague-Dawley rats on bone mass and strength. Bone 2008; 42: 960–968.

69.

Ogur

Uysal

Ogur

, et al. Evaluation of the effect of cola drinks on bone mineral density and associated factors. Basic Clin Pharmacol Toxicol 2007; 100: 334–338.

70.

Kim

Jang

K-H

Lee

E-Y

, et al. The effect of chicory fructan fiber on calcium absorption and bone metabolism in Korean postmenopausal women. Nutr Sci 2004; 7: 151–157.

71.

Abrams

Griffin

Hawthorne

, et al. A combination of prebiotic shortand long-chain inulin-type fructans enhances calcium absorption and bone mineralization in young adolescents. Am J Clin Nutr 2005; 82: 471–476.

72.

Jakeman

Henry

Martin

, et al. Soluble corn fiber increases bone calcium retention in postmenopausal women in a dose-dependent manner: a randomized crossover trial. Am J Clin Nutr 2016; 104: 837–843.

73.

Hejazi

Davoodi

Khosravi

, et al. Nutrition and osteoporosis prevention and treatment. Biomed Res Ther 2020; 7: 3709–3720.

74.

Hayes

Duffy

O’Grady

, et al. Eggs boosted with vitamin D are protective of the winter serum 25-hydroxyvitamin D in a randomized controlled trial in adults. Am J Clin Nutr 2016; 104: 629–637.

75.

Manios

Moschonis

Mavrogianni

, et al. Gouda-type reduced-fat cheese enriched with vitamin D3 effectively prevents vitamin D deficiency during the winter months in postmenopausal women in Greece. Eur J Nutr 2017; 56: 2367–2377.

76.

Tai

Leung

Grey

, et al. Calcium intake and bone mineral density: systematic review and meta-analysis BMJ 2015; 351: h4183.

77.

Vannucci

Masi

Gronchi

, et al. Calcium intake, bone mineral density, and fragility fractures: evidence from an Italian outpatient population. Arch Osteoporos 2017; 12: 40.

78.

Rizzoli

Stevenson

Bauer

, et al. The role of dietary proteins and vitamin D in maintaining musculoskeletal health in postmenopausal women: a declaration of consensus from the European Society for the Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Deadline 2014; 79: 122–132.

79.

George

Waldbott

MD.

Fluoride in food. Am J Clin Nutr 1963; 12: 455–462.

80.

Riggs

Hodgson

O’Fallon

, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990; 322: 802–809.

81.

Kleerekoper

Peterson

Nelson

, et al. A randomized trial of sodium fluoride as a treatment for postmenopausal osteoporosis. Osteoporos Int 1991; 1: 155–161.

82.

Lundy

Stauffer

Wergedal

, et al. Histomorphometric analysis of iliac crest bone biopsies in placebo-treated versus fluoride-treated subjects. Osteoporos Int 1995; 5: 115–129.

83.

Grey

Garg

Dray

, et al. Low-dose fluoride in postmenopausal women: a randomized controlled trial. J Clin Endocrinol Metab 2013; 98: 2301–2307.

84.

Odusan

Familoni

Odewabi

, et al. Patterns and correlates of serum magnesium levels in subsets of type 2 diabetes mellitus patients in Nigeria. Indian J Endocrinol Metab 2017; 21: 439–442.

85.

De Baaij

JHF

Hoenderop

JGJ

Bindels

RJM.

Magnesium in humans: implications for health and disease. Physiol Rev 2015; 95: 1–46.

86.

Mammoli

Castiglioni

Parenti

, et al. Magnesium is a key regulator of the balance between osteoclast and osteoblast differentiation in the presence of vitamin D. Int J Mol Sci 2019; 20: 385.

87.

Uwitonze

Razzaque

MS.

Role of magnesium in the activation and function of vitamin D. J Am Osteopath Bandage 2018; 118: 181–189.

88.

Orchard

Larson

Alghothani

, et al. Magnesium intake, bone mineral density, and fractures: results from the Women’s Health Initiative observational study. Am J Clin Nutr 2014; 99: 926–933.

89.

Veronese

Stubbs

Solmi

, et al. Dietary magnesium intake and fracture risk: data from a large prospective study. Fr J Nutr 2017; 117: 1570–1576.

90.

Weaver

CM.

Potassium and health. Adv Nutr 2013; 4: 368S–77S.

91.

Hoss

Elizur

Luria

, et al. Serum potassium levels and outcome in patients with chronic heart failure. Am J Cardiol 2016; 118: 1868–1874.

92.

Bolton

Trieu

Woodward

, et al. Dietary intake and sources of potassium in a cross-sectional study of Australian adults. Nutrients 2019; 11: 2996.

93.

Lambert

Frassetto

Moore

, et al. The effect of supplementation with alkaline potassium salts on bone metabolism: a meta-analysis. Osteoporos Int 2015; 26: 1311–1318.

94.

Zhu

Devine

Prince

RL.

The effects of high potassium consumption on bone mineral density in a prospective cohort study of older postmenopausal women. Osteoporos Int 2009; 20: 335–340.

95.

Kong

Kim

Hong

, et al. Dietary potassium intake is beneficial for bone health in a low-calcium population: The Korean National Health and Nutrition Examination Survey (KNHANES) (2008–2011). Osteoporos Int 2017; 28: 1577–1585.

96.

Kim

Lim

, et al. The association of potassium intake with bone mineral density and the prevalence of osteoporosis among older Korean adults. Nutr Res Pract 2020; 14: 55–61.

97.

Barzel

US.

The skeleton as an ion exchange system: implications for the role of acid-base imbalance in the genesis of osteoporosis. J Bone Miner Res 1995; 10: 1431–1436.

98.

Intake

DR.

Calcium, phosphorus, magnesium, vitamin D and fluoride. Washington, DC: Institute of Medicine, Food and Nutrition Board, 1997.

99.

O’Brien

Kerstetter

Insonga

. Phosphorus. In: Ross

Caballero

Cousins

, et al. (eds) Modern nutrition in health and disease. 11th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2012, pp. 150–158.

100.

Suki

Moore

LW.

Phosphorus regulation in chronic kidney disease. Methodist Debakey Cardiovasc J 2016; 12(Suppl.): 6–9.

101.

Arnold

Dennison

Kovacs

, et al. Hormonal regulation of biomineralization. Nat Rev Endocrinol 2021; 17: 261–275.

102.

Goretti Penido

Alon

. Phosphate homeostasis and its role in bone health. Pediatr Nephrol 2012; 27: 2039–2048. Erratum in: Pediatr Nephrol 2017; 32: 1999.

103.

Lee

Cho

SS.

Association between phosphorus intake and bone health in the NHANES population. Nutr J 2015; 14: 28.

104.

B-Vitamin Treatment Trialists’ Collaboration. Homocysteine-lowering trials for prevention of cardiovascular events: a review of the design and power of the large randomized trials. Am Heart J 2006; 151: 282–287.

105.

Bailey

van Wijngaarden

JP.

The role of B-vitamins in bone health and disease in older adults. Curr Osteoporos Rep 2015; 13: 256–261.

106.

Herrmann

Umanskaya

Traber

, et al. The effect of B-vitamins on biochemical bone turnover markers and bone mineral density in osteoporotic patients: a 1-year double blind placebo-controlled trial. Clin Chem Lab Med 2007; 45: 1785–1792.

107.

Saito

Marumo

The effects of homocysteine on the skeleton. Curr Osteoporos Rep 2018; 16: 554–560.

108.

Chin

Ima-Nirwana

Vitamin C and bone health: evidence from cell, animal and human studies. Curr Drug Targets 2018; 19: 439–450.

109.

Valdés

Vitamina C [Vitamin C]. Actas Dermosifiliogr 2006; 97: 557–568 (In Spanish).

110.

Finck

Hart

Jennings

, et al. Is there a role for vitamin C in preventing osteoporosis and fractures? A review of the potential underlying mechanisms and current epidemiological evidence. Nutr Res Rev 2014; 27: 268–283.

111.

Brzezińska

Łukasik

Makowska

, et al. Role of vitamin C in osteoporosis development and treatment –a literature review. Nutrients 2020; 12: 2394.

112.

Malmir

Shab-Bidar

Djafarian

Vitamin C intake in relation to bone mineral density and risk of hip fracture and osteoporosis: a systematic review and meta-analysis of observational studies. Br J Nutr 2018; 119: 847–858.

113.

Sizar

Khare

Goyal

, et al. Vitamin D deficiency. In: StatPearls Publishing LLC (ed) StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing, 2022, https://www.ncbi.nlm.nih.gov/books/NBK532266/

114.

Liu

Vitamin D content of food and its contribution to vitamin D status: a brief overview and Australian focus. Photochem Photobiol Sci 2012; 11: 1802–1807.

115.

, et al. Comparisons of different vitamin D supplements for the prevention of osteoporotic fractures: a Bayesian network meta-analysis and meta-regression of randomized controlled trials. Int J Food Sci Nutr 2021; 72: 518–528.

116.

Chapuy

Pamphile

Paris

, et al. Combined calcium and vitamin D3 supplementation in older women: confirmation of the reversal of secondary hyperparathyroidism and risk of hip fracture: the decalyos II study. Osteoporos Int 2002; 13: 257–264.

117.

Adami

Giannini

Bianchi

, et al. Vitamin D status and response to treatment in postmenopausal osteoporosis. Osteoporos Int 2009; 20: 239–244.

118.

DiNicolantonio

Bhutani

O’Keefe

JH.

The health benefits of vitamin K. Open Heart 2015; 2: e000300.

119.

Mott

Bradley

Wright

, et al. Effect of vitamin K on bone mineral density and fractures in adults: an updated systematic review and meta-analysis of randomized controlled trials. Osteoporos Int 2019; 30: 1543–1559.

120.

McCann

Ames

BN.

Vitamin K, an example of triage theory: is the inadequacy of micronutrients linked to the diseases of aging?

Am J Clin Nutr 2009; 90: 889–907.

121.

Booth

Tucker

Chen

, et al. Dietary vitamin K intakes are associated with hip fracture but not with bone mineral density in elderly men and women. Am J Clin Nutr 2000; 71: 120108.

122.

Feskanich

Weber

Willett

, et al. Vitamin K intake and hip fractures in women: a prospective study. Am J Clin Nutr 1999; 69: 74–79.

123.

Knapen

Drummen

Smit

, et al. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int 2013; 24: 2499–2507.

124.

Grieger

Nowson

Jarman

, et al. Multivitamin supplementation improves nutritional status and bone quality in aged care residents. Eur J Clin Nutr 2009; 63: 558–565.

125.

Beeram

Mortensen

Yeritsyan

, et al. Multivitamins and risk of hip fracture fragility: a systematic review and meta-analysis. Arch Osteoporos 2021; 16: 29.

126.

Devirian

Volpe

SL.

The physiological effects of dietary boron. Crit Rev Food Sci Nutr 2003; 43: 219–231.

127.

Hunt

CD.

Dietary boron: progress in establishing essentials roles in human physiology. J Trace Elem Med Biol 2012; 26: 2–3.

128.

Nielsen

Stoecker

BJ.

Boron and fish oil have different beneficial effects on strength and trabecular microarchitecture of bone. J Trace Elem Med Biol 2009; 23: 195–203.

129.

Kubiak

Klimczak

Dziki

, et al. Influence of copper (II) complex on the activity of selected oxidative enzymes. Pol Merkur Lekarski 2010; 28: 22–25.

130.

SF.

In vitro study of the effects of copper ion on osteoclastic resorption in various dental mineralized tissues. Zhonghua Kou Qiang Yi Xue Za Zhi 2007; 42: 110–113 (In Chinese).

131.

Hill

Meunier

Andriollo-Sanchez

, et al. The relationship between the zinc nutritive status and biochemical markers of bone turnover in older European adults: the ZENITH study. Eur J Clin Nutr 2005; 59(Suppl. 2): S73–S78.

132.

Conlan

Korula

Thatantan

Serum copper levels in elderly patients with fractures of the femoral neck. Aging 1990; 19: 212–214.

133.

Nemcikova

Spevackova

Cejchanova

, et al. Relationship of serum manganese and copper levels to bone density and quality in postmenopausal women. A pilot study. Osteol Bull 2009; 14: 97–100.

134.

Hoeg

Gogakos

Murphy

, et al. Bone turnover and bone mineral density are independently related to selenium status in healthy euthyroid postmenopausal women. J Clin Endocrinol Metab 2012; 97: 4061–4070.

135.

Zhang

Munger

West

, et al. Antioxidant intake and risk of osteoporotic hip fracture in Utah: an effect modified by smoking status. Am J Epidemiol 2006; 163: 917.

136.

Cao

Gregoire

Zeng

Selenium deficiency decreases antioxidative capacity and is detrimental to bone microarchitecture in mice. J Nutr 2012; 142: 1526–1531.

137.

Moreno-Reyes

Egrise

Nève

, et al. Selenium deficiency-induced growth retardation is associated with an impaired bone metabolism and osteopenia. J Bone Miner Res 2001; 16: 1556–1563.

138.

Price

Koval

Langford

. Silicon: a review of its potential role in the prevention and treatment of postmenopausal osteoporosis. Int J Endocrinol 2013; 2013: 316783.

139.

Jugdaohsingh

Silicon and bone health. J Nutr Health Aging 2007; 11: 99–110.

140.

Carlisle

EM.

Silicon: a possible factor in bone calcification. Science 1970; 167: 279–280.

141.

Carlisle

EM.

Silicon: an essential element for the chick. Science 1972; 178: 619–621.

142.

Rodella

Bonazza

Labanca

, et al. A review of the effects of dietary silicon intake on bone homeostasis and regeneration. J Nutr Health Aging 2014; 18: 820–826.

143.

Jugdaohsingh

Anderson

Tucker

, et al. Dietary silicon intake and absorption. Am J Clin Nutr 2002; 75: 887–893.

144.

Nielsen

FH.

Update on the possible nutritional importance of silicon. J Trace Elem Med Biol 2014; 28: 379–382.

145.

Reffitt

Ogston

Jugdaohsingh

, et al. Orthosilicic acid stimulates collagen type 1 synthesis and osteoblastic differentiation in human osteoblast-like cells in vitro. Bone 2003; 32: 127–135.

146.

Kim

Sung

, et al. Effects of silicon on osteoblast activity and bone mineralization of MC3T3-E1 cells. Biol Trace Elem Res 2013; 152: 105–112.

147.

Kim

Choi

MK.

Effect of silicon supplementation on bone status in ovariectomized rats under calcium-replete condition. Biol Trace Elem Res 2016; 171: 138–144.

148.

Beck

Jr Ha

Camalier

, et al. Bioactive silica-based nanoparticles stimulate boneforming osteoblasts, suppress bone-resorbing osteoclasts, and enhance bone mineral density in vivo. Nanomedicine 2012; 8: 793–803.

149.

Merkley

Miller

ER.

The effect of sodium fluoride and sodium silicate on growth and bone strength of broilers. Poult Sci 1983; 62: 798–804.

150.

Maehira

Iinuma

Eguchi

, et al. Effects of soluble silicon compound and deep-sea water on biochemical and mechanical properties of bone and the related gene expression in mice. J Bone Miner Metab 2008; 26: 446–455.

151.

Jugdaohsingh

Calomme

Robinson

, et al. Increased longitudinal growth in rats on a silicon-depleted diet. Bone 2008; 43: 596–606.

152.

Jugdaohsingh

Tucker

Qiao

, et al. Dietary silicon intake is positively associated with bone mineral density in men and premenopausal women of the Framingham offspring cohort. J Bone Miner Res 2004; 19: 297–307.

153.

Macdonald

Hardcastle

Jugdaohsingh

, et al. Dietary silicon intake is associated with bone mineral density in premenopausal women and postmenopausal women taking HRT. J Bone Miner Res 2005; 20: S393.

154.

Cabrera

Schrooten

De Broe

, et al. Strontium and bone. J Bone Miner Res 1999; 14: 661–668.

155.

Iolascon

Frizzi

Di Pietro

, et al. Bone quality and bone strength: benefits of the bone-forming approach. Clin Cases Miner Bone Metab 2014; 11: 20–24.

156.

Aslam

Jepsen

Khoury

, et al. Bone structure and function in male C57BL/6 mice: effects of a high-fat Western-style diet with or without trace minerals. Bone Rep 2016; 5: 141–149.

157.

O’Connor

Kanjilal

Teitelbaum

, et al. Zinc as a therapeutic agent in bone regeneration. Materials 2020; 13: 2211.

158.

Suzuki

Kajita

Katsumata

, et al. Zinc deficiency increases serum concentrations of parathyroid hormone through a decrease in serum calcium and induces bone fragility in rats. J Nutr Sci Vitaminol 2015; 61: 382–390.

159.

National Institutes of Health – Office of Dietary Supplements. Nutrient recommendations: dietary reference intakes. Bethsda, MD: US Department of Health & Human Services, National Institutes of Health, https://ods.od.nih.gov/HealthInformation/Dietary_Reference_Intakes.aspx

160.

Marcinowska-Suchowierska

Kupisz-Urbańska

Łukaszkiewicz

, et al. Vitamin D toxicity –a clinical perspective. Front Endocrinol 2018; 9: 550.

161.

Bolland

Avenell

Baron

, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ 2010; 341: c3691.

162.

Xiao

Murphy

Houston

, et al. Dietary and supplemental calcium intake and cardiovascular disease mortality: the National Institutes of Health-AARP diet and health study. JAMA Intern Med 2013; 173: 639–646.

163.

Delimaris

Adverse effects associated with protein intake above the recommended dietary allowance for adults. ISRN Nutr 2013; 2013: 126929.

164.

Kerstetter

Mitnick

Gundberg

, et al. Changes in bone turnover in young women consuming different levels of dietary protein. J Clin Endocrinol Metab 1999; 84: 1052–1055.

165.

Ahn

Park

YK.

Sugar-sweetened beverage consumption and bone health: a systematic review and meta-analysis. Nutr J 2021; 20: 41.

166.

DiNicolantonio

Mehta

Zaman

, et al. Not salt but sugar as aetiological in osteoporosis: a review. Mo Med 2018; 115: 247–252.

167.

Melhus

Michaëlsson

Kindmark

, 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.

168.

Lionikaite

Henning

Drevinge

, et al. Vitamin A decreases the anabolic bone response to mechanical loading by suppressing bone formation. FASEB J 2019; 33: 5237–5247.

169.

Yee

MMF

Chin

Ima-Nirwana

, et al. Vitamin A and bone health: a review on current evidence. Molecules 2021; 26: 1757.

170.

Dai

Koh

WP.

B-vitamins and bone health –a review of the current evidence. Nutrients 2015; 7: 3322–3346.

171.

Dai

Wang

Ang

, et al. Dietary B vitamin intake and risk of hip fracture: the Singapore Chinese Health Study. Osteoporos Int 2013; 24: 2049–2059.

172.

Gupta

Madhavan

Sehgal

, et al. Extrapulmonary manifestations of COVID-19. Nat Med 2020; 26: 1017–1032.

173.

Chan

Yuan

Kok

, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet 2020; 395: 514–523.

174.

Sudre

Murray

Varsavsky

, et al. Attributes and predictors of long COVID. Nat Med 2021; 27: 626–631.

175.

Augustin

Schommers

Stecher

, et al. Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study. Lancet Reg Health Eur 2021; 6: 100122.

176.

Crispo

Bimonte

Porciello

, et al. Strategies to evaluate outcomes in long-COVID-19 and post-COVID survivors. Infect Agent Cancer 2021; 16: 62.

177.

Barrea

Grant

Frias-Toral

, et al. Dietary recommendations for post-COVID-19 syndrome. Nutrients 2022; 14: 1305.

178.

Gérard

Mahmutovic

Malgras

, et al. Long-term evolution of malnutrition and loss of muscle strength after COVID-19: a major and neglected component of long COVID-19. Nutrients 2021; 13: 3964.

179.

Butler

Barrientos

RM.

The impact of nutrition on COVID-19 susceptibility and long-term consequences. Brain Behav Immun 2020; 87: 53–54.

180.

Kottlors

Große Hokamp

Fervers

, et al. Early extrapulmonary prognostic features in chest computed tomography in COVID–19 pneumonia: bone mineral density is a relevant predictor for the clinical outcome – a multicenter feasibility study. Bone 2021; 144: 115790.

181.

Tahtabasi

Kilicaslan

Akin

, et al. The prognostic value of vertebral bone density on chest CT in hospitalized COVID-19 patients. J Clin Densitom 2021; 24: 506–515.

182.

Qiao

Lau

Xie

, et al. Author Correction: SARS-CoV-2 infection induces inflammatory bone loss in golden Syrian hamsters. Nat Commun 2022; 13: 3139. Erratum for: Nat Commun 2022; 13: 2539.

183.

Dam

Harrison

Fink

, et al. Bone mineral density and fractures in older men with chronic obstructive pulmonary disease or asthma. Osteoporos Int 2010; 21: 1341–1349.

184.

Redlich

Smolen

JS.

Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat Rev Drug Disco 2012; 11: 234–250.

185.

Chen

Guo

, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020; 130: 2620–2629.

186.

Guan

Liangand

, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382: 1708–1720.

187.

Adamopoulos

IE.

Inflammation in bone physiology and pathology. Curr Opin Rheumatol 2018; 30: 59–64.

188.

Sollini

Ciccarelli

Cecconi

, et al. Vasculitis changes in COVID-19 survivors with persistent symptoms: an [(18)F]FDG-PET/CT study. Eur J Nucl Med Mol Imaging 2021; 48: 1460–1466.

189.

Orford

Pasco

Kotowicz

MA.

Osteoporosis and the critically ill patient. Crit Care Clin 2019; 35: 301–313.

190.

Amrein

Papinutti

Mathew

, et al. Vitamin D and critical illness: what endocrinology can learn from intensive care and vice versa. Endocr Connect 2018; 7: R304–R315.

191.

Holick

Binkley

Bischoff-Ferrari

, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 1911–1930.

192.

Pal

Sethi

Taywade

, et al. Role of nutrition and diet during COVID-19 pandemic: a narrative review. J Family Med Prim Care 2022; 11: 4942–4948.

193.

Demasi

COVID-19 and metabolic syndrome: could diet be the key?

BMJ Evid Based Med 2021; 26: 1–2.

194.

Feng

Liu

, et al. Risk of malnutrition in hospitalized COVID-19 patients: a systematic review and meta-analysis. Nutrients 2022; 14: 5267.

195.

Bennett

Young

Butler

, et al. The impact of the lockdown during the COVID-19 outbreak on eating habits in various population groups: a review of the scope. Front Nutr 2021; 8: 626432.

196.

Ammar

Brach

Trabelsi

, et al. Effects of COVID-19 home confinement on eating behavior and physical activity: results of the ECLB-COVID19 international online survey. Nutrients 2020; 12: 1583.

197.

Deschasaux-Tanguy

Druesne-Pecollo

Esseddik

, et al. Diet and physical activity during the COVID-19 lockdown period (March-May 2020): results of the NutriNet-Sante cohort study French. Medrxiv[preprint] 2020. DOI: 10.1101/2020.06.04.201 21855.

198.

Rooster

Young

, et al. The impact of isolation measures due to covid-19 on energy intake and physical activity levels in Australian university students. Nutrients 2020; 12: 1–14.

199.

Husain

Ashkanani

COVID-19 changes eating habits and lifestyle behaviors in Kuwait?

Environment Health Prev Med 2020; 25: 1–13.

200.

Pellegrini

Ponzo

Rosato

, et al. Changes in weight and eating habits in adults with obesity during the ‘lockdown’ period caused by the COVID-19 virus emergency. Nutrients 2020; 12: 1–11.

201.

Scarmozzino

Visioli

Covid-19 and the subsequent lockdown have changed the eating habits of almost half of the population in an Italian sample. Alimony 2020; 9: 675.

202.

Sidor

Rzymski

Choices and eating habits during the COVID-19 lockdown: experience from Poland. Nutrients 2020; 12: 1657.

203.

Zachary

Brianna

, et al. Risk factors related to self-quarantine and weight gain during the COVID-19 pandemic. Obes Res Clin Pract 2020; 14: 210–216.

204.

Schelleman-Offermans

Kuntsche

Knibbe

RA.

Associations between reasons for alcohol consumption and changes in adolescent alcohol consumption: a comprehensive cross-lag panel study. Dependency 2011; 106: 1882.

205.

Yoshida

Eguchi

Nagaoka

, et al. Association of nocturnal eating habits with metabolic syndrome and its components: a longitudinal study. BMC Public Health 2018; 18: 1366.

206.

Allabadi

Dabis

Aghabekian

, et al. Impact of the COVID-19 lockdown on dietary and lifestyle behaviors among adolescents in Palestine. Dyn Hum Health 2020; 2020: 7.

207.

Mehta

The impact of COVID-19 on the eating habits of the middle-class population in Mulund, Mumbai, India. AIJR Preprint 2020, https://preprints.aijr.org/index.php/ap/preprint/view/82 (accessed 24 September 2020).

208.

Pietrobelli

Pecoraro

Ferruzzi

, et al. Effects of the COVID-19 lockdown on lifestyle behaviors in children with obesity living in Verona, Italy: a longitudinal study. Obesity 2020; 28: 1382–1385.

209.

Bhutani

Cooper

Vandellen

MR.

Self-reported changes in energy balance behaviors during COVID-19-related home confinement: a cross-sectional study. Medrxiv[preprint] 2020. DOI: 10.1101/2020.06.10.20127753.

210.

Bracale

Vaccaro

CM.

Changes in the choice of food as a result of restrictive measures due to Covid-19. Nutr Metab Cardiovasc Dis 2020; 30: 1423–1426.

211.

Renzo

Gualtieri

Pivari

, et al. Eating habits and lifestyle changes during the COVID-19 lockdown: an Italian survey. J Transl Med 2020; 18: 229.

212.

Matsungo

Chopera

The effect of the COVID-19-induced lockdown on nutrition, health and lifestyle patterns among adults in Zimbabwe. BMJ Nutr Prev Health 2020; 3: 205–212.

213.

Mitchell

Yang

Behr

, et al. Self-reported food choices before and during the COVID-19 lockdown. Medrxiv[preprint] 2020. DOI: 10.1101/2020.06.15.20131888.

214.

Romeo-Arroyo

Mora

Vázquez-Araújo

Consumer behavior in times of confinement: choice of food and culinary attitudes in Spain. Int J Gastron Food Ski 2020; 21: 100226.

215.

Zhao

, et al. Dietary diversity among Chinese residents during the COVID-19 outbreak and associated factors. Nutrients 2020; 12: 1–13.

216.

Kanis

Johansson

Johnell

, et al. Alcohol intake as a risk factor for fracture. Osteoporos Int 2005; 16: 737–742.

217.

Zhang

, et al. Alcohol consumption and risk of hip fracture. Osteoporos Int 2015; 26: 531–542.

218.

Rodríguez-Pérez

Molina-Montes

Verardo

, et al. Changes in eating behaviors during the confinement of the COVID-19 epidemic in the Spanish study COVIDiet. Nutrients 2020; 12: 1–19.

219.

Ruiz-Roso

Padilha

, et al. Covid-19 lockdown and changes in adolescent eating trends in Italy, Spain, Chile, Colombia and Brazil. Nutrients 2020; 12: 1–18.

220.

Uemura

Ohira

Yasumura

, et al. Association between psychological distress and dietary intake among displaced people after the great east Japan earthquake in a cross-sectional study: the Fukushima Health Management Survey. BMJ Open 2016; 6: 11534.

221.

Stephens

Rudd

Stephens

, et al. Secondary prevention of hip fragility fractures during the COVID-19 pandemic: service evaluation of ‘MRS BAD BONES’. JMIR Aging 2020; 3: e25607.

222.

Hampson

Stone

Lindsay

, et al. Diagnosis and management of osteoporosis during COVID-19: systematic review and practical guidance. Calcif Tissue Int 2021; 109: 351–362.

223.

Docimo

Costacurta

Gualtieri

, et al. Cariogenic risk and COVID-19 lockdown in a paediatric population. Int J Environ Res Public Health 2021; 18: 7558.

224.

Jordan

Keding

Stosius

, et al. Changes in vegetable consumption in times of COVID-19-first findings from an international civil science project. Front Nutr 2021; 8: 686786.

225.

Wróbel

Milewska

Marczak

, et al. The impact of the COVID-19 pandemic on the composition of dietary supplements and functional foods notified in Poland. Int J Environ Res Public Health 2021; 18: 11751.

226.

Yang

, et al. Low serum calcium and phosphorus and their clinical performance in detecting COVID-19 patients. J Med Virol 2021; 93: 1639–1651.

227.

van Niekerk

Mitchell

Engelbrecht

. Bone resorption: sup-porting immunometabolism. Biol Lett 2018; 14: 20170783.

228.

Ibrahimagić

Oć

Ercegović

Vujadinović

, et al. Comment on an article: medications in COVID-19 patients: summarizing the current literature from an orthopaedic perspective. Int Orthop 2020; 44: 2811–2812.

229.

Beran

Mhanna

Srour

, et al. Clinical significance of micronutrient supplements in patients with coronavirus disease 2019: a comprehensive systematic review and meta-analysis. Clin Nutr ESPEN 2022; 48: 167–177.

230.

van den Heuvel

EGHM

Steijns

JMJM

. Dairy products and bone health: how strong is the scientific evidence? Nutr Res Rev 2018; 31: 164–178.

231.

Cromer

EW.

Challenges opportunities for osteoporosis care during the COVID-19 pandemic. J Clin Endocrinol Metab 2021; 106: e4795–e4808.

232.

di Filippo

Formenti

Doga

, et al. Radiological thoracic vertebral fractures are highly prevalent in COVID-19 and predict disease outcomes. J Clin Endocrinol Metab 2021; 106: e602–e614.

233.

Ulivieri

Banfi

Camozzi

, et al. Vitamin D in the covid-19 era: a review with recommendations from a G.I.O.S.E.G. Endocrine 2021; 72: 597–603.

234.

ASBMR, Endocrine Society, ECTS, NOF and IOF. Joint guidance on vitamin D in the era of COVID-19 from the ASBMR, AACE, Endocrine Society, ECTS, NOF, and IOF, 2020, https://www.endocrine.org/news-and-advocacy/news-room/2020/joint-guidance-on-vitamin-d

235.

Desai

Dirajlal-Fargo

Durieux

, et al. Vitamin K & D deficiencies are independently associated with COVID-19 disease severity. Open Forum Infect Dis 2021; 8: ofab408.

236.

Ferrari

Ahn-Luong

Garnero

, et al. Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women. J Clin Endocrinol Metab 2003; 88: 255–259.

237.

Visser

MPJ

Dofferhoff

ASM

van den Ouweland

JMW

, et al. Effects of vitamin D and K on interleukin-6 in COVID-19. Front Nutr 2022; 8: 761191. Erratum in: Front Nutr 2022; 9: 868324.

238.

Louca

Murray

Klaser

, et al. Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 symptom study app. BMJ Nutr Prev Health 2021; 4: 149–157.

239.

Ozdemir

Saruhan

Benli

, et al. Comparison of trace element (selenium, iron), electrolyte (calcium, sodium), and physical activity levels in COVID-19 patients before and after the treatment. J Trace Elem Med Biol 2022; 73: 127015.

240.

Du Laing

Petrovic

Lachat

, et al. Course and survival of COVID-19 patients with comorbidities in relation to the trace element status at hospital admission. Nutrients 2021; 13: 3304.

241.

Dharmalingam

Birdi

Tomo

, et al. Trace elements as immunoregulators in SARS-CoV-2 and other viral infections. Indian J Clin Biochem 2021; 36: 416–426.

Bone fragility during the COVID-19 pandemic: the role of macro- and micronutrients

Abstract

Keywords

Background

Bone fragility and nutrition: what does it matter?

Macronutrients and micronutrients

Micronutrients and trace elements

Risks of the overintake of micronutrients

Bone damage due to the COVID-19 pandemic

Bone damage due to SARS-CoV-2 infection

Nutritional issues during the COVID-19 pandemic and their consequences on bone health

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References