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Osteoporosis in children: Possible risk factors and role of antioxidants
2 Department of Family and Community Medicine, Faculty of Medicine, King Khalid University, Abha, Saudi Arabia
3 College of Medicine, Taibah University, Almadinah Almunawwarah, Saudi Arabia
Salah A Sheweita
Department of Clinical Biochemistry, Faculty of Medicine, King Khalid University, Abha
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Sheweita SA, Al Samghan AS, Khoshhal OK. Osteoporosis in children: Possible risk factors and role of antioxidants. J Musculoskelet Surg Res 2019;3:319-325
AbstractOsteoporosis is well recognized in children as a consequence of several factors. Therefore, the present review sheds light on the role of diabetes mellitus (DM), malabsorption, glucocorticoids, nutrition, free radicals, and oxidative stress in the induction of osteoporosis. It may also provide valuable information regarding the early detection of osteoporosis to improve not only the bone health of schoolchildren but also their general quality of life. Measurement of bone mineral density (BMD) does not capture all the risk factors of bone fractures and/or osteoporosis. Therefore, bone resorption and formation markers such as osteoprotegerin; prolidase; osteocalcin; bone alkaline phosphatase and Vitamin D; parathyroid hormones; and macroelements such as calcium, phosphorus, and magnesium should be measured beside BMD in the plasma of school-aged children. Moreover, endocrine abnormalities, high levels of free radicals, and induction of oxidative stress showed an adverse effect on the skeleton and cause osteoporosis. It has been found that there is a strong correlation between osteoporosis and DM, malnutrition, and glucocorticoids in both pediatric and adult patients. Inhibition of antioxidant enzyme activities, such as superoxide dismutase, catalase, and glutathione peroxidase, was found to increase the production of reactive oxygen species by osteoclasts. Therefore, oxidative stress and other factors are important mediators of bone loss and also osteoporosis. Furthermore, antioxidants should be provided to maintain bone integrity because a deficiency of antioxidant vitamins has been found in the osteoporotic children.
Approximately 200 million people in the world are threatened with osteoporosis, and therefore, it has become a health problem globally., Osteoporosis is a silent disease because no asymptomatic signs are observed until a fracture occurs. The main characteristics of osteoporosis include systemic skeletal disorders, which are associated with low bone mass and micro-architectural deterioration of bone tissues, leading to an increase in bone fragility and susceptibility to fracture. However, assessment of bone mineral density (BMD) alone in the absence of any fractures in adults is used to detect osteoporosis. Several epidemiological studies have demonstrated a link between the measurements of bone density at the spine, hips, and wrists, with a subsequent risk of fractures using dual-energy X-ray absorptiometry (DEXA). However, in children, on the basis of the measurements of bone density alone, it is not possible to define osteoporosis. Several previous studies have shown the relationship and the differences between bone density in both healthy children and those with bone fractures., Currently, the reasons of association between the fracture risk and bone density are unknown in children with chronic diseases, and therefore, it is not possible to define the level of bone density below which the fracture risk increases. An additional reason is that body size was found to affect the bone density measurements in children using DEXA scans because there is a strong correlation between areal bone density and bone size. This was illustrated in the study by Gafni and Baron where up to 50% of children had received an inappropriate diagnosis of osteoporosis.
Bone resorption markers
The extracellular matrix of bones is degraded by osteoclasts and released into the circulation. Therefore, measurable concentrations of collagen degradation products in both serum and urine are used as indicators of bone resorption. These indicators include cross-linked carboxyterminal-telopeptide and cross-linked aminoterminal-telopeptide, as well as free pyridinolines and deoxypyridinolines. In addition, acid phosphatase isoenzyme called tartrate-resistant acid phosphatase (TRAP) is produced by osteoclasts. However, the measurement of total TRAP activity can be influenced by various circulating inhibitors because it is originating from both platelets and erythrocytes. In addition, assay of the kinetic activity of the desialylated isoenzyme (type-5b TRAP) which is present only in osteoclasts has been described, because the increased activity has been associated with bone resorption as observed in conditions of hemodialysis, end-stage renal failure, bone disease, and metastatic bone disease., In addition, there are also markers of osteoblastic activity such as osteocalcin levels and bone-specific alkaline phosphatase (ALP) activity which increase after bone fractures. It has been found that the assay of markers of collagen production could indicate the status of bone health at the fracture sites.
The evaluation of bone turnover markers in various metabolic bone diseases as observed in diabetes mellitus (DM) has been improved through the development of biochemical markers which are specific and sensitive in reflecting the overall rate of bone metabolism.,
Predisposing factors of osteoporosis
There are several etiological factors that adversely affect the bone development of a child with a chronic condition. These factors can act either singly or in combination and increase the development of osteoporosis.
In fact, 374 million people all over the world are suffering from diabetic complications., Like osteoporosis, DM is a pandemic and a chronic metabolic disorder that adversely affects bones, nerves, muscles, eyes, and kidneys. Several studies have shown that type 1 DM (T1DM) had increased rates of bone fractures and osteoporosis, in both children, and adults. Several researchers have described different mechanisms that show how DM induces osteoporosis and bone fractures through multiple pathways.,
Supporting these findings, in our previous study, it has been found that levels of both osteocalcin and N-terminal propeptide of type I procollagen (P1NP) were much lower in the serum of diabetic children than that of nondiabetic controls. In agreement with our finding, it has been found that the serum levels of P1NP were lower in diabetic osteopenic patients, which indicated poor bone formation. P1NP has several advantages due to its stability in serum at room temperature and has also been recommended to be used as a stable marker due to its low interindividual variability., Moreover, it has been used as a preliminary biomarker on the effectiveness of a given drug on bone formation.
Bone marrow-derived endothelial progenitor cells (EPCs) play a significant role in bone healing., Bone formation at the fracture sites in DM patients decreases due to the downregulation of the expression of EPCs.,, DM is also responsible for the decrease in the rate of blood flow to the bone due to the deposition of lipid in the bone marrow, thereby leading to the expansion of the marrow cavity. The reduction of osteoblasts available for bone formation might be due to the transformation of osteoblasts to adipocytes., It has been found that advanced glycation end product expression was induced in DM, and this protein has a significant role in bone rigidity., Other osteoporotic factors such as amylin and preptin were also secreted by pancreatic β-cells which could induce bone formation and reduce both bone resorption and apoptosis of osteoblasts. Osteogenesis has been regulated by osteocalcin which is diminished in DM, which consequently leads to the decrease of insulin, amylin, and preptin synthesis.
Celiac disease (CD) and inflammatory bowel disease (IBD) symptoms are varied, and metabolic bone disease is not well recognized among all extradigestive manifestations. Both diseases are associated with osteoporosis, osteopenia, and osteomalacia. The most common causes of malabsorption among gastrointestinal diseases are mainly due to CD and IBD. In contrast to osteoporosis, which occurs in postmenopausal women, patients with CD and IBDs are much younger, and are prone to develop vertebral fractures. Impaired absorption of nutrients such as calcium and Vitamin D and the use of glucocorticoids in the treatment of IBD are the main pathophysiologic factors specific to gastrointestinal diseases. Hyperparathyroidism is associated with increased bone remodeling and results from CD. Therefore, children with CD may be at risk of bone fractures. A gluten-free diet is known to improve BMD, but it cannot normalize bone mass in all patients. Therefore, CD patients should be screened for low BMD, and appropriate follow-up and management of bone disease should be made based on BMD and fracture risk., IBD has been recognized in both the United States (1.4 million) and Europe (2.2 million people). It has been found that osteomalacia and Vitamin D deficiency are not the main causes of diminished BMD in IBD.
The normal growth and development of bones are mainly dependent on adequate nutrition. Recently, it has been found that antioxidant vitamins play a significant role in the healing of bone fractures. It is not surprising; therefore, nutritional and low-body-weight disorders could lead to osteoporosis., Various etiological factors including Vitamin D and protein intake, low body weight, low calcium, gonadal deficiency, growth hormone resistance, and malabsorption are found to play a significant role in the induction of osteoporosis because calcium and Vitamin D are essential for skeletal mineralization. In healthy adults, it has been found that calcium supplementation causes short-term gains in BMD. It is not well known whether such gains are sustainable and could improve peak bone mass or most importantly increase bone strength. Both healthy and ill children should receive calcium as recommended daily doses. Similar to the case of chronically ill children, children living in sunny climates can become Vitamin D deficient without adequate sun exposure. Therefore, the level of Vitamin D in chronically ill children should be evaluated and supplemented at 400 IU/day.
Growing evidences show that nutritional imbalance and endocrine abnormalities could be involved in the pathogenesis of osteoarthrosis (OA) and osteochondritis dissecans (OCD)., Therefore, it has been found that dietary programs play an important role in the management of these disorders. Vitamins (particularly Vitamin C) and essential trace elements (zinc, magnesium, and copper) are critically important for articular cartilage. Therefore, nutraceuticals used with nonsteroidal anti-inflammatory drugs may be beneficial for patients with joint disorders including OA and OCD.
The metabolites of essential fatty acids (EFAs) such as γ-linolenic acid (GLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid show a beneficial effect in the prevention of osteoporosis., Nephrocalcinosis in animals can be prevented by fish oil (FO) by reducing the excretion of calcium in urine. In addition, it has been found that diet rich in saturated fat interferes with calcium absorption. Maintaining higher BMD was found after feeding of mouse for a long term with FO. These improvements in BMD might be due to the induction of antioxidant enzyme activities, decreased expression of receptor activator of nuclear factor kappa-B ligand (RANKL), and increased expression of osteoprotegerin (OPG) in FO-fed mouse. These effects on BMD suggested that FO is important to prevent BMD loss in patients with rheumatoid arthritis.
Severe osteoporosis and increased renal and arterial calcification were found in EFA-deficient animals, which is similar to those occurred in elderly people. Enhanced calcium absorption and bone calcium content were found after the administration of a combination of GLA and EPA. The mechanism of the prevention of osteoporosis by GLA and EPA might be due to the inhibition of pro-inflammatory cytokines such as interleukin (IL) IL-1, IL-2, and tumor necrosis factor (TNF) TNF-α, which have a significant role in osteoporosis.
Several chronic inflammatory conditions have been found to be associated with osteoporotic children with juvenile idiopathic arthritis, systemic lupus erythematosus, and Crohn's disease. It has been found that suppression of osteoblast recruitment and stimulation of osteoclastogenesis occur by increased circulating levels of cytokines such as IL-1A, IL-6, IL-7, TNF-α, and TNF-β. This increment in IL was found to cause an imbalance in bone turnover, leading to osteoporosis. It has been shown that activated T-cells produce higher levels of TNF-α in children with Crohn's disease than those from controls. Glucocorticoids have been used for the treatment of these conditions. Such treatments with glucocorticoids make it difficult to distinguish the impact of the inflammatory condition on bone integrity because osteoporotic fractures can occur in the absence of the use of glucocorticoids. In addition, inflammatory cytokines show an adverse effect on the skeletal muscles, which could compromise the mechanical loading on the skeleton and consequently impact on bone metabolism. Identified significant defects in lean body mass was found in adults and also in children with Crohn's disease. Increases in bone density and levels of bone formation markers have been observed after treatment of patients with Crohn's disease and also treated with infliximab.
Bone fractures are the most serious common adverse events related to the long-term use of glucocorticoids which are used for many medical treatments. It has been found that osteoporosis develops in a time- and dose-dependent manner of glucocorticoid treatment which is slightly induced at low doses, but at higher doses markedly increased risk of bone fractures. Because of potent anti-inflammatory actions of glucocorticoids, they are used in many chronic childhood conditions. However, glucocorticoids have various effects on calcium and bone metabolism. In addition, glucocorticoids show a direct effect on osteoblasts and cause a reduction in bone formation, an inhibition of OPG leading to increased bone resorption by stimulating osteoclastogenesis. It has been found that glucocorticoids reduce calcium absorption by intestines and also increase renal tubular calcium excretion. The vertebral fractures were associated with children with juvenile idiopathic arthritis received 0.62 mg/kg per day of prednisolone. In addition, it has been found that children receiving four or more courses of systemic steroids have an increased incidence of bone fracture. However, Leonard et al. demonstrated that bone mineral content of the lumbar spine and whole body was not different from that of controls.
The toxic effect of glucocorticoids on osteoblasts might be due to their bond to the promoter region of response elements, ultimately leading to altered protein synthesis and regulation. Hormonally active glucocorticoids can be converted into inactive hormone forms by 11 β-hydroxysteroid dehydrogenase; therefore, polymorphism of the gene of this enzyme may explain the susceptibility to glucocorticoid toxicity. The deleterious effect of glucocorticoids on bone formation might be due to change in the expression of gamma receptor 2 (PPARγ2) and also might be due to the inhibition of signaling pathway of the canonical Wnt/β catenin. Decreased production of osteoblasts and ultimately less bone formation after exposure to glucocorticoids could be due to the enhanced expression of Wnt antagonists, sclerostin, and Dickkopf-related protein 1. Glucocorticoids increase the production of RANKL and decrease the production of OPG, resulting in enhanced bone resorption.
Reactive oxygen species and bone integrity
Reactive oxygen species (ROS) have an important role in bone metabolism because they have a dual effect including physiological and pathological conditions., Under physiological conditions, ROS assists in accelerating the destruction of calcified tissue and hence assists in bone remodeling., Increased bone resorption through the activation of nuclear factor-κB (NF-κB) has been found due to high levels of free radicals. It has been found that oxidative stress has adverse effects on bones; therefore, insufficient dietary intake of antioxidant Vitamins (E and C) may substantially increase the risk of hip fracture. Moreover, NADPH oxidase capable of cytokine-regulated generation of ROS is also present in osteoclasts.,,
A remarkably high yield of free radicals is possible when bone fractures occur. However, many skeletal pathologies are linked to enhanced osteoclastic activity and increased production of ROS. It is suggested that increased ROS production overwhelms the antioxidant defenses, subjecting the individual to hyperoxidant stress. There are many complex steps of calcified tissue destruction by osteoclasts. It has been found that osteoclasts could accelerate the destruction of calcified tissue and assist in bone remodeling under controlled production of free radicals. Increased production of ROS, which is evident by increased levels of serum malondialdehyde (MDA) levels, was found to be mainly due to enhanced osteoclastic activity that is observed in bone disorders. Lipid peroxidation is one of the most damaging effects of ROS, and MDA is its end product. In addition, MDA serves as an index of lipid peroxidation and also serves as a measure of osteoclastic activity. Superoxide dismutase and glutathione peroxidase (GSH-PX) activities are one of the defense mechanisms against free radicals that could reduce the antioxidants capacity in the body, and consequently increased superoxide production by the osteoclasts.
Role of antioxidants
It has been found that generation of high levels of free radicals could cause several diseases. It has been found that free radical scavengers have a great role in the amelioration of diseases. For example, polyphenols, which are one of the free radical scavengers, play a significant role in the prevention of cardiovascular diseases, cancers, neurodegenerative diseases, diabetes, or osteoporosis in both animals and human cell lines. 2,6-diisopropylphenol, similar to alpha-tocopherol, has been used for the induction and maintenance of anesthesia and has shown antioxidant effects. Therefore, it has been found that 2,6-diisopropylphenol protects osteoblasts from sodium nitroprusside- and hydrogen peroxide-induced cell damage. Moreover, ascorbic acid (AA) plays a key role in the regulation of differentiation and activation of osteoclasts through the inhibition of RANKL-induced differentiation of osteoclasts (OCL) precursor cells into mature OCL and reduces the formation of bone resorption pits in vitro. In addition, differentiation of embryonic stem cells into osteoblasts has been induced by AA. The mechanisms by which AA induced the differentiation of embryonic stem cells included synthesis of collagen type I, interaction with alpha2- and beta1-integrins, activation of the mitogen-activated protein kinase pathway, and phosphorylation of osteoblast-specific transcription factors. By using DNA microarrays, it has been found that several genes cover a broad range of functional activities, including cell growth, metabolism, morphogenesis, cell death, and cell communication at early-stage stimulation of preosteoblasts by AA in MC3T3-E1 cultured with AA for 24 h. Elucidation of the molecular mechanism of AA may facilitate the clinical implications of AA to accelerate bone regeneration.
Oxidative stress is an important mediator of bone loss because TNF-α, which increases as a result of oxidative stress, was found to play a critical role in bone loss after menopause. In HS-5 hBMSC, TNF-α and H2O2 increase intracellular ROS levels and induce cell apoptosis through the activation of caspases, JNK, and NF-κB. Alpha-lipoic acid, an antioxidant, prevents the induction of ROS2, suggesting its potential therapeutic action in preventing bone loss.,
Reduction in oxidative stress, inhibition of inflammatory cytokine activation, and NF-κB DNA-binding activity were found after the treatment of mice with alpha-lipoic acid. Moreover, inhibition of bone destructionin vivo and osteoclastogenesisin vitro have been seen after treatment with alpha-lipoic acid. The risk of osteoporosis is associated with oxidative stress induced by ROS, and can be reduced by certain dietary antioxidants. Lycopene is an antioxidant known to decrease the risk of osteoporosis through the reduction of oxidative stress and also the levels of bone turnover markers, and may be beneficial in osteoporosis treatment. Markers of oxidative stress including reduced glutathione (GSH), oxidized glutathione (GSSG), and MDA were found in loose and stable hips revised for high rate of wear and osteolysis. Collagen in periprosthetic tissues measured as hydroxyproline content was correlated with MDA, GSH, and GSSG levels. This study provided a new evidence regarding the role of MDA in the destruction of collagen through releasing of hydroxyproline.
Elderly osteoporotic patients have common subclinical vitamin deficiency. Administration of vitamins has been found to treat and prevent osteoporosis in these patients., Bone health and muscle strength in the elderly require higher Vitamin D intake and more sun exposure to keep them in a good condition. The risk of bone fractures in osteoporosis are also linked to the deficiency of Vitamins K, C, or B., Therefore, a diet rich in fruit and vegetables along with fish could fulfill a balance among these vitamins and should be recommended for prevention and/or treatment of osteoporosis.
Oxidative stress in various experimental models could be alleviated after administration of antioxidant vitamins and/or radical scavengers. Furthermore, melatonin can enhance osteogenesis in the case of an individual with a head injury because osteoblastic activity raises up with increased melatonin levels. Melatonin might cause early bone healing and hypertrophic callus, and healing of a fracture of long bone can be accelerated in patients with severe traumatic brain injury after melatonin therapy. Flavones, in contrast to soybean isoflavones, are the most abundant phytoestrogens in Western diets, being present in onions, beans, fruits, red wine, and tea. Quercetin is the most widely distributed type of flavonols, which occurs mainly as glycoside and rutin, but the published data are very scarce regarding the precise mechanism of action of quercetin on bone-resorbing cells. Estrogen receptor (ER)-alpha (ER-alpha), ER-beta, and RANK proteins are present in osteoclasts and osteoclast progenitors. Flavones increase nuclear ER-beta protein and decrease ER-alpha protein of osteoclast progenitors. Moreover, rutin reduces RANK protein, whereas 17 beta-estradiol and quercetin promote apoptosis by cleavage of caspase-8 and caspase-3. Flavones exert the antiresorbing properties of ER proteins through the inhibition of RANK protein or the activation of caspases. In our previous studies, we had found that antioxidants could protect organs against the toxicity of toxic compounds and also improved male infertility.,,,
It is concluded from this review that increased free radical production overwhelms the natural antioxidant defense mechanisms, subjecting individuals to hyperoxidant stress and thus leading to osteoporosis. In addition, administration of antioxidants might protect bones from osteoporosis and also might help in the acceleration of healing of fractured bones.
Unexplained fractures in children or fractures after minor trauma call for an investigation to rule out underlying bone disease, including osteoporosis.
Many different factors could induce and enhance osteoporosis in children. To avoid such a disease at an early stage, it is advisable to check and screen for osteoporosis using biomarkers including OPG, prolidase, bone ALP, osteocalcin, Vitamin D, and parathyroid hormone in susceptible children.
It is recommended that children whom are at risk of osteoporosis at an early stage should receive Vitamin D and antioxidant vitamins. Moreover, children with osteoporotic fractures need supplements to enhance fracture healing.
This article does not contain any study with human participants or animals performed by any of the authors.
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Conflicts of interest
There are no conflicts of interest.
SAS suggested the idea and concept of the review article and shared in writing the text. ASA shared in writing the text. OKK shared in writing the text and the concept of the review article. All authors have critically reviewed and approved the final draft and are responsible for the content and similarity index of the manuscript.
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