Eating disorders

Eating disorders are driven behavioral disorders resulting in significant functional impairment and, in extreme cases, death.

Three major categories of eating disorders: anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS).

Binge-eating disorder (BED) is usually accompanied by obesity and is subsumed under the EDNOS category. BED is currently under consideration as a distinct eating disorder in DSM-V and has become the focus of significant clinical and scientific attention.

Unlike BED, AN and BN are perhaps better thought of as “dieting disorders”. Both are characterized by an overvalued fear of fatness that drives a set of disturbed behaviors, including restricting food intake, binge eating, excessive exercise, self-induced vomiting, and abuse of laxatives, diuretics, and diet pills. Engagement in these behaviors, coupled with the physiologic consequences of starvation and/or the binge-purge-restrict cycle, sustains and heightens food preoccupation and body image disturbance.

BN is a dieting disorder characterized by episodes of binge eating followed by compensatory behaviors aimed at preventing weight gain. Binge eating is defined as consumption of an amount of food definitely larger than most people would eat in a similar period, under similar circumstances, and is associated with a sense of loss of control over eating. Typical binge foods are high-fat, high- calorie, “forbidden” foods, and amounts consumed are 1000 to 2000 calories or more per binge. Between binges, bulimic individuals typically restrict intake and only consume “safe,” low-calorie, low-fat foods. Other compensatory behaviors following a binge can include purging, vomiting, abuse of laxatives or diuretics, or excessive exercise. As in AN, dieting and preoccupation with thinness develop into a consuming passion that is difficult to interrupt and impairs psychologic and social function. The distinction between AN-P and BN is primarily one of weight. Individuals who binge and purge but are less than 85% of ideal body weight or a body mass index (BMI) of about 17.5 and are amenorrheic are given the diagnosis of AN-P, whereas those who are less underweight, or are normal weight or overweight, are given the diagnosis of BN. The two subtypes of BN are purging (BN-P) and nonpurging (BN-NP). Individuals with BN-NP do not self-induce vomiting or abuse laxatives or diuretics; rather, they alternate episodes of binge eating with fasting or excessive  exercise to avoid weight gain.

Eating Disorder Not Otherwise Specified (EDNOS) is a heterogeneous diagnostic category. It includes partial-syndrome cases of AN and BN, BED, and atypical eating disorders. For partial-syndrome AN or BN, the diagnosis of EDNOS does not imply minor clinical significance. Indeed, these cases may be associated with morbidity equal to or greater than full-syndrome cases of AN or BN. An example would be an individual whose baseline weight was obese and who developed intense fear of fatness and extreme dieting behaviors, rapidly losing more than 40% of his or her body weight yet failing to meet the underweight criterion for AN or the binge frequency criterion for BN.

BED is defined as regular binge eating, twice a week or more, associated with a subjective sense of loss of control over eating but lacking the compensatory behaviors typical of BN. BED differs from BN in several additional ways. Individuals with BN restrict their food choices and calorie intake when not bingeing yet often are more impulsive and consume more calories during binges than do individuals with BED. Patients with BED overeat more consistently throughout the day than do patients with BN and are more likely to be overweight or obese.

Examples of atypical eating disorders include globus hystericus, or fear of swallowing, resulting in severe weight loss and functional impairment, and psychogenic vomiting syndromes. In some cases, these may be factitious disorders, conditions in which the behavior persists in part because the sick role has become rewarding to the affected individual.

Research has identified several personality traits associated with eating disorders including elevated harm avoidance, neurotic personality features, and low self-esteem. Perfectionism, conscientiousness, persistence, and obsessive qualities are often discriminating features of AN, whereas elevated impulsivity, novelty seeking, negative emotionality, stress reactivity, and personality traits associated with antisocial, borderline, histrionic, and narcissistic personality disorders are more commonly associated with BN.

Eating disorders are significantly more prevalent in menstruating girls and women than in prepubertal girls, a finding implicating a role for ovarian hormones and sexual development in the activation of disordered eating. Perception of being overweight prepubertally and early-onset menarche have emerged as specific aspects of puberty that may increase eating disorder vulnerability. Early-maturing girls have higher adiposity before menarche, are more dissatisfied with their bodies, and are more likely to engage in weight-loss efforts than girls who go through puberty on time or later in life. Environmental changes associated with the transition to college, including high levels of stress, performance and achievement demands, and role and identity changes, are factors significantly related to disordered eating and may make this developmental milestone one that places late adolescents at risk of developing eating disorders. Past trauma, namely, childhood sexual abuse, may heighten the risk of developing eating disorders; however, early sexual abuse has been associated with other psychiatric conditions, thus making it difficult to determine whether a direct link between eating disorders and childhood sexual abuse exists or whether early sexual abuse and mental health are more broadly linked.

Slender female models and images (e.g., cartoons, computer graphics) saturate the Western mass media. Internalization, or acceptance, of these societal standards of thinness may lead to low self-esteem, negative affect, dieting, and/or eating disorders in girls and women. Experimental studies have consistently shown that girls and women exposed to media images of thinness experience greater body dissatisfaction in comparison with those exposed to heavier or neutral images. The negative effect of these images is heightened when girls and women viewing slender images have already internalized thin beauty ideals or have high baseline levels of body image disturbance.

Parents are the most dominant sociocultural factor affecting young children, and parents’ direct comments about their child’s weight, particularly comments of mothers, have been identified as the most consistent factor associated with children’s concerns and behaviors related to weight and shape. Familial dynamics are also important predisposing factors in eating disorders. Girls who eat alone, who have parents who are not married, or who perceive their family communication, parental caring, and parental expectations as low are at increased risk of disordered eating.

Eating is a highly social activity, and eating disorders inevitably impair interpersonal function. Affected individuals become socially isolated in an attempt to hide or avoid confrontation regarding their food choices or amounts eaten and spend increasing time engaged in eating rituals and exercise routines that take precedence over ageappropriate social engagements. Formation of intimate relationships and sexual function are often impaired by starvation’s effect on libido and heightened body image concerns. Because they primarily affect young women and girls, AN and BN often result in the interruption of normal developmental tasks including separation- individuation from parents, identity formation, and the development of meaningful peer relationships.

Individuals with eating disorders describe a consuming and constant preoccupation with food and weight that occupies much of their waking time and worsens with starvation. Furthermore, starvation results in a syndrome characterized by low mood, apathy, anhedonia, and decreased concentration and energy that is indistinguishable from major depression but reverses within days or weeks of refeeding. Besides starvation-related increases in obsessional preoccupation with food and weight and depressive symptoms, family studies have confirmed increased rates of affective disorders, alcohol abuse, and anxiety disorders in first-degree relatives of individuals with AN and BN. This finding suggests that comorbid psychiatric conditions are common and may complicate the treatment course unless they are addressed in parallel with the eating disorder. Finally, demoralization and loss of self-esteem often accompany patients’ attempts to control their behaviors and the realization that these behaviors have impaired their functioning.

Malnutrition and starvation in AN are associated with numerous physical signs and symptoms. Patients often appear emaciated, with muscle wasting and weakness on examination, and may develop lanugo, the growth of fine, diffuse body hair. Physiologic responses to selfstarvation are aimed at conserving energy and include bradycardia, hypotension, hypothermia, and interruption of the hypothalamic-pituitary-ovarian axis. Estrogen, follicle-stimulating hormone, and luteinizing hormone revert to prepubertal levels, as a result of disturbances in gonadotropin-releasing hormone pulsatility, resulting in amenorrhea and infertility. In prepubertal patients, normal secondary sexual characteristics, such as breast development and height, may be halted by malnutrition.  Patients frequently complain of cold intolerance, fatigue, and gastrointestinal symptoms, including bloating, early satiety, and constipation. Starvation also results in delayed gastric emptying, delayed gastrointestinal transit times, and constipation. Anemia is common, and pancytopenia and bone marrow suppression can occur in severely malnourished patients. Osteoporosis is a largely irreversible consequence of AN, occurring relatively early in the course of the disorder; most affected girls and women develop significant decreases in bone density within a year of onset, and osteoporosis  also can be a complication for boys and men with AN.

Osteoporosis results in elevated fracture risk, and patients with chronic AN are at risk of debilitating hip fractures and spinal compression fractures. Finally, hypoglycemia is common in starvation; and depleted glycogen stores in AN complicate serum glucose regulation. Chronic hypoglycemia also may underlie some of the neuroendocrine disruptions observed in this condition. Disturbances in glucose counter regulatory hormones in AN include alterations in growth hormone, cortisol, and catecholamines. These changes may in turn contribute to the maintenance of anorectic behaviors and cognitions.

AN and BN are behavioral disorders and, like addictions, once established, tend to take on a life of their own. Although certain stressors and risk factors are associated with their onset, disordered eating patterns eventually sustain themselves. Initial treatment goals include normalizing eating patterns and restoring weight in underweight patients by using behavioral psychotherapeutic interventions. Starvation perpetuates a preoccupation with food, and weight restoration is well established as necessary, if not sufficient, for recovery from AN. Similarly, in BN, repeated engagement in the restrict-binge-purge cycle exacerbates symptomatic preoccupations with weight and shape and the drive to diet. Psychotherapy aimed at elucidating underlying individual vulnerabilities to these disorders may provide a meaningful narrative to patients to help them understand the development of their disorder, but it is unlikely to bring about behavioral change.

Patients with AN or BN tend to be ambivalent about treatment because they experience their dieting behaviors as rewarding and do not want to stop them. Successful treatment can be seen as requiring a cognitive shift or conversion, from viewing dieting as a solution to seeing it as the primary impairment to healthy function.

In the case of both AN and BN, education about normal eating should include instruction on scheduling three regular meals a day, eating normal portion sizes, expanding food repertoire (which is often very narrow), and avoiding diet foods. Patients should be encouraged to consume all foods in moderation and in normal combinations and to avoid fat-free or sugar-free diet products. An exception to the latter may be the case for patients with BED or BN who are overweight. These patients are likely to benefit from additional guidance on eating fewer high-calorie, high-fat foods; introducing more fruits, vegetables, and whole-grain unprocessed foods; increasing the water density of foods consumed; and engaging in a regular exercise program as well as decreasing sedentary activities, such as watching television. Vegetarianism that develops after the onset of dieting behavior is common in both AN and BN and should be discouraged because it is often used to disguise dieting. Careful questioning usually reveals that preferred vegetarian foods are limited to those low in calories.

Persistent encouragement, persuasion, and guidance to change dietary patterns usually are necessary to achieve behavior change in this population. Gastrointestinal symptoms and complaints of nausea, heartburn, abdominal pain, gas, and constipation are common during the early stages of refeeding.

AN is characterized by refusal to eat rather than by inability to eat or a nonfunctional gastrointestinal tract. Therefore, oral feeding is the safest method of weight restoration from both a physiologic standpoint and because this disorder is marked by narrowing of the food repertoire  and conditioned avoidance of high-calorie density foods.

Although significant changes in body weight are commonly associated with eating disorders, it is not uncommon for individuals who are clinically depressed to lose or gain weight. Major depression is characterized by depressed mood and diminished interest in pleasurable activities accompanied by changes in sleep patterns, difficulty concentrating, loss of libido, lack of energy, feelings of worthlessness or guilt, thoughts of death or suicide, and a disturbance in appetite. Children who are depressed often present as irritable, instead of sad and tearful, and may fail to gain weight as expected.

In contrast to eating disorders, changes in appetite that occur during depressive episodes are not driven by fear of fatness and obsession with dieting and food. Rather, depressed individuals frequently report that they have lost interest in eating and tend to identify their weight loss as a problem. These individuals are less likely to become distressed over the thought or reality of resuming normal eating and may even express a desire to do so. Furthermore, their eating pattern does not reflect the restriction of fats, sweets, and high-calorie foods that is typical of AN. Rather, they just eat less and describe losing a taste for food. Eating patterns in this population also may reflect decreased consumption of fish, fruits, and vegetables possibly because of decreased motivation to cook or prepare foods.

Schizophrenia is a psychotic disorder often characterized by delusions, hallucinations, disorganized speech and behaviors, and affective flattening. Individuals frequently become paranoid in response to delusional thoughts, which are erroneous, often bizarre, perceptions of reality that are strongly held, even in the presence of clear contradictory evidence. Although the content of delusions may include a variety of themes, they sometimes involve food or eating. An example of a delusion  involving food or eating includes a person’s belief that his or her food is contaminated or that he or she is being watched while eating. Such paranoid thinking often results in refusal to eat and, in turn, significant weight loss. Psychiatric management, which includes antipsychotic medication, supportive psychotherapy, and family-based interventions, is commonly recommended for individuals exhibiting delusional and other psychotic symptoms. Cessation of delusional thinking is often necessary for behaviors, such as eating and self-care, to improve.

Substance use disorders also can affect weight and eating. The effect of different substances on food intake varies depending on substance class and level of use. Substance dependence is characterized by tolerance, withdrawal, extensive and persistent use, functional impairment, and continued use in the presence of physical and psychologic consequences. Substance abuse lacks the tolerance and withdrawal that characterize substance dependence, but includes significant adverse and harmful substance–related consequences, such as legal problems or failure to meet social obligations. Substance intoxication is a more acute reversible psychologic and behavioral reaction to a substance and does not necessarily imply frequent and persistent use. Marijuana use is associated with increased appetite and food intake, and symptoms of cannabis withdrawal include increased irritability, depression, and decreased food intake. Alcoholism is associated with abnormal consummatory behaviors and susceptibility to overweight, obesity, and eating disorders. Patients with severe alcoholism may eat sporadically and obtain most of their caloric intake from alcohol, resulting in nutritional deficiencies, including risk of Wernicke-Korsakoff syndrome from inadequate thiamin intake. Whereas obesity is prevalent among individuals with a history of significant alcohol consumption, overweight is uncommon in the advanced stages of alcoholism, during which multiple, often irreversible, organ dysfunction is accompanied by severe illness, weight loss, and malnutrition. Cocaine and other amphetamines stimulate the central nervous system and usually decrease appetite and food intake, resulting in weight loss, which can be severe at times. Occasionally, individuals with an eating disorder may abuse these substances to lose weight.

Attention Deficit Hyperactivity Disorder - with a prevalence of 2% to 18%, attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric conditions seen in childhood. The cause of ADHD is presumed to be multifactorial, with contributions from both genes and environment. One environmental factor that may play a role in the onset or maintenance of ADHD is diet.

Increased consumption of processed food may worsen ADHD symptoms in some children not only because of the increased intake of food additives but also because of associated nutritional deficiencies associated with a Western diet high in processed foods. Several studies have found omega-3 deficiencies in children with ADHD.

Nutrition and nervous system

Brain function is unavoidably dependent on a constant dietary supply of appropriate nutrients.

The effects of malnutrition on the nervous system may range from isolated involvement of the peripheral nervous system that produces blindness, deafness, paralysis, or sensory deficits to complex lesions of the spinal cord and central nervous system (CNS) that lead to mental retardation, cognitive dysfunction, and gait limitations.

A rampant form of malnutrition peculiar to developed nations is obesity, frequently accompanied by metabolic syndrome, hypertension, and diabetes that may manifest with secondary neurologic signs and symptoms as a result of stroke, obstructive sleep apnea, and peripheral neuropathy.

A constant dietary supply of appropriate nutrients including glucose, amino acids, fatty acids, vitamins, and minerals is required for normal brain function. Food is also needed to maintain the integrity of cellular membranes in the brain and the production of neurotransmitters. Although the brain represents only 2% of the body mass, it consumes 20% of the energy provided by the diet and 20% of the oxygen inhaled. Children consume twice more glucose than adults do, and the newborn brain requires 60% of the energy provided by the diet.

Appropriate dietary supply of amino acids is needed to synthesize proteins and neurotransmitters in the nervous system. The quality of dietary proteins influences brain protein formation. Tryptophan, a precursor of serotonin, the neurotransmitter involved in appetite and satiety, sleep, blood pressure, pain sensitivity, and mood, is particularly important because it cannot cross the blood–brain barrier.

From the public health viewpoint, iodine is the most important micronutrient for the prevention of brain disorders causing lower intellectual functioning, psychomotor delay, and mental retardation. Also of major public health importance is the deficiency of other micronutrients capable of affecting the nervous system; these include deficiencies of iron, copper, zinc, and selenium, as well as vitamin B12, folate, and vitamin A.

IDDs occur in areas of the earth where iodine was leached from the soil by the effects of rain, glaciations, and flooding waters. These areas typically include flood plains and mountainous regions such as the Alps, the Balkans, the Andes, the Himalayas, and the New Guinea Highlands. The populations of these regions suffer from high prevalence of endemic cretinism, goiter, short stature, and deafness. The neurologic importance of IDDs resides in the definite risk of fetal brain damage resulting from thyroid hormone deficiency during critical periods of brain development, both in utero and in the early postpartum period.

Endemic cretinism is a congenital disorder of the CNS manifested by deaf-mutism, mental retardation, spastic diplegia, squint, and signs of bulbar damage. Partial manifestations include isolated deafness or deaf-mutism and mental retardation without pyramidal tract signs. In some endemic places (New Guinea, Thailand, Indonesia, the Andes), the usual signs of childhood myxedema (coarse puffy skin, macroglossia,  umbilical hernia, short stature, and skeletal disproportion) occur rarely, whereas these signs predominate in other endemic areas (China, Congo). Therefore, two forms of the syndrome of endemic cretinism are recognized: neurologic and myxedematous.

Numerous staple foods in the tropics contain large amounts of cyanogenic glycosides. These include cassava, yam, sweet potato, corn, millet, bamboo shoots, and beans. Tobacco smoke also contains considerable amounts of cyanide. Hydrolysis of plant glycosides releases cyanide as hydrocyanic acid. Acute intoxication occurs by rapid cyanide absorption through the gastrointestinal tract or the lungs. Detoxification is mainly to thiocyanate in a reaction mediated by a sulfurtransferase (rhodanase) converting thiosulfate into thiocyanate and sulfite. The sulfurcontaining essential amino acids (cystine, cysteine, and methionine) provide the sulfur for these detoxification reactions. Also important is vitamin B12 with conversion of hydroxocobalamin to cyanocobalamin.

Iron is an essential cofactor for numerous proteins involved in neuronal function. Both iron deficiency anemia and excessive iron accumulation in the brain are associated with neurologic disturbances. The brain has limited access to plasma iron because of the blood–brain barrier.

Dietary zinc deficiency is a common nutritional disorder around the world. Zinc treatment of deficient children improves growth, immunity, and motor development in infants and toddlers. Zinc deprivation during periods of rapid growth impairs brain and sexual development.

Copper is an essential cofactor for numerous enzymes such as copper-zinc superoxide dismutase, ceruloplasmin ferroxidase, and cytochrome oxidase. Copper deficiency may result also from total parenteral nutrition (TPN), prior vitamin B12 deficiency, intestinal malabsorption from gastric resection or bariatric surgery, and zinc overload, particularly with use of zinccontaining adhesive denture creams. Copper deficiency may mimic cobalamin deficiency manifesting with anemia from myelodysplasia, spinal cord involvement with subacute combined degeneration (SCD), peripheral neuropathy, optic neuropathy, and periventricular white matter lesions. Oral copper supplementation improves functional activities of daily living in patients with copper deficiency.

The causes of vitamin A deficiency include defective intake of preformed vitamin A (retinyl esters) of animal origin or of fruits and vegetables containing provitamin A carotenoids, altered intestinal absorption such as in intestinal parasitic infections (giardiasis, ascaridiasis, and strongyloidiasis), or, more rarely, abetalipoproteinemia or after biliopancreatic bypass surgery. Raw soybeans contain the enzyme lipoxidase, which oxidizes and destroys carotene.

The main manifestations of vitamin A deficiency occur in the eye, where it is needed for the synthesis of RNA and glycoproteins in cornea and conjunctiva. Clinical manifestations of vitamin A deficiency include night blindness, conjunctival xerosis, Bitot spots, and corneal xerosis that may lead to corneal ulceration and keratomalacia. Vitamin A deficiency also affects metabolic and immune functions, thus worsening morbidity and mortality in children. Vitamin A attenuates the severity of diarrhea and measles.

Excessive intake of vitamin A produces increased intracranial pressure, with irritability, anorexia, confusion, headache, vomiting, lethargy, malaise, abdominal pain, hepatomegaly, and myalgias. Funduscopic examination reveals papilledema, consistent with pseudotumor cerebri in the absence of focal neurologic signs. In addition to pharmaceutical preparations, foods rich in vitamin A include polar bear liver and halibut liver. Excessive vitamin A intake increases the risk of cleft palate, harelip, macroglossia, eye abnormalities, and hydrocephalus. Retinoids are vitamin A derivatives used in dermatology. Isotretinoin (Accutane) increases blood lipids and has substantial teratogenic effects estimated at 15% to 45% of exposures in utero, mainly in the first trimester of pregnancy; risks persist up to 1 month after discontinuation of the drug. Malformations involve the face, the ears, the CNS, and the heart; there is also a 20% to 30% rate of spontaneous abortion.

The main manifestations of thiamin deficiency are a sensorimotor axonal peripheral neuropathy (dry beriberi) and a cardiac form (Shoshin beriberi) also called wet beriberi because of edema secondary to congestive heart failure. Beriberi was major cause of morbidity and mortality in populations depending on polished rice for their staple diet (China, Japan, Indonesia, the Philippines), but it also occurred among poorly nourished children and adults in the Indian subcontinent, the Far East, Africa and tropical South America. In the tropics, beriberi occurs under conditions of low thiamin intake, carbohydrate-rich diets, and high energy expenditure. Thiamin is not stored in the body, and signs of thiamin depletion occur in just 18 days with a thiamindeficient diet or with TPN.

Thiamin is required for energy production in all metabolically active tissues and is found in high concentrations in skeletal muscle, heart, liver, kidneys, and brain. Thiamin serves as a coenzyme for the mitochondrial enzyme complex and transketolase.

Beriberi may manifest as alcoholic ketoacidosis, characterized by increased levels of lactate from the anaerobic glycolysis of pyruvate as a result of the blockage of the oxidative decarboxylation of pyruvate. Unexplained lactic acidosis from thiamin deficiency may also occur in patients in intensive care settings with serious systemic diseases, liver failure, hemodialysis, severe vomiting, gastric malignancy, intestinal obstruction, pyloric stenosis, severe gastritis, after gastrectomy, or receiving TPN with insufficient thiamin.

The typical presentation in patients with alcoholism is high-output cardiac failure with tachycardia and wide pulse pressure. Cardiomegaly, pedal edema, and pulmonary edema are common. Cardiac beriberi may manifest in Western hospitals with intractable cardiac failure, collapsed peripheral circulation, lactic acidosis, and shock. With intravenous thiamin, cardiac failure responds dramatically, with massive diuresis, correction of acidosis, reduction in pulmonary capillary wedge pressure, and hemodynamic normalization.

Wernicke Encephalopathy - This disorder is characterized by acute onset of nystagmus, abducens, and conjugate gaze palsies; gait ataxia; and mental confusion from lesions of nuclei at the level of the third and fourth ventricle and in the periaqueductal gray. The disease may begin with ataxia, followed by nystagmus and confusion. The typical ocular abnormalities are horizontal and vertical nystagmus, bilateral lateral rectus palsy, and weakness of conjugate gaze. Internuclear ophthalmoplegia is common, and patients with advanced cases may exhibit complete ophthalmoplegia. Ataxia is severe, with wide-based stance and slow, hesitant, short-stepped gait; tandem walking may be impossible. Intention tremor is absent. Drowsiness, confusion, apathy, and loss of executive function, attention, and memory occur in the acute stage. The ocular signs and confusion respond rapidly to intravenous thiamin, but the ataxia and memory deficits may fail to improve.

Korsakoff Syndrome - This syndrome is considered a chronic phase of Wernicke encephalopathy. Usually, patients are completely amnesic of events that occurred during the acute phase of the illness. The memory loss affects both new learning (anterograde amnesia) and past memories (retrograde amnesia). The most severe deficits are those of learning and storage of new information. Patients also exhibit executive dysfunction, loss of spatial organization, and problems with visual and verbal abstractions. Korsakoff syndrome is associated not only with memory impairment but also with global and executive deficits indicative of impairment of frontal lobe connections. Interruption of the hippocampomammillothalamic tract at several levels (mammillary bodies, dorsal medial, and anterior thalamic nuclei) explains the severe amnesia. Other behavioral and cognitive deficits result from interruption of the prefrontal corticosubcortical circuits that underlie executive function and attention.

Vitamin B2 (Riboflavin) Deficiency - Ariboflavinosis is associated with nonspecific signs such as angular cheilosis, glossitis (beefy-red tongue), scaling dermatitis, normochromic normocytic anemia, and superficial interstitial keratitis. Recommended treatment is with vitamin B complex that usually contains a mixture of riboflavin, thiamin, niacin, folic acid, vitamin B12, pantothenic acid, and biotin. In the presence of a deficiency syndrome with interstitial keratitis, vitamin A is also recommended.

Niacin Deficiency (Pellagra) - Dermatitis, diarrhea, and dementia characterize the clinical manifestations of pellagra. The dermatitis typically occurs in areas exposed to sunlight, including the neck. The dermatitis of acute pellagra begins as an erythema that resembles sunburn with slow tanning and exacerbation by sunlight. Oral scalding, burning sensations of the tongue, glossitis, anorexia, abdominal pain, and recurrent bouts of diarrhea also occur. The dementia is preceded by insomnia, fatigue, nervousness, irritability, and depression. Suicide by drowning was said to be a common occurrence. The cognitive deficits include confusion, mental dullness, apathy, and memory impairment. Typical neuropathologic lesions of pellagra affect Betz cells in the motor cortex, smaller pyramidal cortical neurons, large neurons of basal ganglia and motor cranial nuclei, dentate nucleus, and anterior horn cells. Affected neurons appear swollen, rounded, with eccentric nuclei and loss of Nissl particles. Some alcoholic patients have similar brain lesions in the absence of overt pellagra. Pellagra neuropathy is indistinguishable from beriberi neuropathy, but it fails to respond to niacin treatment alone, and B-complex vitamin treatment is recommended.

Vitamin B6 (Pyridoxine) - exists in three natural forms, pyridoxol, pyridoxal, and pyridoxamine. Ingested pyridoxol is phosphorylated and then oxidized to pyridoxal phosphate, an important coenzyme in the metabolism of amino acids, including the conversion of _-ketoglutarate to glutamate and of glutamate to GABA. Vitamin B6 deficiency may cause niacin deficiency as a result of impaired tryptophan metabolism. Increased homocysteine responds to pyridoxine, vitamin B12, or folate, depending on the type of depletion.

Pyridoxine is found in virtually all foods, thus making dietary deficiency unlikely, although increased requirements occur in pregnancy and lactation, estrogen use, hyperthyroidism, high-protein diets, and elderly persons. Faulty preparation may destroy pyridoxine in baby formula, with resulting infantile seizures. Infants of mothers deficient in vitamin B6 may also suffer neonatal seizures. The latter two mechanisms of seizure causation are different from pyridoxine dependency, a rare autosomal recessive disorder causing intractable seizures in neonates and infants.

Vitamin B12 (Cobalamin) - Diverse factors may cause cobalamin deficiency including absent dietary supply (vegans), decreased saliva (Sjögren syndrome), antibodies against IF (pernicious anemia), gastrectomy, antacids such as proton pump inhibitors and histamine (H2)-receptor antagonists, gastritis involving parietal cells in gastric fundus, malabsorption syndromes (tropical sprue), the diabetes medication metformin, surgical resection or bypass of distal ileum, competition for vitamin B12 (by bacterial proliferation in the intestine in the blind-loop syndrome, or by intestinal parasitism with the fish tapeworm Diphyllobothrium latum), and rare genetic enzyme deficiencies (methylmalonic aciduria).

Signs of neurologic involvement in vitamin B12 deficiency may occur before the development of megaloblastic anemia and, rarely, with normal serum levels of vitamin B12. More sensitive indicators of neural damage are increases in serum MMA, homocysteine, and methylcitric acid. The spinal cord, brain, optic nerves, and peripheral nerves may be affected by vitamin B12 deficiency.

Folic Acid - Folate deficiency produces megaloblastic anemia identical to that of vitamin B12 deficiency, but isolated folic acid deficiency rarely produces SCD and peripheral neuropathy. Folic acid deficiency may produce isolated increase of homocysteine.

Vitamin E - Vitamin E deficiency occurs with poor diets, malabsorption, short bowel and blind-loop syndromes, cystic fibrosis, celiac disease, and chronic cholestatic liver disease. There is a rare syndrome of isolated vitamin E deficiency with neurologic manifestations with onset in childhood, without fat malabsorption. Symptoms include tremor, tremulous dysarthric speech, gait ataxia from loss of vibratory sensation and proprioception, and global areflexia. Cerebellar deficits include dysmetria, slowed finger movements, and postural tremor. The gait is wide based, with prominent lordosis and genu recurvatum with pseudodystonic extension of the knees and inversion of the feet. Ophthalmoplegia, retinitis pigmentosa, dysarthria, generalized muscle weakness, and extensor plantar responses are present in some cases. The symptoms progress from hyporeflexia, ataxia, limitations in upward gaze, and strabismus to long-tract defects, weakness, and visual field constriction. Patients with severe, prolonged deficiency may develop complete blindness, dementia, and cardiac arrhythmias.

Vitamin D - Vitamin D receptors are present in the intestine and bone as well as in the brain, heart, stomach, pancreas, activated T and B lymphocytes, skin, and gonads.  Vitamin D is a natural immunoregulator with antiinflammatory action. Low vitamin D status has been implicated in the etiology of autoimmune diseases such as multiple sclerosis (MS).

MS occurs with lower prevalence in equatorial regions of the world that have significantly higher exposure to sunlight; Nordic countries with fewer days of sunlight have a much higher prevalence of MS.

Dietary and vitamin treatment in neurology

Numerous neurologic conditions, ranging from migraine, stroke, and hepatic encephalopathy to rare metabolic disturbances, respond to dietary treatment or to specific vitamins.

Migraine -  The most common dietary recommendations in neurology are given to patients with migraine; advice includes avoidance of ice-cold foods, hypoglycemia, nitrates, monosodium glutamate, and biogenic amines, in particular tyramine and phenylethylamine. Riboflavin supplementation helps to prevent recurrence of migraine.

Mediterranean Diet - Mediterranean diet is the generic name of the typical diet of people living in the olive-growing areas of the Mediterranean basin. Consequently, olive oil is the basic ingredient of this diet and the principal source of dietary fat, providing more calories than any other individual food. Other important components of the diet are of plant origin and include generous amounts of fruits and vegetables, legumes, grains, nuts, cereals cooked with species, and natural sweeteners such as honey and grape juice syrup. Wine, milk and dairy products, fish, and relatively small amounts of saturated fats, meat, and poultry are also characteristic of this diet. The Mediterranean diet has shown protective vascular effects in population-based studies and intervention trials. The main components of the Mediterranean diet include the following: olive oil; fish and seafood; probiotics in sour milk, yogurt, and other dairy products; and flavonoids and polyphenols in grains, vegetables, fruits, spices, and beverages such as red wine, tea, chocolate, and coffee. The Mediterranean diet is rich in fruits and vegetables, legumes, grains, nuts, and cereals, with minimal amounts of saturated fats, meat, and poultry providing a healthy balance of omega-6 and omega-3 fatty acids.

The Mediterranean diet lowers risk for cardiovascular disease, myocardial and cardiovascular mortality, stroke, obesity, arthritis, cancer, and, most recently, Alzheimer disease. The Mediterranean diet provides an appetizing and useful public health approach to prevention of stroke and cognitive dysfunction.

Stroke - Dietary advice for prevention of stroke and for poststroke treatment, as well as for patients with cardiovascular disease, includes recommendations to decrease the intake of saturated animal fats, trans-fats, and sodium to control hypertension, hyperlipidemia, and body mass index. The DASH diet (Dietary Approaches to Stop Hypertension diet) recommends lowering the dietary intake to 150, 100, or 50 mmol/day of sodium, according to the severity of hypertension and to increase consumption of fruits, juices and vegetables. As mentioned earlier, the Mediterranean diet is an excellent dietary approach to stroke prevention.

Orthostatic Hypotension - To increase the circulating volume, patients with orthostatic hypotension are advised to increase their sodium intake to 150 to 250 mEq/day of sodium (10 to 20 g of salt) and to raise their oral fluid intake to 20 oz/day, along with high potassium supplementation when they are taking fludrocortisone.

Idiopathic Intracranial Hypertension - is a syndrome characterized by headache, papilledema, and absence of focal neurologic signs. It may result from thrombosis of venous sinuses and from endocrine conditions. The two most common nutritional causes are obesity and hypervitaminosis A. Weight reduction, either by diet or by bariatric surgery, is effective in controlling the symptoms. A low-salt diet and fluid restriction help to alleviate the edema.

Childhood Epilepsy - The ketogenic diet has been used for many years for the treatment of childhood epilepsy, in particular for refractory cases such as the Lennox-Gastaut syndrome. It is important to maintain ketosis avoiding calorie and fluid restrictions. The ketogenic diet is also used in neonatal seizures resulting from glucose transporter deficiency and in some mitochondrial disorders (benign pyruvate dehydrogenase complex deficiency).

Osteoporosis

Osteoporosis is a progressive deterioration in bone microarchitecture associated with loss of bone mineral density (BMD), leading to increasing risk of fracture with time. The prevalence of this condition in the United States exceeds 12 million adults 50 years old or older, with more than 40 million additional older adults at higher risk of developing osteoporosis because of low BMD. Black adults tend to have a lower prevalence of osteoporosis and fracture than white adults.

Osteoporotic bone tissue shows deterioration of microarchitecture, with thinner trabeculae, reduced mineralization, and thinning of cortical surfaces associated with increased cortical porosity. Total BMD is the result of a delicate balance between bone resorption by osteoclasts and bone formation by osteoblasts during continuous remodeling. During childhood, bone growth requires a balance in favor of bone acquisition and peak bone mass, whereas in young adults, BMD tends to be relatively stable. With aging, osteoclast activity begins to exceed that of osteoblasts and loss of bone occurs. After the onset of menopause in women, bone loss accelerates to two to six times premenopausal rates, and then gradually slows to about 1% annually by 10 years after menopause. Individually, changes in bone mass also reflect numerous

exposures that affect the remodeling balance. Therefore, osteoporosis prevention depends on optimizing peak bone mass, minimizing exposures that lead to bone loss, and optimizing nutritional exposures for bone maintenance throughout life.

Measuring BMD to define osteoporosis is important because an inverse relationship exists with risk of fracture in older adults. Risk of fracture increases with age because of changes in bone quality, declining bone density, and falls, which increase with aging because of declining muscle strength, loss of balance, gait difficulties, arthritis, poor vision, and use of medications.

As living tissue, with constant resorption and rebuilding, bone appears to be responsive to a wide range of nutrients. Some of these have only recently been understood and others continue to be actively investigated.

Calcium is the major mineral component of bone mass, and nearly 99% of the calcium in the adult human body is contained in bones in the form of hydroxyapatite. Children need relatively large amounts of calcium to lay down new bone with rapid growth. It is likely that dietary sources of calcium may be more effective than calcium supplements.

Phosphorus is essential for bone, but too much phosphorus in combination with low calcium intake can lead to reduced calcium bioavailability and potential bone loss. Although uncommon, phosphorus deficiency can lead to reduced mineralization and bone resorption. Deficiency has been seen in older adults with malnutrition, intestinal malabsorption, or long-term use of medications that bind phosphorus, including antacids. In the general population, excess phosphorus is more of a concern than deficiency. The US diet tends to be high in phosphorus relative to calcium. Excess phosphate form complexes with calcium that interfere with calcium absorption, which may in turn lower serum calcium and lead to secretion of parathyroid hormone (PTH), lower 1,25(OH)2D production, lower intestinal calcium absorption and, consequently, bone resorption to release calcium from bone. One major source of excess phosphorus in the US diet is phosphoric acid from cola drinks. Two studies in teenage girls found that cola consumption significantly increased the odds of fracture. In the FOS, women consuming cola daily had significantly lower hip BMD than those who consumed cola less than once per week.

Magnesium is important to the formation of pure hydroxyapatite and may enhance bone strength through its role in crystallization. It also is known to regulate active intestinal calcium transport. In observational studies, magnesium intake was significantly positively associated with BMD, and protective against bone loss. This is important because magnesium intakes tend to be consistently low.

Potassium promotes renal calcium retention and is also important in neutralizing the acid load of most diets, which may protect against calcium loss from the bones. Potassium administration increased serum osteocalcin concentration and decreased urinary hydroxyproline excretion.

Sodium intake in the United States is considerably higher than recommended. Studies have shown that each 1000 mg of additional sodium was associated with a 20-mg increase in urinary calcium loss—the amount likely to be absorbed from 80 mg of dietary calcium, and consequently with lower BMD. The optimal intake balance for protecting bone was approximately 1000 mg calcium and less than 2000 mg sodium per day.

Fluoride has long been known to prevent tooth decay and has been added to most water supplies in the United States. Fluoride substitutes for the hydroxyl group in hydroxyapatite, forming fluorapatite. Fluoride has been shown to result in bone with larger crystals and higher BMD, but lower elasticity.

Iron is an important cofactor for hydroxylases in collagen formation. Both low iron intake and iron overload have been negatively associated with bone. Iron overload has been associated with low BMD in patients with genetic hemochromatosis and with African hemosiderosis. However, low iron is more of a concern in the general population. Rats fed iron-deficient diets showed compromised bone morphology, strength and density, and decreased serum osteocalcin.

Silicon is important for collagen and glycosaminoglycan formation in bone and cartilage, influencing the formation of the organic matrix. Silicon is also a major ion of osteogenic cells. Orthosilicic acid, the form of silicon absorbed in the diet, appears to be associated with bone formation through increased synthesis of collagen type I and stimulation of osteoblasts.

Zinc may affect bone through its role in nucleic acid and protein metabolism. Lower serum and bone zinc and higher urinary zinc have been noted in patients with osteoporosis.

Boron intake may protect bone by decreasing urinary calcium, phosphorus, and magnesium losses and increasing serum estradiol.

Strontium has similarities to calcium, and it has received increasing interest as a treatment for osteoporosis. Doses of 1 to 2 g/day of strontium ranelate for 2 years or longer increased BMD in postmenopausal women by 2% to 3%, relative to placebo, and reduced both vertebral and nonvertebral fracture risk. The increase in BMD is predictable and occurs in all treated individuals because of the ability of strontium to incorporate within the hydroxyapatite crystal. However, fracture risk cannot be predicted based on this increase in BMD.

Manganese also may contribute to bone status, although it has rarely been examined independently from other trace minerals.

Vitamin D (cholecalciferol) promotes positive calcium balance and stimulates bone formation. Hence, it is often considered as a protective vitamin for bone. In the skeleton, activated vitamin D [1,25(OH)2D (calcitriol)] stimulates bone resorption as well as enhances mineralization and bone formation. Vitamin D is obtained from the diet mainly as cholecalciferol (vitamin D3) from animal sources but also as ergocalciferol (vitamin D2) from plant sources. Factors associated with low vitamin D include obesity, older age, female sex, higher latitude, winter season, darker skin pigmentation, less sunlight exposure, and low dietary intake of vitamin D. Dietary intake of vitamin D also has been shown to be protective against fracture.

Vitamin C is an essential cofactor for hydroxylating lysine and proline residues in procollagen.

Vitamin E is a powerful antioxidant and, like vitamin C, may protect against the negative effects of oxidative stress on bone resorption. Bone loss with aging has been associated with prostaglandins, cytokines, and growth factors in the bone microenvironment.

Folate, vitamin B12, and vitamin B6 play important roles in the one-carbon metabolism pathway, which is critical for DNA synthesis, methylation, and repair, and therefore may affect bone formation.

Although vitamin A deficiency is relatively common worldwide, it is retinol excess that is of most concern to bone. Preformed vitamin A is obtained from the diet as retinol and retinyl esters from animal foods and derived from metabolism mainly in the intestine of provitamin A carotenoids.

Carotenoid-rich foods do not contribute to vitamin A toxicity; rather, carotenoids may have a positive effect on bone through their antioxidant activity.       

Metabolic studies have demonstrated that high protein leads to calcium losses, and it has been assumed that calcium is drawn from the skeleton to maintain serum calcium concentrations in the face of an acid load.

Fatty acids are important to numerous aspects of metabolism. The n-3 and n-6 polyunsaturated fatty acids may influence bone health through several complex mechanisms, including opposing effects on inflammatory cytokines, modulation of prostaglandin E2 production, and enhancement of calcium transport and retention.

Some evidence shows that caffeine has a negative effect on bone, although study results vary.

Osteoporosis is commonly seen in chronic alcoholism. Heavy use of alcohol is associated with multiple nutritional deficiencies which are likely to have their own negative effects on bone. In addition, ethanol itself appears to have direct effects on bone remodeling, affecting both BMD and bone strength. Long-term administration (3 months) of alcohol at a dose roughly equivalent to 1 L of wine per day in male adult rats showed a 10% reduction in bone density and a 12% reduction of mechanical strength of the femur.

Numerous studies show that higher total body weight is directly associated with greater BMD and lower risk of fracture. Further, weight loss is associated with loss in BMD.

Many aspects of diet and nutrition are important for bone health, including not only adequate intake of calcium and vitamin D but also of magnesium, potassium, other trace minerals, vitamin K, B vitamins, carotenoids, vitamins C and E, protein, and essential fatty acids. At the same time, it is important to avoid excess intakes of phosphorus, vitamin A, and sodium, and to maintain moderate alcohol intake. Although osteoporosis is one area in which BMI has been shown to be protective, we now understand that abdominal adiposity can have negative effects on bone through the release of certain cytokines. Weight-bearing physical activity is protective and is particularly important during weight loss, which may otherwise lead to bone loss as well. Musclestrengthening exercises also can help to protect against weight loss–associated bone loss and help to strengthen muscles to reduce the risk of falling. Increased muscle mass also may contribute to greater bone strength among individuals across all age groups. 

Bones

Bone is a tissue in which cells make up only 2% to 5% of the volume, and nonliving material make up 95% to 98%. It is the nonliving material that gives the bone its basic mechanical properties of hardness, stiffness, and resiliency. This nonliving material consists of a mineralencrusted protein matrix (also called osteoid), with the mineral comprising about half the volume and the organic matrix the other half. Unlike other connective tissues, virtually no free water is present in the bony material itself. Embedded in this solid material are cells, called osteocytes, residing in lacunae in the matrix and communicating with one another through an extensive network of long cellular processes lying in channels called canaliculi, which ramify throughout the bone. As a consequence of this arrangement, virtually no volume of normal bone is more than a few micrometers from a living cell.

The mineral of bone is a carbonate-rich, imperfect hydroxyapatite with variable stoichiometry. Calcium comprises 37% to 40%, phosphate 50% to 58%, and carbonate 2% to 8% of this mineral. These values vary somewhat from species to species, and the carbonate component is particularly sensitive to systemic acid–base status ( decreasing in acidosis and increasing in alkalosis). In addition, bone mineral contains small amounts of sodium, potassium, magnesium, citrate, and other ions present in the extracellular fluid (ECF) at the time the mineral was deposited, adsorbed onto the crystal surfaces, and trapped there, as the water in the recently deposited matrix is displaced by the growing mineral crystals.

The protein matrix of bone, as for tendons, ligaments, and dermis, consists predominantly of collagen, which comprises approximately 90% of the organic matrix. For bone, the collagen is type I. Collagen is a long, fibrous protein, coiled as a triple helix. For the molecules of the protein to coil tightly, no side chains can project from the peptide backbone on the side facing inward. Hence, every third amino acid in the body of the collagen molecule is glycine, which has no side chain. However, projecting outward are the side chains of various other amino acids, such as

lysine, which allow the posttranslational formation of tight, covalent bonds between collagen fibers. This cross-linking helps to prevent fibers from sliding along one another when bone is stressed along the axis of the fibers.

The four principal bone cells are lining cells, osteoblasts, osteoclasts, and osteocytes. They are responsible both for maintaining the mechanical properties of bone and mediating the calcium homeostatic function of bone. Lining cells are flat, fibrocyte-like cells covering free surfaces of bone. They are most probably derived from, or closely related to, the osteoblast cell line. They form a membrane that completely covers free bone surfaces and insulates bone from the cells and hormones in the general circulation. They demarcate a virtual compartment between the lining cells on one side and mature bone on the other. This compartment is continuous with the space in canaliculi surrounding osteocyte processes and may well have different ionic composition from that of the ECF located outside, that is, between the lining cells and the capillaries of bone. It is possible that lining cells, by adjusting ion fluxes between the ECF and the bone compartment, may contribute to the maintenance of calcium ion concentrations in the ECF.

Osteoblasts are derived from marrow stromal cells; they are the cells that lay down bone, first by synthesizing, depositing, and orienting the fibrous proteins of the matrix, and then by initiating changes that render the matrix capable of mineralization. Osteoblasts deposit this matrix between and beneath themselves on a preexisting bone surface, thereby pushing themselves backward as they add new bone.

Bone consists of a dense outer shell, or cortex, and an internal, chambered system of interconnected plates, rods, and spicules called cancellous or trabecular bone. In the shafts of the long bones, the cortical component predominates, creating a hollow tube, whereas nearer the joints, the cortex becomes thinner and the interior is made up of an extensive latticework of cancellous bone. Bones such as the vertebrae, pelvis, sternum, and shoulder blades possess a thin outer rind of cortex and a more or less even distribution of cancellous bone on the inside. The internal, three-dimensional architecture of cancellous bone is arranged along the lines of force that a particular bone experiences and hence provides maximum structural strength with minimum material.

The end segments of bones are called epiphyses. The shafts of long bones are called diaphyses, and the flared portion of the shaft merging with the region of the growth plate is called a metaphysis. The lining cells on the outside of the bone form a tough sheet or membrane, called the periosteum, whereas the cells on the inside surfaces of both cortical and trabecular bone are called the endosteum.

The spaces between the trabecular plates and spicules are filled with bone marrow. Early in life, much of that marrow is hemopoietic, but later the blood-producing marrow is confined to the bones of the trunk, and the peripheral skeletal marrow spaces are filled mostly with fat.

At their ends, where bones meet one another in a joint, the bony surface is covered with a layer of cartilage rather than with periosteum. In health, this cartilage, is highly hydrated and is lubricated by synovial fluid held there by a tough connective tissue sac called the joint capsule. This arrangement ensures that the bones move on one another smoothly.

In utero, most bones are formed first as cartilage models, which are gradually replaced by bone. In this process, blood vessels invade the cartilage, calcification ensues, and the calcified cartilage is then removed by osteoclasts and replaced by bone laid down by osteoblasts. In infancy and childhood, bone growth and development follow a similar pattern.

Bone serves two distinct functions: the provision of mechanical rigidity and stiffness to our bodies; and the provision of a homeostatic buffer, particularly to help our bodies maintain a constant level of calcium in the circulating body fluids and to provide a reserve supply of phosphorus. The mechanical function is necessary so that we can resist gravity and move about on dry land. The homeostatic function of bone is the older of the two, from the standpoint of evolution, and is in a sense the more fundamental, because the body will sacrifice the structural function before it will risk losing the homeostatic one. In other words, the body will weaken the bone structurally to maintain the calcium levels of the blood and ECF.

In the mechanical function of bone, nature strikes a balance between a skeleton so massive that it would resist most forces, but be too heavy to carry around, and one so flimsy that, although adequate to meet calcium homeostatic needs, it would be too fragile to sustain the mechanical forces of exertion or of minor injuries. Bone finds the middle ground by adjusting its mass using a classic negative feedback loop so it bends under routine use by approximately 0.05% to 0.10% in compression or tension and by 0.10% to 0.20% in shear (Fig. 89.5). This bending set point is a major determinant of bone size during growth and bone density during adult remodeling.

Total nutritional status influences bone cell function just as it does the function of other tissues. However, cellular malnutrition affects mainly bone currently being remodeled, whereas the strength of bony structures at any given time is dependent, not so much on current cell function, as on the mass of bony material accumulated by bone cellular activity over many years. For that reason, acute nutritional stresses or deficiencies rarely produce overt skeletal symptoms in adults, even when they severely compromise bone cell function. Children and growing animals show effects more promptly, both because they have less skeletal capital in their bone banks and because they are revising it much more rapidly. Nevertheless, a few nutrients, when deficient, are more likely than others to produce skeletal manifestations. These include calcium, phosphorus, vitamin D, and certain other trace nutrients.

In addition to buffering absorptive oscillations in blood calcium concentration, bone serves as a nutrient reserve for both calcium and phosphorus. This reserve is to the calcium (and phosphorus) functions of the body as body fat is to energy metabolism. Unlike most nutrient reserves, however, this one (bone) has acquired a distinct function in its own right, that is, mechanical and structural support. In other words, we walk around on our calcium reserve. It follows that any influence, nutritional or otherwise, that alters the size of the calcium reserve will alter bone strength.

Bone is a very rich source of calcium: Total skeletal calcium averages 1100 to 1500 g, and each cubic centimeter of bone contains more calcium than the entire circulating blood volume in an adult. Thus, in comparison with other nutrients, the calcium reserve is huge. Although lowcalcium diets usually deplete the bony reserves, they do so slowly. Thus, whereas the population-level risk of fracture rises immediately, it will take many years for bone strength to be sufficiently reduced to lead to a perceptible increase in an individual person’s risk of fracture.

Low intakes of calcium and phosphorus can both limit bone acquisition during growth and cause bone loss after maturity. Because human calcium requirements rise with age, and because calcium intakes tend to fall in elderly persons, precisely, such depletion occurs in most human

populations as they age.

Inadequate phosphorus availability also affects bone, but in a different way. The osteoblast environment is one of continuous mineralization, with the matrix extracting phosphate (as well as calcium) from the fluid bathing the bone-forming cells. Although calcium makes up approximately 40% of the bone mineral, phosphate accounts for nearly 60%. Thus, phosphorus is fully as important for bone building as is calcium. Rapid growth is not possible without a high blood phosphate concentration, a fact that explains the substantially higher blood phosphate values in children. When phosphate concentrations in the blood entering bone are low, mineralization extracts as much phosphate from the blood as it can, but in so doing, it creates a local environment severely depleted of phosphate. Osteoblasts, like all cells, need phosphate for their own metabolism. The result is serious interference with osteoblast function: matrix deposition is slowed, and osteoblast initiation of mineralization is reduced even more. These abnormalities produce the typical histologic pattern of rickets and osteomalacia in bone.

Vitamin D has many bony effects, such as facilitating the development of osteoclast precursors at an activated remodeling locus and augmenting osteoclast response to resorptive stimuli. The vitamin also stimulates synthesis and release of osteocalcin by osteoblasts. However, its major importance for bone is its facilitation of intestinal absorption of calcium (and to some extent phosphorus) from the diet. Severe vitamin D deficiency causes rickets and osteomalacia. Milder shortages of the vitamin reduce calcium availability to the body and produce a situation of calcium deficiency, resulting in osteoporosis. Because of the traditional identification of vitamin D deficiency with rickets and osteomalacia, it has been customary to refer to less extreme degrees of vitamin D shortage as insufficiency. This distinction is no longer useful. All degrees of vitamin D inadequacy that produce disease should be termed deficiency.

Vitamin K deficiency results both in undercarboxylation of osteocalcin and in reduced osteocalcin synthesis. The net effect of these changes on bone strength or integrity is not certain. However, low v itamin K status is associated in epidemiologic studies with low bone mass, increased hip fracture risk, and increased cardiovascular mortality.

Vitamin C and certain trace minerals (notably copper, zinc, and manganese) are important cofactors for the synthesis or cross-linking of matrix proteins. Copper is the cofactor for lysyl oxidase, the enzyme responsible for cross-linking collagen fibrils. Interference with crosslinking results in structurally weak bone. Ascorbic acid is also a required cofactor for the cross-linking of collagen fibrils; and in its absence, bone strength is impaired. In the presence of deficiencies of these micronutrients during growth, severe bone abnormalities can result. These abnormalities include stunting of growth, deformity of bones, and epiphyseal dysplasia. Whether adults can develop sufficient deficiencies of these nutrients to interfere significantly with bone integrity remains unknown.

Osteoporosis is a multifactorial condition of the skeleton in which skeletal strength is reduced sufficiently so that fractures occur on minor trauma. Generally, osteoporosis exhibits reduced bone mass (i.e., both matrix and mineral) as well as various microstructural disturbances of bony architecture. A simple decrease in quantity of bone is sometimes called osteopenia (literally, “shortage of bone”). Osteopenia is characterized by a BMD value at hip or spine between 1 and 2.5 standard deviations than 2.5 standard deviations below young adult normal are now called osteoporosis, whether or not a fracture is present. BMD is, unfortunately, a poor way to represent bone structural strength, because it explicitly eliminates the important influence of bone size. A larger bone with a lower density is usually stronger—less likely to fracture— than a smaller, denser bone.

A common feature of most cases of osteoporosis is elevated bone remodeling, particularly in postmenopausal women. Remodeling activity, although designed to repair weakened bone, actually makes it temporarily weaker during the remodeling process; and when remodeling is in excess of mechanical need, it causes only weakness. Estrogen deficiency, low calcium intake, and vitamin D deficiency all contribute to a harmful postmenopausal rise in bone remodeling.

Rickets is a disorder of the growth apparatus of bone in which the growth cartilage fails to mature and mineralize normally. Growth is stunted, and various deformities about the growth plates occur. Osteomalacia is the corresponding disorder in adults, in whom newly deposited bone matrix fails to mineralize adequately. New matrix formation is slowed in both conditions, but mineralization is retarded even more; thus, unmineralized matrix accumulates on microscopic bone surfaces. For this reason, the proportion of mineral to matrix drops. In severe cases, unmineralized bone may constitute so large a proportion of the skeleton that individual bones lose their stiffness and become severely deformed (bowed legs and misshapen pelves). The stereotypical forms of rickets and osteomalacia are those associated with vitamin D deficiency. The principal pathogenesis of these common forms follows from insufficient intestinal absorption mainly of calcium (and to some extent phosphorus) from the diet. In attempting to keep blood calcium concentrations close to normal values, the body raises PTH secretion. Rickets and osteomalacia also develop for reasons other than vitamin D deficiency, including extreme calcium deficiency, fluoride toxicity, and cadmium poisoning, as well as in association with certain rare vascular malignant diseases.

Paget’s disease is a local but often multifocal disorder of the bone remodeling process of uncertain etiology. Resorption proceeds erratically, with formation filling in with new bone behind it. Bone  architecture and even external bone shape are disordered. During the early resorptive phase, the bone is excessively fragile and may fracture readily. The high level of bone remodeling is usually accompanied by high concentrations of remodeling markers, particularly serum alkaline phosphatase. When the process involves the skull, bony growths may constrict the cranial nerve passages and may lead to deafness, for example. No nutritional correlates of this disorder are known.

Osteogenesis imperfecta (OI) is a group of heritable disorders in which one of several mutations may occur in the genes encoding for the collagen molecules that comprise the bulk of bone matrix. Patients with OI have fragile skeletons with reduced bone mass. In one of the common forms of OI, long bones typically have narrow shafts as well as reduced mass. Patients with OI commonly suffer many fractures throughout life, often starting in utero. Fractures heal normally.

Patients with chronic liver disease, but especially with biliary cirrhosis, commonly have a bone disease that is basically osteoporosis. Patients who are to undergo liver transplantation often have severe osteoporosis, attributable to a combination of the underlying disease, the immobilization that inevitably accompanies the severe disability of these very sick patients, and the treatments they have received.                 

Patients with end stage renal disease often have a complex bone disease consisting of a varying mixture of osteosclerosis, osteomalacia, and hyperparathyroid bone disease. Exact expression of these varied abnormalities depends on the medical regimens the patients receive, specifically the way in which these regimens manage calcium, phosphorus, and vitamin D metabolism for the patient. Patients with a variety of disorders of the small intestine, but especially those with gluten-sensitive enteropathy, malabsorb fat-soluble vitamins and hypersecrete calcium and magnesium into the digestive juices. As a result, these patients are commonly deficient in vitamin D, calcium, and magnesium. They often have severe osteoporosis and may have osteomalacia as well. Patients who have had organ transplants commonly have osteoporosis, in part because they present for organ transplantation with already reduced bone mass and in part because the immunosuppressive therapy used to sustain the transplant itself causes bone loss.

Aluminum (Al) is not strictly speaking a nutrient, but it is extremely common in the environment, is a major component of antacids, and is widely used as cookware. Only a small fraction of ingested Al is absorbed, and absorbed Al is promptly excreted in the urine in healthy persons. However, in patients with severely compromised renal function, particularly in those treated with large doses of Al-containing antacids to block phosphorus absorption, Al accumulates at the mineralizing sites of the bone remodeling process.

As noted, the cells of bone are as dependent on total nutrition as are other cells, and bone suffers in starvation just as do other tissues. However, bone strength is not immediately affected in acute malnutrition, especially in adults. The bony effects of protein-calorie malnutrition are most obvious in two situations: one is during growth, when both growth rates and bone mass accumulation are retarded by malnutrition; and the other is in the repair of fractures, especially in elderly persons. Protein-calorie malnutrition is common among elderly persons, and when they break a bone, such as the hip, serious complications and even death may ensue. Protein supplementation has been shown to reduce these complications substantially, and it is an important and necessary component of the treatment of most patients with hip fractures. The reason for the trophic effect of protein on bone is partly that dietary protein helps to sustain normal insulinlike growth factor-I (IGF-1) concentrations, needed for bone growth and repair, and partly that, as discussed, bone formation requires fresh dietary protein.

Magnesium deficiency occurs in severe intestinal malabsorption (e.g., gluten-sensitive enteropathy, fistulas, or ileal resection, especially with high-fat diets) or with urinary losses from renal tubular defects. Initially, magnesium deficiency impairs bony responsiveness to PTH and thus leads to hypocalcemia despite a rising PTH level. As deficiency progresses, parathyroid response falters, and PTH secretion falls. The hypocalcemia of magnesium deficiency is thus the result of impairment of the calcium regulatory system and is unresponsive to calcium supplementation. Less severe degrees of magnesium deficiency in these same syndromes are associated with reduced bone mass, also unresponsive to calcium supplementation. In addition to other needed treatments (e.g., calcium), magnesium supplements are necessary in these patients. Finally, silent magnesium deficiency often accompanies low vitamin D status. The mechanism is uncertain. The deficiency manifests itself as a failure to elevate PTH secretion in response to the poor calcium absorption of vitamin D deficiency.

As noted, the effects of nutrient deficiencies on the skeleton express themselves slowly in adults. For this same reason, nutrient effects on the skeleton of any kind are difficult to detect and easy to misinterpret.